Viread

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 123 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 123 mg of tenofovir disoproxil (as fumarate). 
 
Excipient with known effect 
Each tablet contains 82 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
White, triangle-shaped, film-coated tablets, 8.5 mm in diameter, debossed on one side with “GSI” and 
on the other side with “150”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
HIV-1 infection 
Viread 123 mg film-coated tablets are indicated in combination with other antiretroviral medicinal 
products for the treatment of HIV-1 infected paediatric patients, with NRTI resistance or toxicities 
precluding the use of first line agents, aged 6 to < 12 years who weigh from 17 kg to less than 22 kg. 
 
The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based 
on individual viral resistance testing and/or treatment history of patients. 
 
Hepatitis B infection 
Viread 123 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in paediatric 
patients aged 6 to < 12 years who weigh from 17 kg to less than 22 kg, with: 
 
• compensated liver disease and evidence of immune active disease, i.e. active viral replication 

and persistently elevated serum ALT levels, or histological evidence of moderate to severe 
inflammation and/or fibrosis.  With respect to the decision to initiate treatment in paediatric 
patients, see sections 4.2, 4.4, 4.8 and 5.1. 

 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection and/or 
treatment of chronic hepatitis B. 
 
Posology 
 
HIV-1 and Chronic hepatitis B 
The recommended dose for the treatment of HIV-1 infection and chronic hepatitis B in paediatric 
patients aged 6 to < 12 years weighing 17 kg to < 22 kg who are able to swallow film-coated tablets is 
one 123 mg tablet once daily taken orally with food. 
 



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Please refer to the Summaries of Product Characteristics for Viread 163 mg and 204 mg film-coated 
tablets for the treatment of HIV-1 infection and chronic hepatitis B in paediatric patients aged 
6 to < 12 years weighing 22 kg to < 28 kg and 28 kg to < 35 kg, respectively. 
 
Viread is also available as 33 mg/g granules for the treatment of HIV-1 infection and chronic hepatitis 
B in paediatric patients aged 2 to < 12 years who weigh < 17 kg or who are unable to swallow 
film-coated tablets.  Please refer to the Summary of Product Characteristics for Viread 33 mg/g 
granules. 
 
The decision to treat paediatric patients should be based on careful consideration of individual patient 
needs and with reference to current paediatric treatment guidelines including the value of baseline 
histological information.  The benefits of long-term virologic suppression with continued therapy must 
be weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis B 
virus and the uncertainties as regards the long term impact of bone and renal toxicity (see section 4.4). 
 
Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric 
patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 
months in patients with HBeAg negative disease. 
 
Duration of therapy in paediatric patients with chronic hepatitis B 
 
The optimal duration of treatment is unknown.  Treatment discontinuation may be considered as 
follows: 
 
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 

12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection 
on two consecutive serum samples at least 3-6 months apart) is confirmed or until 
HBs seroconversion or there is loss of efficacy (see section 4.4).  Serum ALT and HBV DNA 
levels should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 

 
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until 

HBs seroconversion or there is evidence of loss of efficacy.  Treatment discontinuation may 
also be considered after stable virological suppression is achieved (i.e. for at least 3 years) 
provided serum ALT and HBV DNA levels are followed regularly after treatment 
discontinuation to detect any late virological relapse.  With prolonged treatment for more than 
2 years, regular reassessment is recommended to confirm that continuing the selected therapy 
remains appropriate for the patient. 

 
Missed dose 
If a patient misses a dose of Viread within 12 hours of the time it is usually taken, the patient should 
take Viread with food as soon as possible and resume their normal dosing schedule.  If a patient 
misses a dose of Viread by more than 12 hours and it is almost time for their next dose, the patient 
should not take the missed dose and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Viread, another tablet should be taken.  If the patient 
vomits more than 1 hour after taking Viread they do not need to take another dose. 
 
Special populations 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.4). 
 
Hepatic impairment 
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). 
 



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If Viread 123 mg film-coated tablets are discontinued in patients co-infected with HIV and hepatitis B 
virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis 
(see section 4.4). 
 
Paediatric population 
The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with 
chronic hepatitis B under 2 years of age have not been established.  No data are available. 
 
Method of administration 
Viread 123 mg film-coated tablets should be taken once daily, orally with food. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
General 
HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir 
disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). 
 
HIV-1 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines. 
 
Hepatitis B 
Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of 
transmission of HBV to others through sexual contact or contamination with blood.  Appropriate 
precautions must continue to be used. 
 
Co-administration of other medicinal products 
- Viread should not be administered concomitantly with other medicinal products containing 

tenofovir disoproxil or tenofovir alafenamide. 
- Viread should not be administered concomitantly with adefovir dipivoxil. 
- Co-administration of tenofovir disoproxil and didanosine is not recommended (see Section 4.5).   
 
Triple therapy with nucleosides/nucleotides 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well 
as with lamivudine and didanosine as a once-daily regimen. 
 
Renal and bone effects in adult population 
Renal effects 
Tenofovir is principally eliminated via the kidney.  Renal failure, renal impairment, elevated 
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been 
reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). 
 
Renal impairment 
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with 
impaired renal function (creatinine clearance < 80 ml/min). 
 
Bone effects 
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain 
and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-
induced proximal renal tubulopathy (see section 4.8). 
 



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Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).  In HIV infected 
patients, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in 
BMD of the hip and spine were observed in both treatment groups.  Decreases in BMD of spine and 
changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil 
treatment group at 144 weeks.  Decreases in BMD of hip were significantly greater in this group until 
96 weeks.  However, there was no increased risk of fractures or evidence for clinically relevant bone 
abnormalities over 144 weeks in this study. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 
inhibitor.  Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the 
limitations of long term data on the impact of tenofovir disoproxil on bone health and fracture risk, 
alternative treatment regimens should be considered for patients with osteoporosis that are at a high 
risk for fractures. 
 
If bone abnormalities are suspected or detected then appropriate consultation should be obtained. 
 
Renal and bone effects in paediatric population 
There are uncertainties associated with the long term effects of bone and renal toxicity.  Moreover, the 
reversibility of renal toxicity cannot be fully ascertained.  Therefore, a multidisciplinary approach is 
recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide 
the appropriate monitoring during treatment (including decision for treatment withdrawal) and 
consider the need for supplementation. 
 
Renal effects 
Renal adverse reactions consistent with proximal renal tubulopathy have been reported in 
HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see 
sections 4.8 and 5.1). 
 
Renal monitoring 
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all 
patients prior to initiating therapy with tenofovir disoproxil and that it is also monitored after two to 
four weeks of treatment, after three months of treatment and every three to six months thereafter in 
patients without renal risk factors.  In patients at risk for renal impairment, a more frequent monitoring 
of renal function is required. 
 
Renal management 
If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving 
tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements 
of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal 
tubulopathy).  If renal abnormalities are suspected or detected then consultation with a nephrologist 
should be obtained to consider interruption of tenofovir disoproxil treatment.  Interrupting treatment 
with tenofovir disoproxil should also be considered in case of progressive decline of renal function 
when no other cause has been identified. 
 
Co-administration and risk of renal toxicity 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, 
vancomycin, cidofovir or interleukin-2).  If concomitant use of tenofovir disoproxil and nephrotoxic 
agents is unavoidable, renal function should be monitored weekly. 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If tenofovir disoproxil is co-administered with an NSAID, renal function should 
be monitored adequately. 
 



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A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in 
combination with a ritonavir or cobicistat boosted protease inhibitor.  A close monitoring of renal 
function is required in these patients (see section 4.5).  In patients with renal risk factors, the 
co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully 
evaluated. 
 
Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which 
are secreted by the same renal pathway, including the transport proteins human organic anion 
transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product).  These 
renal transport proteins may be responsible for tubular secretion and in part, renal elimination of 
tenofovir and cidofovir.  Consequently, the pharmacokinetics of these medicinal products, which are 
secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be 
modified if they are co-administered.  Unless clearly necessary, concomitant use of these medicinal 
products which are secreted by the same renal pathway is not recommended, but if such use is 
unavoidable, renal function should be monitored weekly (see section 4.5). 
 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.2).  Tenofovir disoproxil should not be initiated in paediatric patients with renal impairment 
and should be discontinued in paediatric patients who develop renal impairment during tenofovir 
disoproxil therapy. 
 
Bone effects 
Viread may cause a reduction in BMD.  The effects of tenofovir disoproxil-associated changes in 
BMD on long-term bone health and future fracture risk are uncertain (see section 5.1). 
 
If bone abnormalities are detected or suspected in paediatric patients, consultation with an 
endocrinologist and/or nephrologist should be obtained. 
 
Liver disease 
Tenofovir and tenofovir disoproxil are not metabolised by liver enzymes.  A pharmacokinetic study 
has been performed in non-HIV infected adult patients with various degrees of hepatic impairment.  
No significant pharmacokinetic alteration has been observed in these patients (see section 5.2). 
 
Exacerbations of hepatitis 
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 
characterised by transient increases in serum ALT.  After initiating antiviral therapy, serum ALT may 
increase in some patients (see section 4.8).  In patients with compensated liver disease, these increases 
in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 
hepatic decompensation.  Patients with cirrhosis may be at a higher risk for hepatic decompensation 
following hepatitis exacerbation, and therefore should be monitored closely during therapy. 
 
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in 
patients who have discontinued hepatitis B therapy.  Post-treatment exacerbations are usually 
associated with rising HBV DNA, and the majority appears to be self-limited.  However, severe 
exacerbations, including fatalities, have been reported.  Hepatic function should be monitored at 
repeated intervals with both clinical and laboratory follow-up for at least 6 months after 
discontinuation of hepatitis B therapy.  If appropriate, resumption of hepatitis B therapy may be 
warranted.  In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 
recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 
 
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease. 
 
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients 
co-infected with hepatitis C or D virus. 
 



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Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir 
disoproxil should only be used as part of an appropriate antiretroviral combination regimen in 
HIV/HBV co-infected patients.  Patients with pre-existing liver dysfunction, including chronic active 
hepatitis, have an increased frequency of liver function abnormalities during combination 
antiretroviral therapy (CART) and should be monitored according to standard practice.  If there is 
evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must 
be considered.  However, it should be noted that increases of ALT can be part of HBV clearance 
during therapy with tenofovir, see above Exacerbations of hepatitis. 
 
Use with certain hepatitis C virus antiviral agents 
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, 
especially when used together with an HIV regimen containing tenofovir disoproxil and a 
pharmacokinetic enhancer (ritonavir or cobicistat).  The safety of tenofovir disoproxil in the setting of 
ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a 
pharmacokinetic enhancer has not been established.  The potential risks and benefits associated with 
co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV 
protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at 
increased risk of renal dysfunction.  Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV 
protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil. 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Mitochondrial dysfunction following exposure in utero 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such 
neurological disorders are transient or permanent is currently unknown.  These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of institution of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause 
serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed 
within the first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment. 
 



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Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
Excipients 
 
Viread 123 mg film-coated tablets contain lactose monohydrate.  Patients with rare hereditary 
problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should 
not take this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the 
potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low. 
 
Concomitant use not recommended 
Viread should not be administered concomitantly with other medicinal products containing tenofovir 
disoproxil or tenofovir alafenamide. 
 
Viread should not be administered concomitantly with adefovir dipivoxil. 
 
Didanosine 
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and 
Table 1). 
 
Renally eliminated medicinal products 
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with 
medicinal products that reduce renal function or compete for active tubular secretion via transport 
proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir 
and/or the co-administered medicinal products. 
 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product.  Some examples include, but are not limited to, aminoglycosides, amphotericin B, 
foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4). 
 
Given that tacrolimus can affect renal function, close monitoring is recommended when it is 
co-administered with tenofovir disoproxil. 
 
Other interactions 
Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily 
as “q.d.”). 
 



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Table 1: Interactions between tenofovir disoproxil and other medicinal products 
 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
ANTI-INFECTIVES 
Antiretrovirals 
Protease inhibitors 
Atazanavir/Ritonavir 
(300 q.d./100 q.d.) 

Atazanavir: 
AUC: ↓ 25% 
Cmax: ↓ 28% 
Cmin: ↓ 26% 
Tenofovir: 
AUC: ↑ 37% 
Cmax: ↑ 34% 
Cmin: ↑ 29% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders.  Renal function should 
be closely monitored 
(see section 4.4). 

Lopinavir/Ritonavir 
(400 b.i.d./100 b.i.d.) 

Lopinavir/ritonavir: 
No significant effect on 
lopinavir/ritonavir PK parameters. 
Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders.  Renal function should 
be closely monitored 
(see section 4.4). 

Darunavir/Ritonavir 
(300/100 b.i.d.) 

Darunavir: 
No significant effect on 
darunavir/ritonavir PK parameters. 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders.  Renal function should 
be closely monitored 
(see section 4.4). 

NRTIs 
Didanosine Co-administration of tenofovir 

disoproxil and didanosine results in 
a 40-60% increase in systemic 
exposure to didanosine. 

Co-administration of tenofovir 
disoproxil and didanosine is not 
recommended (see section 4.4). 
 
Increased systemic exposure to 
didanosine may increase 
didanosine related adverse 
reactions.  Rarely, pancreatitis and 
lactic acidosis, sometimes fatal, 
have been reported.  
Co-administration of tenofovir 
disoproxil and didanosine at a 
dose of 400 mg daily has been 
associated with a significant 
decrease in CD4 cell count, 
possibly due to an intracellular 
interaction increasing 
phosphorylated (i.e. active) 
didanosine.  A decreased dosage 
of 250 mg didanosine 
co-administered with tenofovir 
disoproxil therapy has been 
associated with reports of high 
rates of virological failure within 
several tested combinations for the 
treatment of HIV-1 infection. 



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Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Adefovir dipivoxil AUC: ↔ 

Cmax: ↔ 
Tenofovir disoproxil should not be 
administered concurrently with 
adefovir dipivoxil 
(see section 4.4). 

Hepatitis C virus antiviral agents 
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil  
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↑ 96% 
Cmax: ↑ 68% 
Cmin: ↑ 118% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 63% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 45% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 47% 
Cmin: ↑ 47% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, ledipasvir/sofosbuvir 
and atazanavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring, if other alternatives 
are not available (see section 4.4). 



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Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↓ 27% 
Cmax: ↓ 37% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 48% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 50% 
Cmax: ↑ 64% 
Cmin: ↑ 59% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, ledipasvir/sofosbuvir 
and darunavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring, if other alternatives 
are not available (see section 4.4). 



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Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil  
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↓ 34% 
Cmax: ↓ 34% 
Cmin: ↓ 34% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 98% 
Cmax: ↑ 79% 
Cmin: ↑ 163% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofovir 
disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↔ 
Cmin: ↑ 91% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



13 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Dolutegravir (50 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072 

AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Dolutegravir  
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Tenofovir: 
AUC: ↑ 65% 
Cmax: ↑ 61% 
Cmin: ↑ 115% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



14 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔  
Cmax: ↔  
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Velpatasvir: 
AUC: ↑ 142% 
Cmax: ↑ 55% 
Cmin: ↑ 301% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 39% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 29% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 55% 
Cmin: ↑ 39% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, sofosbuvir/velpatasvir 
and atazanavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 



15 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC:  ↓28% 
Cmax: ↓ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 24% 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 55% 
Cmin: ↑ 52% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, sofosbuvir/velpatasvir 
and darunavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 



16 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Lopinavir/Ritonavir 
(800 mg/200 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↓ 29% 
Cmax: ↓ 41% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: ↑ 63% 
 
Lopinavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 42% 
Cmin: ↔ 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, sofosbuvir/velpatasvir 
and lopinavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 



17 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Raltegravir 
(400 mg b.i.d) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Raltegravir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 21% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 46% 
Cmin: ↑ 70% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↓ 53% 
Cmax: ↓ 47% 
Cmin: ↓ 57% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 81% 
Cmax: ↑ 77% 
Cmin: ↑ 121% 

Concomitant administration of 
sofosbuvir/velpatasvir and 
efavirenz is expected to decrease 
plasma concentrations of 
velpatasvir.  Co-administration of 
sofosbuvir/velpatasvir with 
efavirenz-containing regimens is 
not recommended. 



18 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofovir 
disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 44% 
Cmin: ↑ 84% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



19 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir/ 
Voxilaprevir (400 mg/100 mg/ 
100 mg+100 mg q.d.)3 + Darunavir 
(800 mg q.d.) + Ritonavir (100 mg 
q.d.) + Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: N/A 
 
GS-3310072: 
AUC: ↔ 
Cmax:↔ 
Cmin: N/A 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Voxilaprevir: 
AUC: ↑ 143% 
Cmax:↑ 72% 
Cmin: ↑ 300% 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 34% 
 
Ritonavir: 
AUC: ↑ 45% 
Cmax: ↑ 60% 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 48% 
Cmin: ↑ 47% 

Increased plasma concentrations 
of tenofovir resulting from co-
administration of tenofovir 
disoproxil, 
sofosbuvir/velpatasvir/voxilaprevir 
and darunavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  
The safety of tenofovir disoproxil 
when used with 
sofosbuvir/velpatasvir/voxilaprevir 
and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has 
not been established.  
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 
 



20 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir 
(400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil  
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 19% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↓ 23% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 25% 
Cmin: ↔ 

No dose adjustment is required. 

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir.  Staggered administration (12 hours apart) provided 
similar results. 
2 The predominant circulating metabolite of sofosbuvir. 
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 
 
Studies conducted with other medicinal products 
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was 
co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir 
boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive 
norgestimate/ethinyl oestradiol. 
 
Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir 
(see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no 
malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.  Animal studies do not 
indicate reproductive toxicity (see section 5.3).  The use of tenofovir disoproxil may be considered 
during pregnancy, if necessary. 
 
In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to 
reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, 
in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.  

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were 
administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 
months postpartum; women and their infants were followed for up to 12 months after delivery.  No 
safety signal has emerged from these data. 

Breastfeeding 
Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with 
hepatitis B may breast feed her infant. 
 



21 

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is 
considered negligible. Although long-term data is limited, no adverse reactions have been reported in 
breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed.   
 
As a general rule, it is recommended that HIV infected mothers do not breastfeed their infants in order 
to avoid transmission of HIV to the infant. 
 
Fertility 
There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility.  Animal 
studies do not indicate harmful effects of tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
patients should be informed that dizziness has been reported during treatment with tenofovir 
disoproxil. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, 
renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) 
sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.  
Monitoring of renal function is recommended for patients receiving Viread (see section 4.4). 
 
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following 
treatment with tenofovir disoproxil in combination with other antiretroviral agents.  These reactions 
are usually mild to moderate gastrointestinal events.  Approximately 1% of tenofovir 
disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events. 
 
 
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions 
following treatment with tenofovir disoproxil, most of which are mild.  In clinical trials of 
HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was 
nausea (5.4%). 
 
Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who 
have discontinued hepatitis B therapy (see section 4.4). 
 
Tabulated summary of adverse reactions 
Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies 
and post-marketing experience.  All adverse reactions are presented in Table 2. 
 
HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on 
experience in two studies in 653 treatment-experienced adult patients receiving treatment with 
tenofovir disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal 
products for 24 weeks and also in a double-blind comparative controlled study in which 600 
treatment-naïve adult patients received treatment with tenofovir disoproxil 245 mg (n = 299) or 
stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks. 
 
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is 
primarily based on experience in two double-blind comparative controlled studies in which 641 adult 
patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir 
disoproxil 245 mg  daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.  The 
adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 
profile of tenofovir disoproxil.  After an initial decline of approximately -4.9 ml/min (using 
Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease 



22 

[MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal 
function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using 
Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation). 
 
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil in patients with 
decompensated liver disease was assessed in a double-blind active controlled study 
(GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n = 45) or 
emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks. 
 
In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse 
event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant 
differences between the combined tenofovir-containing arms and the entecavir arm.  After 168 weeks, 
16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil 
group, and 14% (3/22) of the entecavir group experienced tolerability failure.  Thirteen percent (6/45) 
of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 
9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl. 
 
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 
13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil 
group and 14% (3/22) in the entecavir group.  The rate of hepatocellular carcinoma was 18% (8/45) in 
the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% 
(2/22) in the entecavir group. 
 
Subjects with a high baseline CPT score were at higher risk of developing serious adverse events 
(see section 4.4). 
 
Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir 
disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 
lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or 
emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks. 
 
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by 
body system organ class and frequency.  Within each frequency grouping, undesirable effects are 
presented in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on 
clinical study and post-marketing experience 
 
Frequency Tenofovir disoproxil  
Metabolism and nutrition disorders: 
Very common: hypophosphataemia1 
Uncommon: hypokalaemia1 
Rare: lactic acidosis 

Nervous system disorders: 
Very common: dizziness 
Gastrointestinal disorders: 
Very common: diarrhoea, vomiting, nausea 
Common: flatulence 
Uncommon: pancreatitis 
Hepatobiliary disorders: 
Common: increased transaminases 
Rare: hepatic steatosis, hepatitis 



23 

Frequency Tenofovir disoproxil  
Skin and subcutaneous tissue disorders: 
Very common: rash 
Rare: angioedema 
Musculoskeletal and connective tissue disorders: 
Uncommon: rhabdomyolysis1, muscular weakness1 

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 

2, myopathy1 
Renal and urinary disorders: 
Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconi syndrome) 

Rare: acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute 
interstitial nephritis)2, nephrogenic diabetes insipidus 

General disorders and administration site conditions: 
Very common: asthenia 
1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 
associated with tenofovir disoproxil in the absence of this condition. 
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical 
trials or the tenofovir disoproxil expanded access program.  The frequency category was estimated from a statistical 
calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and 
the expanded access program (n = 7,319). 
 
Description of selected adverse reactions 
HIV-1 and hepatitis B: 
Renal impairment 
As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 
4.8 Summary of the safety profile).  Proximal renal tubulopathy generally resolved or improved after 
tenofovir disoproxil discontinuation.  However, in some patients, declines in creatinine clearance did 
not completely resolve despite tenofovir disoproxil discontinuation.  Patients at risk of renal 
impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients 
receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete 
recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4). 
 
Lactic acidosis 
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with 
other antiretrovirals.  Patients with predisposing factors such as patients with decompensated liver 
disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased 
risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal 
outcomes. 
 
HIV-1: 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune 
disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 
reported time to onset is more variable and these events can occur many months after initiation of 
treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART.  The frequency of this is unknown 
(see section 4.4). 
 



24 

Hepatitis B: 
Exacerbations of hepatitis during treatment 
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit 
of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients.  ALT 
elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a 
majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or 
coincided with the ALT elevation.  Periodic monitoring of hepatic function is recommended during 
treatment (see section 4.4). 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred 
after discontinuation of HBV therapy (see section 4.4). 
 
Paediatric population 
HIV-1 
Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and 
GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received 
treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with 
other antiretroviral agents for 48 weeks (see section 5.1).  The adverse reactions observed in paediatric 
patients who received treatment with tenofovir disoproxil were consistent with those observed in 
clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse 
reactions and 5.1). 
 
Reductions in BMD have been reported in paediatric patients.  In HIV-1 infected adolescents, the 
BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed 
in subjects who received placebo.  In HIV-1 infected children, the BMD Z-scores observed in subjects 
who switched to tenofovir disoproxil were lower than those observed in subjects who remained on 
their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1). 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse 
events.  Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal 
tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy.  Seven patients had estimated 
glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2.  Among them, 3 patients 
experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of 
tenofovir disoproxil. 
 
Chronic hepatitis B 
Assessment of adverse reactions is based on a randomised study (Study GS-US-174-0115) in 
106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with 
tenofovir disoproxil 245 mg  (n = 52) or placebo (n = 54) for 72 weeks and on a randomised study 
(Study GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to  < 12 years of age) receiving 
treatment with tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks.  The adverse reactions 
observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with 
those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary 
of adverse reactions and 5.1). 
 
Reductions in BMD have been observed in HBV infected paediatric patients 2 to < 18 years of age.  
The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those 
observed in subjects who received placebo (see sections 4.4 and 5.1). 
 
Other special population(s) 
Patients with renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
sections 4.2 and 4.4). 
 



25 

Exacerbations of hepatitis after discontinuation of treatment 
In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have 
occurred after discontinuation of tenofovir disoproxil (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It 
allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), 
and standard supportive treatment applied as necessary. 
 
Management 
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 
134 ml/min.  It is not known whether tenofovir can be removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC code: J05AF07 
 
Mechanism of action and pharmacodynamic effects 
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.  Tenofovir 
disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside 
monophosphate (nucleotide) analogue.  Tenofovir is then converted to the active metabolite, tenofovir 
diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes.  Tenofovir 
diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral 
blood mononuclear cells (PBMCs).  Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and 
the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate 
and, after incorporation into DNA, by DNA chain termination.  Tenofovir diphosphate is a weak 
inhibitor of cellular polymerases α, β, and γ.  At concentrations of up to 300 µmol/l, tenofovir has also 
shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro 
assays. 
 
Data pertaining to HIV 
HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the 
wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against 
primary HIV-1 subtype B isolates in PBMCs.  Tenofovir is also active against HIV-1 subtypes A, C, 
D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells.  Tenofovir shows 
activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells. 
 
Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse 
transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety).  
Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring 
the K65R mutation (see section 4.4).  In addition, a K70E substitution in HIV-1 reverse transcriptase 
has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. 
 
Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir 
disoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors.  The results 
indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

(TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced 
response to tenofovir disoproxil 245 mg therapy. 
 
Clinical efficacy and safety 
The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults 
have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively. 
 
In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir 
disoproxil 245 mg for 24 weeks.  The mean baseline CD4 cell count was 427 cells/mm3, the mean 
baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of 
< 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years.  Baseline genotypic 
analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance 
mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated 
with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase 
inhibitors. 
 
At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels 
(DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 
245 mg recipients (p < 0.0001).  A statistically significant difference in favour of tenofovir disoproxil 
245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 
count (+13 cells/mm3 for tenofovir disoproxil 245 mg versus -11 cells/mm3 for placebo, 
p-value = 0.0008).  The antiviral response to tenofovir disoproxil was durable through 48 weeks 
(DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 
50 copies/ml was 41% and 18% respectively).  Eight (2%) tenofovir disoproxil 245 mg treated patients 
developed the K65R mutation within the first 48 weeks. 
 
The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and 
safety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine and 
efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy.  The mean baseline CD4 cell 
count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of 
patients had symptomatic HIV-1 infection and 18% had AIDS.  Patients were stratified by baseline 
HIV-1 RNA and CD4 count.  Forty-three percent of patients had baseline viral loads 
> 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml. 
 
By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as 
failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 
48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm, 
compared to 84% and 80% in the stavudine arm.  At 144 weeks, the proportion of patients with 
HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir 
disoproxil 245 mg arm, compared to 64% and 63% in the stavudine arm. 
 
The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was 
similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the 
tenofovir disoproxil 245 mg and stavudine groups, respectively).  At 144 weeks of treatment, the 
average change from baseline remained similar in both treatment groups (-3.07 and 
-3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg and stavudine 
groups, respectively).  A consistent response to treatment with tenofovir disoproxil 245 mg was seen 
regardless of baseline HIV-1 RNA and CD4 count. 
 
The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil 
group than the active control group (2.7% versus 0.7%).  Efavirenz or lamivudine resistance either 
preceded or was coincident with the development of K65R in all cases.  Eight patients had HIV that 
expressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks 
of treatment and the last one at week 96.  No further K65R development was observed up to 
week 144.  One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus.  
From both the genotypic and phenotypic analyses there was no evidence for other pathways of 
resistance to tenofovir. 



27 

 
Data pertaining to HBV 
HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessed in 
the HepG2 2.2.15 cell line.  The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l, with 
CC50 (50% cytotoxicity concentration) values > 100 µmol/l. 
 
Resistance: No HBV mutations associated with tenofovir disoproxil resistance have been identified 
(see Clinical efficacy and safety).  In cell based assays, HBV strains expressing the rtV173L, 
rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a 
susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus.  HBV strains 
expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with 
resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-
type virus.  HBV strains expressing the adefovir-associated resistance mutations rtA181V and 
rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.  
Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold 
that of wild-type virus. 
 
Clinical efficacy 
The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is 
based on virological, biochemical and serological responses in adults with HBeAg positive and 
HBeAg negative chronic hepatitis B.  Treated patients included those who were treatment-naïve, 
lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir 
dipivoxil resistance mutations at baseline.  Benefit has also been demonstrated based on histological 
responses in compensated patients. 
 
Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and 
GS-US-174-0103) 
Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir 
disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in 
Table 3 below.  Study GS-US-174-0103 was conducted in 266 (randomised and treated) 
HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) 
patients negative for HBeAg and positive for HBeAb. 
 
In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the 
primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis).  Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater 
proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg 
treatment.  Both treatments produced similar results with regard to histological response (defined as 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis) at week 48 (see Table 3 below). 
 
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil 
group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 
(see Table 3 below). 
 



28 

Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at 
week 48 
 
 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg  
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 

Complete 
response (%)a 

71* 49 67* 12 

Histology     
Histological response 
(%)b 

72 
 

69 74 68 

Median HBV DNA 
reduction from 
baselinec 
(log10 copies/ml) 

-4.7* -4.0 -6.4* -3.7 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

 
93* 

 
63 

 
76* 

 
13 

ALT (%) 
Normalised ALTd 

 
76 

 
77 

 
68* 

 
54 

Serology (%) 
HBeAg 
loss/seroconversion 

 
n/a 

 
n/a 

 
22/21 

 
18/18 

HBsAg 
loss/seroconversion 

0/0 0/0 3*/1 0/0 

* p-value versus adefovir dipivoxil < 0.05. 
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at 
least 2 points without worsening in Knodell fibrosis. 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 
c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of 
detection (LOD) of the assay. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
n/a = not applicable. 
 
Tenofovir disoproxil was associated with significantly greater proportions of patients with 
undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas 
Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and 
study GS-US-174-0103; 69%, 9%), respectively. 
 
Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) 
and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT 
(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined.  
Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine.  
Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved 
complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients 
achieved HBV DNA suppression < 400 copies/ml.  All patients with normal ALT at baseline and 88% 
of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. 
 
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 
In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 
48 weeks (either tenofovir disoproxil 245 mg or adefovir dipivoxil 10 mg), patients rolled over with 
no interruption in treatment to open-label tenofovir disoproxil.  In studies GS-US-174-0102 and 
GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively.  
At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses 
were maintained with continued tenofovir disoproxil treatment (see Tables 4 and 5 below). 
 



29 

Table 4: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 

Week 96b 144e 192g 240i 288l 384o 96c 144f 192h 240j 288m 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

90 87 84 83 80 74 89 88 87 84 84 76 

ALT (%) 
Normalised 
ALTd 

72 73 67 70 68 64 68 70 77 76 74 69 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

HBsAg loss/ 
seroconversion 

0/0 0/0 0/0 0/0 0/0 1/1n 0/0 0/0 0/0 0/0k 1/1n 1/1n 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at 
the time of the data cut-off.  However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit. 
l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF). 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
n/a = not applicable. 
 
Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0103 (HBeAg positive) 
Parametera Tenofovir disoproxil 245 mg  

n = 176 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 90 

Week 96b 144e 192h 240j 288m 384o 96c 144f 192i 240k 288n 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

76 72 68 64 61 56 74 71 72 66 65 61 

ALT (%) 
Normalised 
ALTd 

60 55 56 46 47 47 65 61 59 56 57 56 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
26/ 
23 

 
29/ 
23 

 
34/ 
25 

 
38/ 
30 

 
37/ 
25 

 
30/ 
20 

 
24/ 
20 

 
33/ 
26 

 
36/ 
30 

 
38/ 
31 

 
40/ 
31 

 
35/ 
24 

HBsAg loss/ 
seroconversion 

5/ 
4 

8/ 
6g 

11/ 
8g 

11/ 
8l 

12/ 
8l 

15/ 
12l 

6/ 
5 

8/ 
7g 

8/ 
7g 

10/ 
10l 

11/ 
10l 

13/ 
11l 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 



30 

e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT). 
h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF). 
m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
 
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in 
studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below).  Ninety-five percent 
(225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at 
baseline had either no change or an improvement in fibrosis (Ishak fibrosis score).  Of the 94 patients 
with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak 
fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak 
fibrosis score of at least 2 points. 
 
Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects 
at week 240 compared to baseline 
 
 Study 174-0102 

(HBeAg negative) 
Study 174-0103 

(HBeAg positive) 
Tenofovir disoproxil 

245 mg  
n = 250c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 125d 

Tenofovir disoproxil 
245 mg  
n = 176c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 90d 

Histological 
responsea,b (%)  

88 
[130/148] 

85 
[63/74] 

90 
[63/70] 

92 
[36/39] 

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) 
by week 240.  Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).  
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. 
c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label. 
d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil. 
 
Experience in patients with HIV co-infection and prior lamivudine experience 
In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg in adult 
patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study 
ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir 
arm were 9.45 log10 copies/ml (n = 27).  Treatment with tenofovir disoproxil 245 mg was associated 
with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week 
data, of -5.74 log10 copies/ml (n = 18).  In addition, 61% of patients had normal ALT at week 48. 
 
Experience in patients with persistent viral replication (study GS-US-174-0106) 
The efficacy and safety of tenofovir disoproxil 245 mg or tenofovir disoproxil 245 mg plus 200 mg 
emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in 
HBeAg positive and HBeAg negative adult patients who had persistent viraemia 
(HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks.  At 
baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to 
emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine.  
Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with 
HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine 
plus tenofovir disoproxil (p = 0.672).  In addition 55% (29/53) of patients treated with tenofovir 
disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of 
the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus 
tenofovir disoproxil (p = 0.504).  Comparisons between treatment groups beyond week 24 are difficult 



31 

to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus 
tenofovir disoproxil.  Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine 
plus tenofovir disoproxil in HBV monoinfected patients are ongoing. 
 
Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) 
Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety 
and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and 
entecavir (n = 22), in patients with decompensated liver disease.  In the tenofovir disoproxil treatment 
arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum 
ALT of 61 U/l at baseline.  Forty-two percent (19/45) of patients had at least 6 months of prior 
lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 
45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline.  The 
co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in 
serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. 
 
In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of 
emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 
48 weeks of treatment. 
 
Overall, the data derived from this study are too limited to draw any definitive conclusions on the 
comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 7 below). 
 
Table 7: Safety and efficacy parameters in decompensated patients at week 48 
 
 Study 174-0108 
Parameter Tenofovir disoproxil 

245 mg  
(n = 45) 

Emtricitabine 200 mg/ 
tenofovir disoproxil 

245 mg  
(n = 45) 

Entecavir 
(0.5 mg or 1 mg) 

n = 22 

Tolerability failure 
(permanent 
discontinuation of study 
drug due to a treatment 
emergent AE) 
n (%)a 

3 (7%) 2 (4%) 2 (9%) 

Confirmed increase in 
serum creatinine 
≥ 0.5 mg/dl from 
baseline or confirmed 
serum phosphate of 
< 2 mg/dl 
n (%)b 

4 (9%) 3 (7%) 1 (5%) 

HBV DNA n (%) 
< 400 copies/ml 
n (%) 

31/44 (70%) 36/41 (88%) 16/22 (73%) 

ALT n (%) 
Normal ALT 

25/44 (57%) 31/41 (76%) 12/22 (55%) 

≥ 2 point decrease in 
CPT from baseline 
n (%) 

7/27 (26%) 12/25 (48%) 5/12 (42%) 

Mean change from 
baseline in CPT score 

-0.8 -0.9 -1.3 

Mean change from 
baseline in MELD score 

-1.8 -2.3 -2.6 

a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622, 
b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000. 
 



32 

Experience beyond 48 weeks in study GS-US-174-0108 
Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir 
disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) 
of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. 
 
Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121) 
The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind 
study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with 
compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of 
lamivudine resistance (rtM204I/V +/- rtL180M).  Only five had adefovir-associated resistance 
mutations at baseline.  One hundred forty-one and 139 adult subjects were randomised to a tenofovir 
disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively.  Baseline 
demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were 
HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and 
mean ALT was 79 U/l, respectively. 
 
After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had 
HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation.  After 240 weeks of 
treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had 
HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation.  Among the 
HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced 
HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240.  In 
the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects 
(19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion 
through week 240.  Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by 
Week 240, but not seroconversion to anti-HBs.  Five subjects randomised to emtricitabine plus 
tenofovir disoproxil experienced HBsAg loss, with 2 of these 5 subjects experiencing seroconversion 
to anti-HBs. 
 
Clinical resistance 
Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive 
(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil 
treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic 
changes in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 
(n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive 
(GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment 
and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes 
in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 
(n = 1) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil 
resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks.  Genotypic data 
from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA 
> 400 copies/ml at week 48.  No amino acid substitutions associated with resistance to tenofovir 
disoproxil were identified in these isolates.  Genotypic analysis was conducted for 5 subjects in the 
tenofovir disoproxil arm post week 48.  No amino acid substitutions associated with tenofovir 
disoproxil resistance were detected in any subject. 
 
In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received 
tenofovir disoproxil for up to 240 weeks.  Cumulatively, there were 4 patients who experienced a 
viremic episode (HBV DNA>400 copies/ml) at their last timepoint on TDF.  Among them, sequence 



33 

data from paired baseline and on treatment HBV isolates were available for 2 of 4 patients.  No amino 
acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. 
 
In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance 
mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 
51/52 patients switched to open-label tenofovir disoproxil (TDF-TDF group).  Genotypic evaluations 
were performed on all patients within this group with HBV DNA > 400 copies/ml at week 48 (n = 6), 
week 72 (n = 5), week 96 (n = 4), week 144 (n = 2), and week 192 (n = 3).  Fifty-four patients 
(including 2 patients with lamivudine resistance mutations at baseline) initially received blinded 
placebo treatment for 72 weeks, and 52/54 patients followed with tenofovir disoproxil (PLB-TDF 
group).  Genotypic evaluations were performed on all patients within this group with HBV DNA 
> 400 copies/ml at week 96 (n = 17), week 144 (n = 7), and week 192 (n = 8).  No amino acid 
substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. 
 
In a paediatric study (GS-US-174-0144), genotypic data from paired baseline and on treatment HBV 
isolates from patients who received tenofovir disoproxil were available for 9 of 10 patients who had 
plasma HBV DNA > 400 copies/ml. No amino acid substitutions associated with resistance to 
tenofovir disoproxil were identified in these isolates by week 48. 
 
Paediatric population 
HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years 
of age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an 
optimised background regimen (OBR) for 48 weeks.  Due to limitations of the study, a benefit of 
tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at 
week 24.  However, a benefit is expected for the adolescent population based on extrapolation of adult 
data and comparative pharmacokinetic data (see section 5.2). 
 
In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine 
BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, 
respectively, at baseline.  Mean changes at week 48 (end of double-blind phase) were -0.215 and 
-0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the 
tenofovir disoproxil and placebo groups, respectively.  The mean rate of BMD gain was less in the 
tenofovir disoproxil group compared to the placebo group.  At week 48, six adolescents in the 
tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD 
loss (defined as > 4% loss).  Among 28 patients receiving 96 weeks of treatment with tenofovir 
disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. 
 
In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, 
virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either 
replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original 
regimen (n = 49) for 48 weeks.  At week 48, 83% of patients in the tenofovir disoproxil treatment 
group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA 
concentrations < 400 copies/ml.  The difference in the proportion of patients who maintained 
< 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the 
tenofovir disoproxil treatment group.  When missing data were excluded, 91% of patients in the 
tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment 
group had HIV-1 RNA concentrations < 400 copies/ml at week 48. 
 
Reductions in BMD have been reported in paediatric patients.  In patients who received treatment with 
tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and 
-0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline.  Mean 
changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, 
and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or 
zidovudine groups, respectively.  The mean rate of lumbar spine bone gain at week 48 was similar 
between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group.  
Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine 
or zidovudine treatment group.  One tenofovir disoproxil treated subject and no stavudine or 



34 

zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48.  
BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who 
were treated with tenofovir disoproxil for 96 weeks.  BMD Z-scores were not adjusted for height and 
weight. 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
discontinued study drug due to renal adverse events.  Five subjects (5.6%) had laboratory findings 
clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil 
therapy (median tenofovir disoproxil exposure 331 weeks). 
 
Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients 
aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT 
(≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks.  Subjects must have been naïve 
to tenofovir disoproxil, but could have received interferon based regimens (> 6 months prior to 
screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotide 
therapy (> 16 weeks prior to screening).  At week 72, overall 88% (46/52) of patients in the tenofovir 
disoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA 
< 400 copies/ml.  Seventy-four percent (26/35) of patients in the tenofovir disoproxil group had 
normalised ALT at week 72 compared to 31% (13/42) in the placebo group.  Response to treatment 
with tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-
experienced (n = 32) patients, including lamivudine-resistant patients (n = 6).  Ninety-five percent of 
nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine-
resistant patients achieved HBV DNA < 400 copies/ml at week 72.  Thirty-one of the 32 nucleos(t)ide-
experienced patients had prior lamivudine experience.  At week 72, 96% (27/28) of immune-active 
patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil treatment 
group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml.  Seventy-five 
percent (21/28) of immune-active patients in the tenofovir disoproxil group had normal ALT at 
week 72 compared to 34% (11/32) in the placebo group. 
 
After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir 
disoproxil treatment up to week 192.  After week 72, virologic suppression was maintained for those 
receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (TDF-TDF 
group): 86.5% (45/52) of subjects in the TDF-TDF group had HBV DNA < 400 copies/ml at 
week 192.  Among the subjects who received placebo during the double-blind period, the proportion 
of subjects with HBV DNA < 400 copies/mL rose sharply after they began treatment with open-label 
TDF (PLB-TDF group): 74.1% (40/54) of subjects in the PLB-TDF group had HBV DNA 
< 400 copies/ml at week 192.  The proportion of subjects with ALT normalization at week 192 in the 
TDF-TDF group was 75.8% (25/33) among those who were HBeAg positive at baseline and 100.0% 
(2 of 2 subjects) among those who were HBeAg negative at baseline.  Similar percentages of subjects 
in the TDF-TDF and PLB-TDF groups (37.5% and 41.7%, respectively) experienced seroconversion 
to anti-HBe through week 192. 
 
Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 8: 
 
Table 8: Bone Mineral Density Evaluation at Baseline, Week 72 and 192 
 

 Baseline Week 72 Week 192 
TDF-TDF PLB-TDF TDF-TDF PLB-TDF TDF-TDF PLB-TDF 

Lumbar spine mean 
(SD) BMD Z-scorea 

−0.42  
(0.762) 

-0.26  
(0.806) 

-0.49  
(0.852)  

-0.23 
(0.893)  

-0.37 
(0.946)  

-0.44 
(0.920)  

Lumbar spine mean 
(SD) change from 
baseline 
BMD Z-scorea 

NA NA -0.06  
(0.320) 

0.10  
(0.378) 

0.02  
(0.548) 

-0.10 
(0.543) 

Whole body mean 
(SD) BMD Z-scorea 

−0.19  
(1.110) 

−0.23 
(0.859) 

−0.36 
 (1.077) 

−0.12 
(0.916) 

−0.38 
(0.934) 

−0.42 
 (0.942) 

Whole body mean NA NA −0.16 0.09 -0.16 -0.19  



35 

 Baseline Week 72 Week 192 
TDF-TDF PLB-TDF TDF-TDF PLB-TDF TDF-TDF PLB-TDF 

(SD) change from 
baseline 
BMD Z-scorea 

(0.355) (0.349) (0.521) (0.504) 

Lumbar spine BMD at 
least 6% decreaseb NA NA 1.9% 

(1 subject) 0% 3.8% 
(2 subjects) 

3.7% 
(2 subjects) 

Whole body BMD at 
least 6% decreaseb NA NA 0% 0% 0% 1.9% 

(1 subject) 
Lumbar spine BMD 
mean % increase NA NA 5.14% 8.08% 10.05% 11.21% 

Whole body BMD 
mean % increase NA NA 3.07% 5.39% 6.09% 7.22% 

NA = Not Applicable 
a BMD Z-scores not adjusted for height and weight 
b Primary safety endpoint through week 72 
 
In study GS-US-174-0144, 89 HBeAg-negative and -positive patients aged 2 to < 12 years with 
chronic hepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of 245 mg 
(n = 60) or placebo (n = 29) once daily for 48 weeks. Subjects must have been naïve to tenofovir 
disoproxil, with HBV DNA > 105 copies/mL (~ 4.2 log10 IU/mL) and ALT >1.5 × the upper 
limit of normal (ULN) at screening. At week 48, 77% (46 of 60) of patients in the tenofovir 
disoproxil treatment group and 7% (2 of 29) of patients in the placebo group had HBV DNA 
< 400 copies/mL (69 IU/mL). Sixty-six percent (38 of 58) of patients in the tenofovir 
disoproxil group had normalized ALT at week 48 compared with 15% (4 of 27) in the placebo 
group.  Twenty-five percent (14 of 56) of patients in the tenofovir disoproxil group and 24% (7 of 29) 
of patients in the placebo group achieved HBeAg seroconversion at Week 48.Response to treatment 
with tenofovir disoproxil was comparable in treatment-naïve and treatment-experienced subjects with 
76% (38/50) of treatment-naïve and 80% (8/10) of treatment-experienced subjects achieving HBV 
DNA < 400 copies/mL (69 IU/ml) at Week 48. Response to treatment with tenofovir disoproxil was 
also similar in subjects who were HBeAg-negative compared with those who were HBeAg-positive at 
baseline with 77% (43/56) HBeAg-positive and 75.0% (3/4) HBeAg-negative subjects achieving HBV 
DNA < 400 copies/mL (69 IU/mL) at Week 48. The distribution of HBV genotypes at baseline was 
similar between the TDF and Placebo groups. The majority of subjects were either genotypes C 
(43.8%) or D (41.6%) with a lower and similar frequency of genotypes A and B (6.7% each). Only 1 
subject randomized to the TDF group was genotype E at baseline. In general, treatment responses to 
tenofovir disoproxil were similar for genotypes A, B, C and E [75-100% of subjects achieved HBV 
DNA < 400 copies/mL (69 IU/mL) at Week 48] with a lower response rate in subjects with genotype 
D infection (55%). 

Bone Mineral Density (BMD) data from Study GS-US-174-0144 are summarized in Table 9: 

 
Table 9: Bone Mineral Density Evaluation at Baseline and Week 48 
 

 Baseline Week 48 
TDF PLB TDF PLB 

Lumbar spine mean 
(SD) BMD Z-scorea 

0.02  
(0.977) 

-0.29  
(1.229) 

-0.11 
(0.983) 

-0.11 
(1.234) 

Lumbar spine mean 
(SD) change from 
baseline BMD Z-scorea 

NA NA -0.12  
(0.411) 

0.14 
(0.330) 

Whole body mean (SD) 
BMD Z-scorea 

0.11 
(0.743) 

−0.05 
(1.497) 

-0.34 
(0.939) 

0.20 
(1.299) 

Whole body mean (SD) 
change from baseline 
BMD Z-scorea 

NA NA −0.18 
(0.334) 

0.22 
(0.446) 

Lumbar spine BMD at NA NA 18.3% 6.9% 



36 

 Baseline Week 48 
TDF PLB TDF PLB 

least 4% decreaseb (11 subjects) (2 subjects) 
Whole body BMD at 
least 4% decrease NA NA 6.7% 

(4 subjects) 0% 

Lumbar spine BMD 
mean % increaseb NA NA 3.8% 7.6% 

Whole body BMD mean 
% increase NA NA 4.5% 8.9% 

NA = Not Applicable 
a BMD Z-scores only available for a limited set of subjects with matched reference data 
b Secondary endpoint through week 48 
 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Viread in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir 
and formaldehyde. 
 
Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, 
tenofovir diphosphate. 
 
Absorption 
Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is 
rapidly absorbed and converted to tenofovir.  Administration of multiple doses of tenofovir disoproxil 
with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 
326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively.  Maximum tenofovir 
concentrations are observed in serum within one hour of dosing in the fasted state and within two 
hours when taken with food.  The oral bioavailability of tenofovir from tenofovir disoproxil in fasted 
patients was approximately 25%.  Administration of tenofovir disoproxil with a high fat meal 
enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax 
by approximately 14%.  Following the first dose of tenofovir disoproxil in fed patients, the median 
Cmax in serum ranged from 213 to 375 ng/ml.  However, administration of tenofovir disoproxil with a 
light meal did not have a significant effect on the pharmacokinetics of tenofovir. 
 
Distribution 
Following intravenous administration the steady-state volume of distribution of tenofovir was 
estimated to be approximately 800 ml/kg.  After oral administration of tenofovir disoproxil, tenofovir 
is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the 
intestinal contents (preclinical studies).  In vitro protein binding of tenofovir to plasma or serum 
protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 
25 µg/ml. 
 
Biotransformation 
In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 
CYP450 enzymes.  Moreover, at concentrations substantially higher (approximately 300-fold) than 
those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major 
human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, 
CYP2E1, or CYP1A1/2).  Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any 
of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction 
in metabolism of CYP1A1/2 substrate was observed.  Based on these data, it is unlikely that clinically 
significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 
would occur. 
 



37 

Elimination 
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system 
with approximately 70-80% of the dose excreted unchanged in urine following intravenous 
administration.  Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 
300 ml/min).  Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 
210 ml/min), which is in excess of the glomerular filtration rate.  This indicates that active tubular 
secretion is an important part of the elimination of tenofovir.  Following oral administration the 
terminal half-life of tenofovir is approximately 12 to 18 hours. 
 
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal 
tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the 
multidrug resistant protein 4 (MRP 4). 
 
Linearity/non-linearity 
The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 
75 to 600 mg and were not affected by repeated dosing at any dose level. 
 
Gender 
Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. 
 
Ethnicity 
Pharmacokinetics have not been specifically studied in different ethnic groups. 
 
Paediatric population 
Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients 
(aged 12 to < 18 years) with body weight ≥ 35 kg and in 23 HIV-1 infected children aged 
2 to < 12 years (see Table 10 below).  Tenofovir exposure achieved in these paediatric patients 
receiving oral daily doses of tenofovir disoproxil 245 mg or 6.5 mg/kg body weight tenofovir 
disoproxil up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving 
once-daily doses of tenofovir disoproxil 245 mg. 
 
Table 10: Mean (± SD) tenofovir pharmacokinetic parameters by age groups for paediatric 
patients 
 

Dose and formulation 245 mg film-coated tablet 
12 to < 18 years (n = 8) 

6.5 mg/kg granules 
2 to < 12 years (n = 23) 

Cmax (μg/ml) 0.38 ± 0.13 0.24 ± 0.13 
AUCtau (μg·h/ml) 3.39 ± 1.22 2.59 ± 1.06 

 
Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients 
(12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg was similar to 
exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg. 
 
Tenofovir exposure in HBV infected paediatric patients 2 to <12 years of age receiving an oral daily 
dose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of 
245 mg  was similar to exposures achieved in HIV-1 infected paediatric patients 2 to <12 years of age 
receiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovir 
disoproxil 245 mg. 
 
Pharmacokinetic studies have not been performed in children under 2 years. 
 
Renal impairment 
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of 
tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of 
renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function 
when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and 
severe with CrCl = 10-29 ml/min).  Compared with patients with normal renal function, the mean 



38 

(%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to 
respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with 
mild, moderate and severe renal impairment. 
 
The pharmacokinetics of tenofovir in non-haemodialysis adult patients with creatinine clearance 
< 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not 
been studied. 
 
The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied.  
No data are available to make dose recommendations (see sections 4.2 and 4.4). 
 
Hepatic impairment 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult 
patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) 
classification.  Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic 
impairment suggesting that no dose adjustment is required in these subjects.  The mean (%CV) 
tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, 
in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with 
moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with 
severe hepatic impairment. 
 
Intracellular pharmacokinetics 
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir 
diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-
stimulated PBMCs was found to be approximately 10 hours. 
 
5.3 Preclinical safety data 
 
Non-clinical safety pharmacology studies reveal no special hazard for humans.  Findings in repeated 
dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical 
exposure levels and with possible relevance to clinical use include renal and bone toxicity and a 
decrease in serum phosphate concentration.  Bone toxicity was diagnosed as osteomalacia (monkeys) 
and reduced bone mineral density (BMD) (rats and dogs).  The bone toxicity in young adult rats and 
dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred 
in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the 
exposure in patients).  Findings in the rat and monkey studies indicated that there was a substance-
related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD. 
 
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results 
in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat 
hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay. 
 
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an 
extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 
 
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal 
parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in peri-
postnatal toxicity studies at maternally toxic doses. 
 
Environmental Risk Assessment (ERA) 
The active substance tenofovir disoproxil and its main transformation products are persistent in the 
environment. 
 
 



39 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate (E572) 
Microcrystalline cellulose (E460) 
Starch pregelatinised 
 
Film-coating 
Glycerol triacetate (E1518) 
Hypromellose (E464) 
Lactose monohydrate 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
30 film-coated tablets and a silica gel desiccant. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/004 
EU/1/01/200/005 
 
 



40 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 February 2002 
Date of latest renewal: 14 December 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



41 

1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 163 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 163 mg of tenofovir disoproxil (as fumarate). 
 
Excipient with known effect 
Each tablet contains 109 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
White, round-shaped, film-coated tablets, 10.7 mm in diameter, debossed on one side with “GSI” and 
on the other side with “200”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
HIV-1 infection 
Viread 163 mg film-coated tablets are indicated in combination with other antiretroviral medicinal 
products for the treatment of HIV-1 infected paediatric patients, with NRTI resistance or toxicities 
precluding the use of first line agents, aged 6 to < 12 years who weigh from 22 kg to less than 28 kg. 
 
The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based 
on individual viral resistance testing and/or treatment history of patients. 
 
Hepatitis B infection 
Viread 163 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in paediatric 
patients aged 6 to < 12 years who weigh from 22 kg to less than 28 kg, with: 
 
• compensated liver disease and evidence of immune active disease, i.e. active viral replication 

and persistently elevated serum ALT levels, or histological evidence of moderate to severe 
inflammation and/or fibrosis.  With respect to the decision to initiate treatment in paediatric 
patients, see sections 4.2, 4.4, 4.8 and 5.1. 

 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection and/or 
treatment of chronic hepatitis B. 
 
Posology 
 
HIV-1 and Chronic hepatitis B 
The recommended dose for the treatment of HIV-1 infection and chronic hepatitis B in paediatric 
patients aged 6 to < 12 years weighing 22 kg to < 28 kg who are able to swallow film-coated tablets is 
one 163 mg tablet once daily taken orally with food. 
 



42 

Please refer to the Summaries of Product Characteristics for Viread 123 mg and 204 mg film-coated 
tablets for the treatment of HIV-1 infect ion and chronic hepatitis B in paediatric patients aged 
6 to < 12 years weighing 17 kg to < 22 kg and 28 kg to < 35 kg, respectively. 
 
Viread is also available as 33 mg/g granules for the treatment of HIV-1 infection and chronic hepatitis 
B in paediatric patients aged 2 to < 12 years who weigh < 17 kg or who are unable to swallow 
film-coated tablets.  Please refer to the Summary of Product Characteristics for Viread 33 mg/g 
granules. 
 
The decision to treat paediatric patients should be based on careful consideration of individual patient 
needs and with reference to current paediatric treatment guidelines including the value of baseline 
histological information.  The benefits of long-term virologic suppression with continued therapy must 
be weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis B 
virus and the uncertainties as regards the long term impact of bone and renal toxicity (see section 4.4). 
 
Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric 
patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 
months in patients with HBeAg negative disease. 
 
Duration of therapy in paediatric patients with chronic hepatitis B 
 
The optimal duration of treatment is unknown.  Treatment discontinuation may be considered as 
follows: 
 
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 

12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection 
on two consecutive serum samples at least 3-6 months apart) is confirmed or until 
HBs seroconversion or there is loss of efficacy (see section 4.4).  Serum ALT and HBV DNA 
levels should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 

 
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until 

HBs seroconversion or there is evidence of loss of efficacy.  Treatment discontinuation may 
also be considered after stable virological suppression is achieved (i.e. for at least 3 years) 
provided serum ALT and HBV DNA levels are followed regularly after treatment 
discontinuation to detect any late virological relapse.  With prolonged treatment for more than 
2 years, regular reassessment is recommended to confirm that continuing the selected therapy 
remains appropriate for the patient. 

 
Missed dose 
If a patient misses a dose of Viread within 12 hours of the time it is usually taken, the patient should 
take Viread with food as soon as possible and resume their normal dosing schedule.  If a patient 
misses a dose of Viread by more than 12 hours and it is almost time for their next dose, the patient 
should not take the missed dose and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Viread, another tablet should be taken.  If the patient 
vomits more than 1 hour after taking Viread they do not need to take another dose. 
 
Special populations 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.4). 
 
Hepatic impairment 
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). 
 



43 

If Viread 163 mg film-coated tablets are discontinued in patients co-infected with HIV and hepatitis B 
virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis 
(see section 4.4). 
 
Paediatric population 
The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with 
chronic hepatitis B under 2 years of age have not been established.  No data are available. 
 
Method of administration 
Viread 163 mg film-coated tablets should be taken once daily, orally with food. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
General 
HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir 
disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). 
 
HIV-1 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines. 
 
Hepatitis B 
Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of 
transmission of HBV to others through sexual contact or contamination with blood.  Appropriate 
precautions must continue to be used. 
 
Co-administration of other medicinal products 
- Viread should not be administered concomitantly with other medicinal products containing 

tenofovir disoproxil or tenofovir alafenamide. 
- Viread should not be administered concomitantly with adefovir dipivoxil. 
- Co-administration of tenofovir disoproxil and didanosine is not recommended (see Section 4.5).   
 
Triple therapy with nucleosides/nucleotides 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well 
as with lamivudine and didanosine as a once-daily regimen. 
 
Renal and bone effects in adult population 
Renal effects 
Tenofovir is principally eliminated via the kidney.  Renal failure, renal impairment, elevated 
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been 
reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). 
 
Renal impairment 
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with 
impaired renal function (creatinine clearance < 80 ml/min). 
 
Bone effects 
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain 
and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-
induced proximal renal tubulopathy (see section 4.8). 



44 

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD). In HIV infected 
patients, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in 
BMD of the hip and spine were observed in both treatment groups.  Decreases in BMD of spine and 
changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil 
treatment group at 144 weeks.  Decreases in BMD of hip were significantly greater in this group until 
96 weeks.  However, there was no increased risk of fractures or evidence for clinically relevant bone 
abnormalities over 144 weeks in this study. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 
inhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the 
limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, 
alternative treatment regimens should be considered for patients with osteoporosis that are at a high 
risk for fractures. 
 
If bone abnormalities are suspected or detected then appropriate consultation should be obtained. 
 
Renal and bone effects in paediatric population 
There are uncertainties associated with the long term effects of bone and renal toxicity.  Moreover, the 
reversibility of renal toxicity cannot be fully ascertained.  Therefore, a multidisciplinary approach is 
recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide 
the appropriate monitoring during treatment (including decision for treatment withdrawal) and 
consider the need for supplementation. 
 
Renal effects 
Renal adverse reactions consistent with proximal renal tubulopathy have been reported in 
HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see 
sections 4.8 and 5.1). 
 
Renal monitoring 
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all 
patients prior to initiating therapy with tenofovir disoproxil and that it is also monitored after two to 
four weeks of treatment, after three months of treatment and every three to six months thereafter in 
patients without renal risk factors.  In patients at risk for renal impairment, a more frequent monitoring 
of renal function is required. 
 
Renal management 
If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving 
tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements 
of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal 
tubulopathy).  If renal abnormalities are suspected or detected then consultation with a nephrologist 
should be obtained to consider interruption of tenofovir disoproxil treatment.  Interrupting treatment 
with tenofovir disoproxil should also be considered in case of progressive decline of renal function 
when no other cause has been identified. 
 
Co-administration and risk of renal toxicity 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, 
vancomycin, cidofovir or interleukin-2).  If concomitant use of tenofovir disoproxil and nephrotoxic 
agents is unavoidable, renal function should be monitored weekly. 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If tenofovir disoproxil is co-administered with an NSAID, renal function should 
be monitored adequately. 
 



45 

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in 
combination with a ritonavir or cobicistat boosted protease inhibitor.  A close monitoring of renal 
function is required in these patients (see section 4.5).  In patients with renal risk factors, the 
co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully 
evaluated. 
 
Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which 
are secreted by the same renal pathway, including the transport proteins human organic anion 
transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product).  These 
renal transport proteins may be responsible for tubular secretion and in part, renal elimination of 
tenofovir and cidofovir.  Consequently, the pharmacokinetics of these medicinal products, which are 
secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be 
modified if they are co-administered.  Unless clearly necessary, concomitant use of these medicinal 
products which are secreted by the same renal pathway is not recommended, but if such use is 
unavoidable, renal function should be monitored weekly (see section 4.5). 
 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.2).  Tenofovir disoproxil should not be initiated in paediatric patients with renal impairment 
and should be discontinued in paediatric patients who develop renal impairment during tenofovir 
disoproxil therapy. 
 
Bone effects 
Viread may cause a reduction in BMD.  The effects of tenofovir disoproxil-associated changes in 
BMD on long-term bone health and future fracture risk are uncertain (see section 5.1). 
 
If bone abnormalities are detected or suspected in paediatric patients, consultation with an 
endocrinologist and/or nephrologist should be obtained. 
 
Liver disease 
Tenofovir and tenofovir disoproxil are not metabolised by liver enzymes.  A pharmacokinetic study 
has been performed in non-HIV infected adult patients with various degrees of hepatic impairment.  
No significant pharmacokinetic alteration has been observed in these patients (see section 5.2). 
 
Exacerbations of hepatitis 
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 
characterised by transient increases in serum ALT.  After initiating antiviral therapy, serum ALT may 
increase in some patients (see section 4.8).  In patients with compensated liver disease, these increases 
in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 
hepatic decompensation.  Patients with cirrhosis may be at a higher risk for hepatic decompensation 
following hepatitis exacerbation, and therefore should be monitored closely during therapy. 
 
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in 
patients who have discontinued hepatitis B therapy.  Post-treatment exacerbations are usually 
associated with rising HBV DNA, and the majority appears to be self-limited.  However, severe 
exacerbations, including fatalities, have been reported.  Hepatic function should be monitored at 
repeated intervals with both clinical and laboratory follow-up for at least 6 months after 
discontinuation of hepatitis B therapy.  If appropriate, resumption of hepatitis B therapy may be 
warranted.  In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 
recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 
 
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease. 
 
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients 
co-infected with hepatitis C or D virus. 
 



46 

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir 
disoproxil should only be used as part of an appropriate antiretroviral combination regimen in 
HIV/HBV co-infected patients.  Patients with pre-existing liver dysfunction, including chronic active 
hepatitis, have an increased frequency of liver function abnormalities during combination 
antiretroviral therapy (CART) and should be monitored according to standard practice.  If there is 
evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must 
be considered.  However, it should be noted that increases of ALT can be part of HBV clearance 
during therapy with tenofovir, see above Exacerbations of hepatitis. 
 
Use with certain hepatitis C virus antiviral agents 
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, 
especially when used together with an HIV regimen containing tenofovir disoproxil and a 
pharmacokinetic enhancer (ritonavir or cobicistat).  The safety of tenofovir disoproxil in the setting of 
ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a 
pharmacokinetic enhancer has not been established.  The potential risks and benefits associated with 
co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV 
protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at 
increased risk of renal dysfunction.  Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV 
protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil. 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Mitochondrial dysfunction following exposure in utero 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such 
neurological disorders are transient or permanent is currently unknown.  These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of institution of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause 
serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed 
within the first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment. 
 



47 

Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
Excipients 
 
Viread 163 mg film-coated tablets contain lactose monohydrate.   Patients with rare hereditary 
problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should 
not take this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the 
potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low. 
 
Concomitant use not recommended 
Viread should not be administered concomitantly with other medicinal products containing tenofovir 
disoproxil or tenofovir alafenamide. 
 
Viread should not be administered concomitantly with adefovir dipivoxil. 
 
Didanosine 
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and 
Table 1). 
 
Renally eliminated medicinal products 
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with 
medicinal products that reduce renal function or compete for active tubular secretion via transport 
proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir 
and/or the co-administered medicinal products. 
 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product.  Some examples include, but are not limited to, aminoglycosides, amphotericin B, 
foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4). 
 
Given that tacrolimus can affect renal function, close monitoring is recommended when it is 
co-administered with tenofovir disoproxil. 
 
Other interactions 
Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily 
as “q.d.”). 
 



48 

Table 1: Interactions between tenofovir disoproxil and other medicinal products 
 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

ANTI-INFECTIVES 
Antiretrovirals 
Protease inhibitors 
Atazanavir/Ritonavir 
(300 q.d./100 q.d.) 

Atazanavir: 
AUC: ↓ 25% 
Cmax: ↓ 28% 
Cmin: ↓ 26% 
Tenofovir: 
AUC: ↑ 37% 
Cmax: ↑ 34% 
Cmin: ↑ 29% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
tenofovir-associated adverse 
events, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Lopinavir/Ritonavir 
(400 b.i.d./100 b.i.d.) 

Lopinavir/ritonavir: 
No significant effect on lopinavir/ritonavir 
PK parameters. 
Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
tenofovir-associated adverse 
events, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Darunavir/Ritonavir 
(300/100 b.i.d.) 

Darunavir: 
No significant effect on darunavir/ritonavir 
PK parameters. 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
tenofovir-associated adverse 
events, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



49 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

NRTIs 
Didanosine Co-administration of tenofovir disoproxil 

and didanosine results in a 40-60% increase 
in systemic exposure to didanosine. 

Co-administration of 
tenofovir disoproxil and 
didanosine is not 
recommended 
(see section 4.4). 
 
Increased systemic exposure 
to didanosine may increase 
didanosine related adverse 
reactions.  Rarely, 
pancreatitis and lactic 
acidosis, sometimes fatal, 
have been reported.  
Co-administration of 
tenofovir disoproxil and 
didanosine at a dose of 
400 mg daily has been 
associated with a significant 
decrease in CD4 cell count, 
possibly due to an 
intracellular interaction 
increasing phosphorylated 
(i.e. active) didanosine.  A 
decreased dosage of 250 mg 
didanosine co-administered 
with tenofovir disoproxil 
therapy has been associated 
with reports of high rates of 
virological failure within 
several tested combinations 
for the treatment of 
HIV-1 infection. 

Adefovir dipivoxil AUC: ↔ 
Cmax: ↔ 

Tenofovir disoproxil should 
not be administered 
concurrently with adefovir 
dipivoxil (see section 4.4). 



50 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Hepatitis C virus antiviral agents 
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↑ 96% 
Cmax: ↑ 68% 
Cmin: ↑ 118% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 63% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 45% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 47% 
Cmin: ↑ 47% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
ledipasvir/sofosbuvir and 
atazanavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring, if 
other alternatives are not 
available (see section 4.4). 



51 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↓ 27% 
Cmax: ↓ 37% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 48% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 50% 
Cmax: ↑ 64% 
Cmin: ↑ 59% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
ledipasvir/sofosbuvir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring, if 
other alternatives are not 
available (see section 4.4). 



52 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovi
r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↓ 34% 
Cmax: ↓ 34% 
Cmin: ↓ 34% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 98% 
Cmax: ↑ 79% 
Cmin: ↑ 163% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
adverse reactions associated 
with tenofovir disoproxil, 
including renal disorders.  
Renal function should be 
closely monitored (see 
section 4.4). 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofo
vir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↔ 
Cmin: ↑ 91% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
adverse reactions associated 
with tenofovir disoproxil, 
including renal disorders.  
Renal function should be 
closely monitored (see 
section 4.4). 



53 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Dolutegravir (50 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072 

AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Dolutegravir  
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Tenofovir: 
AUC: ↑ 65% 
Cmax: ↑ 61% 
Cmin: ↑ 115% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
adverse reactions associated 
with tenofovir disoproxil, 
including renal disorders.  
Renal function should be 
closely monitored (see 
section 4.4). 



54 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔  
Cmax: ↔  
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Velpatasvir: 
AUC: ↑ 142% 
Cmax: ↑ 55% 
Cmin: ↑ 301% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 39% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 29% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 55% 
Cmin: ↑ 39% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
atazanavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



55 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC:  ↓28% 
Cmax: ↓ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 24% 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 55% 
Cmin: ↑ 52% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



56 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Lopinavir/Ritonavir 
(800 mg/200 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↓ 29% 
Cmax: ↓ 41% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: ↑ 63% 
 
Lopinavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 42% 
Cmin: ↔ 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
lopinavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



57 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Raltegravir 
(400 mg b.i.d) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Raltegravir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 21% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 46% 
Cmin: ↑ 70% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
adverse reactions associated 
with tenofovir disoproxil, 
including renal disorders.  
Renal function should be 
closely monitored (see 
section 4.4). 

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/ 
Tenofovir disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↓ 53% 
Cmax: ↓ 47% 
Cmin: ↓ 57% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 81% 
Cmax: ↑ 77% 
Cmin: ↑ 121% 

Concomitant administration 
of sofosbuvir/velpatasvir and 
efavirenz is expected to 
decrease plasma 
concentrations of velpatasvir.  
Co-administration of 
sofosbuvir/velpatasvir with 
efavirenz-containing 
regimens is not 
recommended. 



58 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Emtricitabine/Rilpivirine/ 
Tenofovir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 44% 
Cmin: ↑ 84% 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
adverse reactions associated 
with tenofovir disoproxil, 
including renal disorders.  
Renal function should be 
closely monitored (see 
section 4.4). 



59 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir/ 
Voxilaprevir (400 mg/100 mg/ 
100 mg+100 mg q.d.)3 + 
Darunavir (800 mg q.d.) + 
Ritonavir (100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: N/A 
 
GS-3310072: 
AUC: ↔ 
Cmax:↔ 
Cmin: N/A 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Voxilaprevir: 
AUC: ↑ 143% 
Cmax:↑ 72% 
Cmin: ↑ 300% 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 34% 
 
Ritonavir: 
AUC: ↑ 45% 
Cmax: ↑ 60% 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 48% 
Cmin: ↑ 47% 

Increased plasma 
concentrations of tenofovir 
resulting from co-
administration of tenofovir 
disoproxil, 
sofosbuvir/velpatasvir/voxila
previr and darunavir/ritonavir 
may increase adverse 
reactions related to tenofovir 
disoproxil, including renal 
disorders.  
The safety of tenofovir 
disoproxil when used with 
sofosbuvir/velpatasvir/voxila
previr and a pharmacokinetic 
enhancer (e.g. ritonavir or 
cobicistat) has not been 
established.  
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 
 



60 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir 
(400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovi
r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 19% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↓ 23% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 25% 
Cmin: ↔ 

No dose adjustment is 
required. 

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir.  Staggered administration (12 hours apart) provided 
similar results. 
2 The predominant circulating metabolite of sofosbuvir. 
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 
 
Studies conducted with other medicinal products 
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was 
co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir 
boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive 
norgestimate/ethinyl oestradiol. 
 
Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir 
(see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no 
malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.  Animal studies do not 
indicate reproductive toxicity (see section 5.3).  The use of tenofovir disoproxil may be considered 
during pregnancy, if necessary. 
 
In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to 
reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, 
in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.  

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were 
administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 
months postpartum; women and their infants were followed for up to 12 months after delivery.  No 
safety signal has emerged from these data. 

Breastfeeding 
Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with 
hepatitis B may breast-feed her infant. 



61 

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is 
considered negligible. Although long-term data is limited, no adverse reactions have been reported in 
breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed. 
 
As a general rule, it is recommended that HIV infected mothers do not breastfeed their infants in order 
to avoid transmission of HIV to the infant. 
 
Fertility 
There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility.  Animal 
studies do not indicate harmful effects of tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
patients should be informed that dizziness has been reported during treatment with tenofovir 
disoproxil. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, 
renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) 
sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.  
Monitoring of renal function is recommended for patients receiving Viread (see section 4.4). 
 
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following 
treatment with tenofovir disoproxil in combination with other antiretroviral agents.  These reactions 
are usually mild to moderate gastrointestinal events.  Approximately 1% of tenofovir 
disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events. 
 
 
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions 
following treatment with tenofovir disoproxil, most of which are mild.  In clinical trials of 
HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was 
nausea (5.4%). 
 
Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who 
have discontinued hepatitis B therapy (see section 4.4). 
 
Tabulated summary of adverse reactions 
HIV-1 clinical studies:  Assessment of adverse reactions for tenofovir disoproxil is based on safety 
data from clinical studies and post-marketing experience.  All adverse reactions are presented in 
Table 2. 
 
Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies 
in 653 treatment-experienced adult patients receiving treatment with tenofovir disoproxil (n = 443) or 
placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in 
a double-blind comparative controlled study in which 600 treatment-naïve adult patients received 
treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) in combination with 
lamivudine and efavirenz for 144 weeks. 
 
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is 
primarily based on experience in two double-blind comparative controlled studies in which 641 adult 
patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir 
disoproxil 245 mg  daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.  The 
adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 
profile of tenofovir disoproxil.  After an initial decline of approximately -4.9 ml/min (using 



62 

Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease 
[MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal 
function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using 
Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation). 
 
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil in patients with 
decompensated liver disease was assessed in a double-blind active controlled study 
(GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n = 45) or 
emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks. 
 
In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse 
event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant 
differences between the combined tenofovir-containing arms and the entecavir arm.  After 168 weeks, 
16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil 
group, and 14% (3/22) of the entecavir group experienced tolerability failure.  Thirteen percent (6/45) 
of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 
9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl. 
 
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 
13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil 
group and 14% (3/22) in the entecavir group.  The rate of hepatocellular carcinoma was 18% (8/45) in 
the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% 
(2/22) in the entecavir group. 
 
Subjects with a high baseline CPT score were at higher risk of developing serious adverse events 
(see section 4.4). 
 
Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir 
disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 
lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or 
emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks. 
 
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by 
body system organ class and frequency.  Within each frequency grouping, undesirable effects are 
presented in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on 
clinical study and post-marketing experience 
 
Frequency Tenofovir disoproxil  
Metabolism and nutrition disorders: 
Very common: hypophosphataemia1 
Uncommon: hypokalaemia1 
Rare: lactic acidosis 

Nervous system disorders: 
Very common: dizziness 
Gastrointestinal disorders: 
Very common: diarrhoea, vomiting, nausea 
Common: flatulence 
Uncommon: pancreatitis 
Hepatobiliary disorders: 
Common: increased transaminases 
Rare: hepatic steatosis, hepatitis 



63 

Frequency Tenofovir disoproxil  
Skin and subcutaneous tissue disorders: 
Very common: rash 
Rare: angioedema 
Musculoskeletal and connective tissue disorders: 
Uncommon: rhabdomyolysis1, muscular weakness1 

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 

2, myopathy1 
Renal and urinary disorders: 
Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconi syndrome) 

Rare: acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute 
interstitial nephritis)2, nephrogenic diabetes insipidus 

General disorders and administration site conditions: 
Very common: asthenia 
1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 
associated with tenofovir disoproxil in the absence of this condition. 
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical 
trials or the tenofovir disoproxil expanded access program.  The frequency category was estimated from a statistical 
calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and 
the expanded access program (n = 7,319). 
 
Description of selected adverse reactions 
HIV-1 and hepatitis B: 
Renal impairment 
As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 
4.8 Summary of the safety profile).  Proximal renal tubulopathy generally resolved or improved after 
tenofovir disoproxil discontinuation.  However, in some patients, declines in creatinine clearance did 
not completely resolve despite tenofovir disoproxil discontinuation.  Patients at risk of renal 
impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients 
receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete 
recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4). 
 
Lactic acidosis 
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with 
other antiretrovirals.  Patients with predisposing factors such as patients with decompensated liver 
disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased 
risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal 
outcomes. 
 
HIV-1: 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune 
disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 
reported time to onset is more variable and these events can occur many months after initiation of 
treatment (see section 4.4). 
 



64 

Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally 
acknowledged risk factors, advanced HIV disease or long-term exposure to CART.  The 
frequency of this is unknown (see section 4.4).  
 
Hepatitis B: 
Exacerbations of hepatitis during treatment 
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit 
of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients.  ALT 
elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a 
majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or 
coincided with the ALT elevation.  Periodic monitoring of hepatic function is recommended during 
treatment (see section 4.4). 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred 
after discontinuation of HBV therapy (see section 4.4). 
 
Paediatric population 
HIV-1 
Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and 
GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received 
treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with 
other antiretroviral agents for 48 weeks (see section 5.1).  The adverse reactions observed in paediatric 
patients who received treatment with tenofovir disoproxil were consistent with those observed in 
clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse 
reactions and 5.1). 
 
Reductions in BMD have been reported in paediatric patients.  In HIV-1 infected adolescents, the 
BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed 
in subjects who received placebo.  In HIV-1 infected children, the BMD Z-scores observed in subjects 
who switched to tenofovir disoproxil were lower than those observed in subjects who remained on 
their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1). 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse 
events.  Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal 
tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy.  Seven patients had estimated 
glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2.  Among them, 3 patients 
experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of 
tenofovir disoproxil. 
 
Chronic hepatitis B 
Assessment of adverse reactions is based on a randomised study (Study GS-US-174-0115) in 
106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks and on a randomised study 
(Study GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to  < 12 years of age) receiving 
treatment with tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks.  The adverse reactions 
observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with 
those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary 
of adverse reactions and 5.1). 
 
Reductions in BMD have been observed in HBV infected paediatric patients 2 to < 18 years of age.  
The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those 
observed in subjects who received placebo (see sections 4.4 and 5.1). 
 



65 

Other special population(s) 
Patients with renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
sections 4.2 and 4.4). 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have 
occurred after discontinuation of tenofovir disoproxil (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  
It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), 
and standard supportive treatment applied as necessary. 
 
Management 
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 
134 ml/min.  It is not known whether tenofovir can be removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC code: J05AF07 
 
Mechanism of action and pharmacodynamic effects 
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.  Tenofovir 
disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside 
monophosphate (nucleotide) analogue.  Tenofovir is then converted to the active metabolite, tenofovir 
diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes.  Tenofovir 
diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral 
blood mononuclear cells (PBMCs).  Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and 
the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate 
and, after incorporation into DNA, by DNA chain termination.  Tenofovir diphosphate is a weak 
inhibitor of cellular polymerases α, β, and γ.  At concentrations of up to 300 µmol/l, tenofovir has also 
shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro 
assays. 
 
Data pertaining to HIV 
HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the 
wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against 
primary HIV-1 subtype B isolates in PBMCs.  Tenofovir is also active against HIV-1 subtypes A, C, 
D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells.  Tenofovir shows 
activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells. 
 

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66 

Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse 
transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety).  
Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring 
the K65R mutation (see section 4.4).  In addition, a K70E substitution in HIV-1 reverse transcriptase 
has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. 
 
Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir 
disoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors.  The results 
indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations 
(TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced 
response to tenofovir disoproxil 245 mg therapy. 
 
Clinical efficacy and safety 
The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults 
have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively. 
 
In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir 
disoproxil 245 mg for 24 weeks.  The mean baseline CD4 cell count was 427 cells/mm3, the mean 
baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of 
< 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years.  Baseline genotypic 
analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance 
mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated 
with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase 
inhibitors. 
 
At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels 
(DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 
245 mg recipients (p < 0.0001).  A statistically significant difference in favour of tenofovir disoproxil 
245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 
count (+13 cells/mm3 for tenofovir disoproxil 245 mg versus -11 cells/mm3 for placebo, 
p-value = 0.0008).  The antiviral response to tenofovir disoproxil was durable through 48 weeks 
(DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 
50 copies/ml was 41% and 18% respectively).  Eight (2%) tenofovir disoproxil 245 mg treated patients 
developed the K65R mutation within the first 48 weeks. 
 
The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and 
safety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine and 
efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy.  The mean baseline CD4 cell 
count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of 
patients had symptomatic HIV-1 infection and 18% had AIDS.  Patients were stratified by baseline 
HIV-1 RNA and CD4 count.  Forty-three percent of patients had baseline viral loads 
> 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml. 
 
By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as 
failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 
48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm, 
compared to 84% and 80% in the stavudine arm.  At 144 weeks, the proportion of patients with 
HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir 
disoproxil 245 mg arm, compared to 64% and 63% in the stavudine arm. 
 
The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was 
similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the 
tenofovir disoproxil 245 mg and stavudine groups, respectively).  At 144 weeks of treatment, the 
average change from baseline remained similar in both treatment groups (-3.07 and 
-3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg and stavudine 
groups, respectively).  A consistent response to treatment with tenofovir disoproxil 245 mg was seen 
regardless of baseline HIV-1 RNA and CD4 count. 



67 

 
The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil 
group than the active control group (2.7% versus 0.7%).  Efavirenz or lamivudine resistance either 
preceded or was coincident with the development of K65R in all cases.  Eight patients had HIV that 
expressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks 
of treatment and the last one at week 96.  No further K65R development was observed up to 
week 144.  One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus.  
From both the genotypic and phenotypic analyses there was no evidence for other pathways of 
resistance to tenofovir. 
 
Data pertaining to HBV 
HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessed in 
the HepG2 2.2.15 cell line.  The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l, with 
CC50 (50% cytotoxicity concentration) values > 100 µmol/l. 
 
Resistance: No HBV mutations associated with tenofovir disoproxil resistance have been identified 
(see Clinical efficacy and safety).  In cell based assays, HBV strains expressing the rtV173L, 
rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a 
susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus.  HBV strains 
expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with 
resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-
type virus.  HBV strains expressing the adefovir-associated resistance mutations rtA181V and 
rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.  
Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold 
that of wild-type virus. 
 
Clinical efficacy and safety 
The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is 
based on virological, biochemical and serological responses in adults with HBeAg positive and 
HBeAg negative chronic hepatitis B.  Treated patients included those who were treatment-naïve, 
lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir 
dipivoxil resistance mutations at baseline.  Benefit has also been demonstrated based on histological 
responses in compensated patients. 
 
Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and 
GS-US-174-0103) 
Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir 
disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in 
Table 3 below.  Study GS-US-174-0103 was conducted in 266 (randomised and treated) 
HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) 
patients negative for HBeAg and positive for HBeAb. 
 
In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the 
primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis).  Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater 
proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg 
treatment.  Both treatments produced similar results with regard to histological response (defined as 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis) at week 48 (see Table 3 below). 
 
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil 
group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 
(see Table 3 below). 
 



68 

Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at 
week 48 
 
 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg  
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 

Complete 
response (%)a 

71* 49 67* 12 

Histology     
Histological response 
(%)b 

72 
 

69 74 68 

Median HBV DNA 
reduction from 
baselinec 
(log10 copies/ml) 

-4.7* -4.0 -6.4* -3.7 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

 
93* 

 
63 

 
76* 

 
13 

ALT (%) 
Normalised ALTd 

 
76 

 
77 

 
68* 

 
54 

Serology (%) 
HBeAg 
loss/seroconversion 

 
n/a 

 
n/a 

 
22/21 

 
18/18 

HBsAg 
loss/seroconversion 

0/0 0/0 3*/1 0/0 

* p-value versus adefovir dipivoxil < 0.05. 
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at 
least 2 points without worsening in Knodell fibrosis. 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 
c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of 
detection (LOD) of the assay. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
n/a = not applicable. 
 
Tenofovir disoproxil was associated with significantly greater proportions of patients with 
undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas 
Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and 
study GS-US-174-0103; 69%, 9%), respectively. 
 
Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) 
and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT 
(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined.  
Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine.  
Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved 
complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients 
achieved HBV DNA suppression < 400 copies/ml.  All patients with normal ALT at baseline and 88% 
of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. 
 
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 
In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 
48 weeks (either tenofovir disoproxil 245 mg  or adefovir dipivoxil 10 mg), patients rolled over with 
no interruption in treatment to open-label tenofovir disoproxil.  In studies GS-US-174-0102 and 
GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively.  
At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses 
were maintained with continued tenofovir disoproxil treatment (see Tables 4 and 5 below). 
 



69 

Table 4: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 

Week 96b 144e 192g 240i 288l 384o 96c 144f 192h 240j 288m 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

90 87 84 83 80 74 89 88 87 84 84 76 

ALT (%) 
Normalised 
ALTd 

72 73 67 70 68 64 68 70 77 76 74 69 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

HBsAg loss/ 
seroconversion 

0/0 0/0 0/0 0/0 0/0 1/1n 0/0 0/0 0/0 0/0k 1/1n 1/1n 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at 
the time of the data cut-off.  However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit. 
l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF). 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
n/a = not applicable. 
 
Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0103 (HBeAg positive) 
Parametera Tenofovir disoproxil 245 mg  

n = 176 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 90 

Week 96b 144e 192h 240j 288m 384o 96c 144f 192i 240k 288n 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

76 72 68 64 61 56 74 71 72 66 65 61 

ALT (%) 
Normalised 
ALTd 

60 55 56 46 47 47 65 61 59 56 57 56 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
26/ 
23 

 
29/ 
23 

 
34/ 
25 

 
38/ 
30 

 
37/ 
25 

 
30/ 
20 

 
24/ 
20 

 
33/ 
26 

 
36/ 
30 

 
38/ 
31 

 
40/ 
31 

 
35/ 
24 

HBsAg loss/ 
seroconversion 

5/ 
4 

8/ 
6g 

11/ 
8g 

11/ 
8l 

12/ 
8l 

15/ 
12l 

6/ 
5 

8/ 
7g 

8/ 
7g 

10/ 
10l 

11/ 
10l 

13/ 
11l 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 



70 

e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT). 
h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF). 
m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
 
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in 
studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below).  Ninety-five percent 
(225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at 
baseline had either no change or an improvement in fibrosis (Ishak fibrosis score).  Of the 94 patients 
with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak 
fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak 
fibrosis score of at least 2 points. 
 
Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects 
at week 240 compared to baseline 
 
 Study 174-0102 

(HBeAg negative) 
Study 174-0103 

(HBeAg positive) 
Tenofovir disoproxil 

245 mg  
n = 250c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 125d 

Tenofovir disoproxil 
245 mg  
n = 176c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 90d 

Histological 
responsea,b (%)  

88 
[130/148] 

85 
[63/74] 

90 
[63/70] 

92 
[36/39] 

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) 
by week 240.  Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).  
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. 
c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label. 
d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil. 
 
Experience in patients with HIV co-infection and prior lamivudine experience 
In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg  in adult 
patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study 
ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir 
arm were 9.45 log10 copies/ml (n = 27).  Treatment with tenofovir disoproxil 245 mg  was associated 
with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week 
data, of -5.74 log10 copies/ml (n = 18).  In addition, 61% of patients had normal ALT at week 48. 
 
Experience in patients with persistent viral replication (study GS-US-174-0106) 
The efficacy and safety of tenofovir disoproxil 245 mg  or tenofovir disoproxil 245 mg  plus 200 mg 
emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in 
HBeAg positive and HBeAg negative adult patients who had persistent viraemia 
(HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks.  At 
baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to 
emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine.  
Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with 
HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine 
plus tenofovir disoproxil (p = 0.672).  In addition 55% (29/53) of patients treated with tenofovir 
disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of 
the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus 
tenofovir disoproxil (p = 0.504).  Comparisons between treatment groups beyond week 24 are difficult 



71 

to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus 
tenofovir disoproxil.  Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine 
plus tenofovir disoproxil in HBV monoinfected patients are ongoing. 
 
Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) 
Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety 
and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and 
entecavir (n = 22), in patients with decompensated liver disease.  In the tenofovir disoproxil treatment 
arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum 
ALT of 61 U/l at baseline.  Forty-two percent (19/45) of patients had at least 6 months of prior 
lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 
45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline.  The 
co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in 
serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. 
 
In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of 
emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 
48 weeks of treatment. 
 
Overall, the data derived from this study are too limited to draw any definitive conclusions on the 
comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 7 below). 
 
Table 7: Safety and efficacy parameters in decompensated patients at week 48 
 
 Study 174-0108 
Parameter Tenofovir disoproxil 

245 mg  
(n = 45) 

Emtricitabine 200 mg/ 
tenofovir disoproxil 

245 mg  
(n = 45) 

Entecavir 
(0.5 mg or 1 mg) 

n = 22 

Tolerability failure 
(permanent 
discontinuation of study 
drug due to a treatment 
emergent AE) 
n (%)a 

3 (7%) 2 (4%) 2 (9%) 

Confirmed increase in 
serum creatinine 
≥ 0.5 mg/dl from 
baseline or confirmed 
serum phosphate of 
< 2 mg/dl 
n (%)b 

4 (9%) 3 (7%) 1 (5%) 

HBV DNA n (%) 
< 400 copies/ml 
n (%) 

31/44 (70%) 36/41 (88%) 16/22 (73%) 

ALT n (%) 
Normal ALT 

25/44 (57%) 31/41 (76%) 12/22 (55%) 

≥ 2 point decrease in 
CPT from baseline 
n (%) 

7/27 (26%) 12/25 (48%) 5/12 (42%) 

Mean change from 
baseline in CPT score 

-0.8 -0.9 -1.3 

Mean change from 
baseline in MELD score 

-1.8 -2.3 -2.6 

a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622, 
b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000. 
 



72 

Experience beyond 48 weeks in study GS-US-174-0108 
Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir 
disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) 
of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. 
 
Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121) 
The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind 
study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with 
compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of 
lamivudine resistance (rtM204I/V +/- rtL180M).  Only five had adefovir-associated resistance 
mutations at baseline.  One hundred forty-one and 139 adult subjects were randomised to a tenofovir 
disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively.  Baseline 
demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were 
HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and 
mean ALT was 79 U/l, respectively. 
 
After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had 
HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation.  After 240 weeks of 
treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had 
HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation.  Among the 
HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced 
HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240.  In 
the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects 
(19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion 
through week 240.  Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by 
Week 240, but not seroconversion to anti-HBs.  Five subjects randomised to emtricitabine plus 
tenofovir disoproxil experienced HBsAg loss, with 2 of these 5 subjects experiencing seroconversion 
to anti-HBs. 
 
Clinical resistance 
Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive 
(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil 
treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic 
changes in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 
(n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive 
(GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment 
and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes 
in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 
(n = 1) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil 
resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks.  Genotypic data 
from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA 
> 400 copies/ml at week 48.  No amino acid substitutions associated with resistance to tenofovir 
disoproxil were identified in these isolates.  Genotypic analysis was conducted for 5 subjects in the 
tenofovir disoproxil arm post week 48.  No amino acid substitutions associated with tenofovir 
disoproxil resistance were detected in any subject. 
 
In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received 
tenofovir disoproxil for up to 240 weeks.  Cumulatively, there were 4 patients who experienced a 
viremic episode (HBV DNA>400 copies/ml) at their last timepoint on TDF.  Among them, sequence 



73 

data from paired baseline and on treatment HBV isolates were available for 2 of 4 patients.  No amino 
acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. 
 
In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance 
mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 
51/52 patients switched to open-label tenofovir disoproxil (TDF-TDF group).  Genotypic evaluations 
were performed on all patients within this group with HBV DNA > 400 copies/ml at week 48 (n = 6), 
week 72 (n = 5), week 96 (n = 4), week 144 (n = 2), and week 192 (n = 3).  Fifty-four patients 
(including 2 patients with lamivudine resistance mutations at baseline) initially received blinded 
placebo treatment for 72 weeks, and 52/54 patients followed with tenofovir disoproxil (PLB-TDF 
group).  Genotypic evaluations were performed on all patients within this group with HBV DNA 
> 400 copies/ml at week 96 (n = 17), week 144 (n = 7), and week 192 (n = 8).  No amino acid 
substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. 
 
In a paediatric study (GS-US-174-0144), genotypic data from paired baseline and on treatment HBV 
isolates from patients who received tenofovir disoproxil were available for 9 of 10 patients who had 
plasma HBV DNA > 400 copies/ml. No amino acid substitutions associated with resistance to 
tenofovir disoproxil were identified in these isolates by week 48. 
 
Paediatric population 
HIV-1:  In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years 
of age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an 
optimised background regimen (OBR) for 48 weeks.  Due to limitations of the study, a benefit of 
tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at 
week 24.  However, a benefit is expected for the adolescent population based on extrapolation of adult 
data and comparative pharmacokinetic data (see section 5.2). 
 
In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine 
BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, 
respectively, at baseline.  Mean changes at week 48 (end of double-blind phase) were -0.215 and 
-0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the 
tenofovir disoproxil and placebo groups, respectively.  The mean rate of BMD gain was less in the 
tenofovir disoproxil group compared to the placebo group.  At week 48, six adolescents in the 
tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD 
loss (defined as > 4% loss).  Among 28 patients receiving 96 weeks of treatment with tenofovir 
disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. 
 
In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, 
virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either 
replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original 
regimen (n = 49) for 48 weeks.  At week 48, 83% of patients in the tenofovir disoproxil treatment 
group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA 
concentrations < 400 copies/ml.  The difference in the proportion of patients who maintained 
< 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the 
tenofovir disoproxil treatment group.  When missing data were excluded, 91% of patients in the 
tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment 
group had HIV-1 RNA concentrations < 400 copies/ml at week 48. 
 
Reductions in BMD have been reported in paediatric patients.  In patients who received treatment with 
tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and 
-0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline.  Mean 
changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, 
and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or 
zidovudine groups, respectively.  The mean rate of lumbar spine bone gain at week 48 was similar 
between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group.  
Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine 
or zidovudine treatment group.  One tenofovir disoproxil treated subject and no stavudine or 



74 

zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48.  
BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who 
were treated with tenofovir disoproxil for 96 weeks.  BMD Z-scores were not adjusted for height and 
weight. 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
discontinued study drug due to renal adverse events.  Five subjects (5.6%) had laboratory findings 
clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil 
therapy (median tenofovir disoproxil exposure 331 weeks). 
 
Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients 
aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT 
(≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks.  Subjects must have been naïve 
to tenofovir disoproxil, but could have received interferon based regimens (> 6 months prior to 
screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotide 
therapy (> 16 weeks prior to screening).  At week 72, overall 88% (46/52) of patients in the tenofovir 
disoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA 
< 400 copies/ml.  Seventy-four percent (26/35) of patients in the tenofovir disoproxil group had 
normalised ALT at week 72 compared to 31% (13/42) in the placebo group.  Response to treatment 
with tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-
experienced (n = 32) patients, including lamivudine-resistant patients (n = 6).  Ninety-five percent of 
nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine-
resistant patients achieved HBV DNA < 400 copies/ml at week 72.  Thirty-one of the 32 nucleos(t)ide-
experienced patients had prior lamivudine experience.  At week 72, 96% (27/28) of immune-active 
patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil treatment 
group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml.  Seventy-five 
percent (21/28) of immune-active patients in the tenofovir disoproxil group had normal ALT at 
week 72 compared to 34% (11/32) in the placebo group. 
 
After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir 
disoproxil treatment up to week 192.  After week 72, virologic suppression was maintained for those 
receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (TDF-TDF 
group): 86.5% (45/52) of subjects in the TDF-TDF group had HBV DNA < 400 copies/ml at 
week 192.  Among the subjects who received placebo during the double-blind period, the proportion 
of subjects with HBV DNA < 400 copies/mL rose sharply after they began treatment with open-label 
TDF (PLB-TDF group): 74.1% (40/54) of subjects in the PLB-TDF group had HBV DNA 
< 400 copies/ml at week 192.  The proportion of subjects with ALT normalization at week 192 in the 
TDF-TDF group was 75.8% (25/33) among those who were HBeAg positive at baseline and 100.0% 
(2 of 2 subjects) among those who were HBeAg negative at baseline.  Similar percentages of subjects 
in the TDF-TDF and PLB-TDF groups (37.5% and 41.7%, respectively) experienced seroconversion 
to anti-HBe through week 192. 
 
Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 8: 
 
Table 8: Bone Mineral Density Evaluation at Baseline, Week 72 and 192 
 

 Baseline Week 72 Week 192 
TDF-TDF PLB-TDF TDF-TDF PLB-TDF TDF-TDF PLB-TDF 

Lumbar spine mean 
(SD) BMD Z-scorea 

−0.42  
(0.762) 

-0.26  
(0.806) 

-0.49  
(0.852)  

-0.23 
(0.893)  

-0.37 
(0.946)  

-0.44 
(0.920)  

Lumbar spine mean 
(SD) change from 
baseline 
BMD Z-scorea 

NA NA -0.06  
(0.320) 

0.10  
(0.378) 

0.02  
(0.548) 

-0.10 
(0.543) 

Whole body mean 
(SD) BMD Z-scorea 

−0.19  
(1.110) 

−0.23 
(0.859) 

−0.36 
 (1.077) 

−0.12 
(0.916) 

−0.38 
(0.934) 

−0.42 
 (0.942) 

Whole body mean NA NA −0.16 0.09 -0.16 -0.19  



75 

 Baseline Week 72 Week 192 
TDF-TDF PLB-TDF TDF-TDF PLB-TDF TDF-TDF PLB-TDF 

(SD) change from 
baseline 
BMD Z-scorea 

(0.355) (0.349) (0.521) (0.504) 

Lumbar spine BMD at 
least 6% decreaseb NA NA 1.9% 

(1 subject) 0% 3.8% 
(2 subjects) 

3.7% 
(2 subjects) 

Whole body BMD at 
least 6% decreaseb NA NA 0% 0% 0% 1.9% 

(1 subject) 
Lumbar spine BMD 
mean % increase NA NA 5.14% 8.08% 10.05% 11.21% 

Whole body BMD 
mean % increase NA NA 3.07% 5.39% 6.09% 7.22% 

NA = Not Applicable 
a BMD Z-scores not adjusted for height and weight 
b Primary safety endpoint through week 72 
 
In study GS-US-174-0144, 89 HBeAg-negative and -positive patients aged 2 to < 12 years with 
chronic hepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of 245 mg 
(n = 60) or placebo (n = 29) once daily for 48 weeks. Subjects must have been naïve to tenofovir 
disoproxil, with HBV DNA > 105 copies/mL (~ 4.2 log10 IU/mL) and ALT >1.5 × the upper limit of 
normal (ULN) at screening.  At Week 48, 77% (46 of 60) of patients in the tenofovir disoproxil 
treatment group and 7% (2 of 29) of patients in the placebo group had HBV DNA < 400 copies/mL 
(69 IU/mL). Sixty-six percent (38 of 58) of patients in the tenofovir disoproxil group had normalized 
ALT at week 48 compared with 15% (4 of 27) in the placebo group.  Twenty-five percent(14 of 56) of 
patients in the tenofovir disoproxil group and 24% (7 of 29) of patients in the placebo group  achieved 
HBeAg seroconversion at Week 48. 

Response to treatment with tenofovir disoproxil was comparable in treatment-naïve and treatment-
experienced subjects with 76% (38/50) of treatment-naïve and 80% (8/10) of treatment-experienced 
subjects achieving HBV DNA < 400 copies/mL (69 IU/ml) at Week 48. Response to treatment with 
tenofovir disoproxil was also similar in subjects who were HBeAg-negative compared with those who 
were HBeAg-positive at baseline with 77% (43/56) HBeAg-positive and 75.0% (3/4) HBeAg-negative 
subjects achieving HBV DNA < 400 copies/mL (69 IU/mL) at Week 48. The distribution of HBV 
genotypes at baseline was similar between the TDF and Placebo groups. The majority of subjects were 
either genotypes C (43.8%) or D (41.6%) with a lower and similar frequency of genotypes A and B 
(6.7% each). Only 1 subject randomized to the TDF group was genotype E at baseline. In general, 
treatment responses to tenofovir disoproxil were similar for genotypes A, B, C and E [75-100% of 
subjects achieved HBV DNA < 400 copies/mL (69 IU/mL) at Week 48] with a lower response rate in 
subjects with genotype D infection (55%). 
 
Bone Mineral Density (BMD) data from Study GS-US-174-0144 are summarized in Table 9: 
 
Table 9: Bone Mineral Density Evaluation at Baseline and Week 48 
 

 Baseline Week 48 
TDF PLB TDF PLB 

Lumbar spine mean 
(SD) BMD Z-scorea 

0.02  
(0.977) 

-0.29  
(1.229) 

-0.11 
(0.983) 

-0.11 
(1.234) 

Lumbar spine mean 
(SD) change from 
baseline BMD Z-scorea 

NA NA -0.12  
(0.411) 

0.14 
(0.330) 

Whole body mean (SD) 
BMD Z-scorea 

0.11 
(0.743) 

−0.05 
(1.497) 

-0.34 
(0.939) 

0.20 
(1.299) 

Whole body mean (SD) 
change from baseline 
BMD Z-scorea 

NA NA −0.18 
(0.334) 

0.22 
(0.446) 

Lumbar spine BMD at 
least 4% decreaseb NA NA 18.3% 

(11 subjects) 
6.9% 

(2 subjects) 



76 

 Baseline Week 48 
TDF PLB TDF PLB 

Whole body BMD at 
least 4% decrease NA NA 6.7% 

(4 subjects) 0% 

Lumbar spine BMD 
mean % increaseb NA NA 3.8% 7.6% 

Whole body BMD mean 
% increase NA NA 4.5% 8.9% 

NA = Not Applicable 
a BMD Z-scores only available for a limited set of subjects with matched reference data 
b Secondary endpoint through week 48 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Viread in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir 
and formaldehyde. 
 
Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, 
tenofovir diphosphate. 
 
Absorption 
Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is 
rapidly absorbed and converted to tenofovir.  Administration of multiple doses of tenofovir disoproxil 
with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 
326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively.  Maximum tenofovir 
concentrations are observed in serum within one hour of dosing in the fasted state and within two 
hours when taken with food.  The oral bioavailability of tenofovir from tenofovir disoproxil in fasted 
patients was approximately 25%.  Administration of tenofovir disoproxil with a high fat meal 
enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax 
by approximately 14%.  Following the first dose of tenofovir disoproxil in fed patients, the median 
Cmax in serum ranged from 213 to 375 ng/ml.  However, administration of tenofovir disoproxil with a 
light meal did not have a significant effect on the pharmacokinetics of tenofovir. 
 
Distribution 
Following intravenous administration the steady-state volume of distribution of tenofovir was 
estimated to be approximately 800 ml/kg.  After oral administration of tenofovir disoproxil, tenofovir 
is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the 
intestinal contents (preclinical studies).  In vitro protein binding of tenofovir to plasma or serum 
protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 
25 µg/ml. 
 
Biotransformation 
In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 
CYP450 enzymes.  Moreover, at concentrations substantially higher (approximately 300-fold) than 
those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major 
human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, 
CYP2E1, or CYP1A1/2).  Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any 
of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction 
in metabolism of CYP1A1/2 substrate was observed.  Based on these data, it is unlikely that clinically 
significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 
would occur. 
 



77 

Elimination 
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system 
with approximately 70-80% of the dose excreted unchanged in urine following intravenous 
administration.  Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 
300 ml/min).  Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 
210 ml/min), which is in excess of the glomerular filtration rate.  This indicates that active tubular 
secretion is an important part of the elimination of tenofovir.  Following oral administration the 
terminal half-life of tenofovir is approximately 12 to 18 hours. 
 
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal 
tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the 
multidrug resistant protein 4 (MRP 4). 
 
Linearity/non-linearity 
The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 
75 to 600 mg and were not affected by repeated dosing at any dose level. 
 
Gender 
Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. 
 
Ethnicity 
Pharmacokinetics have not been specifically studied in different ethnic groups. 
 
Paediatric population 
HIV-1:  Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent 
patients (aged 12 to < 18 years) with body weight ≥ 35 kg and in 23 HIV-1 infected children aged 
2 to < 12 years (see Table 10 below).  Tenofovir exposure achieved in these paediatric patients 
receiving oral daily doses of tenofovir disoproxil 245 mg or 6.5 mg/kg body weight tenofovir 
disoproxil up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving 
once-daily doses of tenofovir disoproxil 245 mg. 
 
Table 10: Mean (± SD) tenofovir pharmacokinetic parameters by age groups for paediatric 
patients 
 

Dose and formulation 245 mg film-coated tablet 
12 to < 18 years (n = 8) 

6.5 mg/kg granules 
2 to < 12 years (n = 23) 

Cmax (μg/ml) 0.38 ± 0.13 0.24 ± 0.13 
AUCtau (μg·h/ml) 3.39 ± 1.22 2.59 ± 1.06 

 
Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients 
(12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg  was similar to 
exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg . 
 
Tenofovir exposure in HBV infected paediatric patients 2 to <12 years of age receiving an oral daily 
dose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of 
245 mg  was similar to exposures achieved in HIV-1 infected paediatric patients 2 to <12 years of age 
receiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovir 
disoproxil 245 mg . 
 
Pharmacokinetic studies have not been performed in children under 2 years. 
 
Renal impairment 
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of 
tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of 
renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function 
when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and 
severe with CrCl = 10-29 ml/min).  Compared with patients with normal renal function, the mean 



78 

(%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to 
respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with 
mild, moderate and severe renal impairment. 
 
The pharmacokinetics of tenofovir in non-haemodialysis adult patients with creatinine clearance 
< 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not 
been studied. 
 
The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied.  
No data are available to make dose recommendations (see sections 4.2 and 4.4). 
 
Hepatic impairment 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult 
patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) 
classification.  Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic 
impairment suggesting that no dose adjustment is required in these subjects.  The mean (%CV) 
tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, 
in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with 
moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with 
severe hepatic impairment. 
 
Intracellular pharmacokinetics 
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir 
diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-
stimulated PBMCs was found to be approximately 10 hours. 
 
5.3 Preclinical safety data 
 
Non-clinical safety pharmacology studies reveal no special hazard for humans.  Findings in repeated 
dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical 
exposure levels and with possible relevance to clinical use include renal and bone toxicity and a 
decrease in serum phosphate concentration.  Bone toxicity was diagnosed as osteomalacia (monkeys) 
and reduced bone mineral density (BMD) (rats and dogs).  The bone toxicity in young adult rats and 
dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred 
in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the 
exposure in patients).  Findings in the rat and monkey studies indicated that there was a substance-
related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD. 
 
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results 
in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat 
hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay. 
 
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an 
extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 
 
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal 
parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in peri-
postnatal toxicity studies at maternally toxic doses. 
 
Environmental Risk Assessment (ERA) 
The active substance tenofovir disoproxil and its main transformation products are persistent in the 
environment. 
 
 



79 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate (E572) 
Microcrystalline cellulose (E460) 
Starch pregelatinised 
 
Film-coating 
Glycerol triacetate (E1518) 
Hypromellose (E464) 
Lactose monohydrate 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
30 film-coated tablets and a silica gel desiccant. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/006 
EU/1/01/200/007 
 
 



80 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 February 2002 
Date of latest renewal: 14 December 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



81 

1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 204 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 204 mg of tenofovir disoproxil (as fumarate). 
 
Excipient with known effect 
Each tablet contains 137 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
White, capsule-shaped, film-coated tablets, of dimensions 15.4 mm x 7.3 mm, debossed on one side 
with “GSI” and on the other side with “250”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
HIV-1 infection 
Viread 204 mg film-coated tablets are indicated in combination with other antiretroviral medicinal 
products for the treatment of HIV-1 infected paediatric patients, with NRTI resistance or toxicities 
precluding the use of first line agents, aged 6 to < 12 years who weigh from 28 kg to less than 35 kg. 
 
The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based 
on individual viral resistance testing and/or treatment history of patients. 
 
Hepatitis B infection 
Viread 204 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in paediatric 
patients aged 6 to < 12 years who weigh from 28 kg to less than 35 kg, with: 
 
• compensated liver disease and evidence of immune active disease, i.e. active viral replication 

and persistently elevated serum ALT levels or histological evidence of moderate to severe 
inflammation and/or fibrosis.  With respect to the decision to initiate treatment in paediatric 
patients, see sections 4.2, 4.4, 4.8 and 5.1. 

 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection and/or 
treatment of chronic hepatitis B. 
 
Posology 
 
HIV-1 and Chronic hepatitis B 
The recommended dose for the treatment of HIV-1 infection and chronic hepatitis B in paediatric 
patients aged 6 to < 12 years weighing 28 kg to < 35 kg who are able to swallow film-coated tablets is 
one 204 mg tablet once daily taken orally with food. 
 



82 

Please refer to the Summaries of Product Characteristics for Viread 123 mg and 163 mg film-coated 
tablets for the treatment of HIV-1 infection and chronic hepatitis B in paediatric patients aged 
6 to < 12 years weighing 17 kg to < 22 kg and 22 kg to < 28 kg, respectively. 
 
Viread is also available as 33 mg/g granules for use in the treatment of HIV-1 infection and chronic 
hepatitis B in paediatric patients aged 2 to < 12 years who weigh < 17 kg or who are unable to 
swallow film-coated tablets.  Please refer to the Summary of Product Characteristics for Viread 
33 mg/g granules. 
 
The decision to treat paediatric patients should be based on careful consideration of individual patient 
needs and with reference to current paediatric treatment guidelines including the value of baseline 
histological information.  The benefits of long-term virologic suppression with continued therapy must 
be weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis B 
virus and the uncertainties as regards the long term impact of bone and renal toxicity (see section 4.4). 
 
Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric 
patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 
months in patients with HBeAg negative disease. 
 
Duration of therapy in paediatric patients with chronic hepatitis B 
 
The optimal duration of treatment is unknown.  Treatment discontinuation may be considered as 
follows: 
 
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 

12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection 
on two consecutive serum samples at least 3-6 months apart) is confirmed or until 
HBs seroconversion or there is loss of efficacy (see section 4.4).  Serum ALT and HBV DNA 
levels should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 

 
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until 

HBs seroconversion or there is evidence of loss of efficacy.  Treatment discontinuation may 
also be considered after stable virological suppression is achieved (i.e. for at least 3 years) 
provided serum ALT and HBV DNA levels are followed regularly after treatment 
discontinuation to detect any late virological relapse.  With prolonged treatment for more than 
2 years, regular reassessment is recommended to confirm that continuing the selected therapy 
remains appropriate for the patient. 

 
Missed dose 
If a patient misses a dose of Viread within 12 hours of the time it is usually taken, the patient should 
take Viread with food as soon as possible and resume their normal dosing schedule.  If a patient 
misses a dose of Viread by more than 12 hours and it is almost time for their next dose, the patient 
should not take the missed dose and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Viread, another tablet should be taken.  If the patient 
vomits more than 1 hour after taking Viread they do not need to take another dose. 
 
Special populations 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.4). 
 
Hepatic impairment 
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). 
 



83 

If Viread 204 mg film-coated tablets are discontinued in patients co-infected with HIV and hepatitis B 
virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis 
(see section 4.4). 
 
Paediatric population 
The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with 
chronic hepatitis B under 2 years of age have not been established.  No data are available. 
 
Method of administration 
Viread 204 mg film-coated tablets should be taken once daily, orally with food. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
General 
HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir 
disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). 
 
HIV-1 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines. 
 
Hepatitis B 
Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of 
transmission of HBV to others through sexual contact or contamination with blood.  Appropriate 
precautions must continue to be used. 
 
Co-administration of other medicinal products 
- Viread should not be administered concomitantly with other medicinal products containing 

tenofovir disoproxil or tenofovir alafenamide. 
- Viread should not be administered concomitantly with adefovir dipivoxil. 
- Co-administration of tenofovir disoproxil and didanosine is not recommended (see Section 4.5).   
 
Triple therapy with nucleosides/nucleotides 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well 
as with lamivudine and didanosine as a once-daily regimen. 
 
Renal and bone effects in adult population 
Renal effects 
Tenofovir is principally eliminated via the kidney.  Renal failure, renal impairment, elevated 
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been 
reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). 
 
Renal impairment 
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with 
impaired renal function (creatinine clearance < 80 ml/min). 
 
Bone effects 
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain 
and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-
induced proximal renal tubulopathy (see section 4.8). 



84 

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD). In HIV infected 
patients, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in 
BMD of the hip and spine were observed in both treatment groups.  Decreases in BMD of spine and 
changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil 
treatment group at 144 weeks.  Decreases in BMD of hip were significantly greater in this group until 
96 weeks.  However, there was no increased risk of fractures or evidence for clinically relevant bone 
abnormalities over 144 weeks in this study. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 
inhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the 
limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, 
alternative treatment regimens should be considered for patients with osteoporosis that are at a high 
risk for fractures. 
 
If bone abnormalities are suspected or detected then appropriate consultation should be obtained. 
 
Renal and bone effects in paediatric population 
There are uncertainties associated with the long term effects of bone and renal toxicity.  Moreover, the 
reversibility of renal toxicity cannot be fully ascertained.  Therefore, a multidisciplinary approach is 
recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide 
the appropriate monitoring during treatment (including decision for treatment withdrawal) and 
consider the need for supplementation. 
 
Renal effects 
Renal adverse reactions consistent with proximal renal tubulopathy have been reported in 
HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see 
sections 4.8 and 5.1). 
 
Renal monitoring 
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all 
patients prior to initiating therapy with tenofovir disoproxil and that it is also monitored after two to 
four weeks of treatment, after three months of treatment and every three to six months thereafter in 
patients without renal risk factors.  In patients at risk for renal impairment, a more frequent monitoring 
of renal function is required. 
 
Renal management 
If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving 
tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements 
of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal 
tubulopathy).  If renal abnormalities are suspected or detected then consultation with a nephrologist 
should be obtained to consider interruption of tenofovir disoproxil treatment.  Interrupting treatment 
with tenofovir disoproxil should also be considered in case of progressive decline of renal function 
when no other cause has been identified. 
 
Co-administration and risk of renal toxicity 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, 
vancomycin, cidofovir or interleukin-2).  If concomitant use of tenofovir disoproxil and nephrotoxic 
agents is unavoidable, renal function should be monitored weekly. 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If tenofovir disoproxil is co-administered with an NSAID, renal function should 
be monitored adequately. 
 



85 

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in 
combination with a ritonavir or cobicistat boosted protease inhibitor.  A close monitoring of renal 
function is required in these patients (see section 4.5).  In patients with renal risk factors, the 
co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully 
evaluated. 
 
Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which 
are secreted by the same renal pathway, including the transport proteins human organic anion 
transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product).  These 
renal transport proteins may be responsible for tubular secretion and in part, renal elimination of 
tenofovir and cidofovir.  Consequently, the pharmacokinetics of these medicinal products, which are 
secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be 
modified if they are co-administered.  Unless clearly necessary, concomitant use of these medicinal 
products which are secreted by the same renal pathway is not recommended, but if such use is 
unavoidable, renal function should be monitored weekly (see section 4.5). 
 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.2).  Tenofovir disoproxil should not be initiated in paediatric patients with renal impairment 
and should be discontinued in paediatric patients who develop renal impairment during tenofovir 
disoproxil therapy. 
 
Bone effects 
Viread may cause a reduction in BMD.  The effects of tenofovir disoproxil-associated changes in 
BMD on long-term bone health and future fracture risk are uncertain (see section 5.1). 
 
If bone abnormalities are detected or suspected in paediatric patients, consultation with an 
endocrinologist and/or nephrologist should be obtained. 
 
 
Liver disease 
Tenofovir and tenofovir disoproxil are not metabolised by liver enzymes.  A pharmacokinetic study 
has been performed in non-HIV infected adult patients with various degrees of hepatic impairment.  
No significant pharmacokinetic alteration has been observed in these patients (see section 5.2). 
 
Exacerbations of hepatitis 
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 
characterised by transient increases in serum ALT.  After initiating antiviral therapy, serum ALT may 
increase in some patients (see section 4.8).  In patients with compensated liver disease, these increases 
in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 
hepatic decompensation.  Patients with cirrhosis may be at a higher risk for hepatic decompensation 
following hepatitis exacerbation, and therefore should be monitored closely during therapy. 
 
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in 
patients who have discontinued hepatitis B therapy.  Post-treatment exacerbations are usually 
associated with rising HBV DNA, and the majority appears to be self-limited.  However, severe 
exacerbations, including fatalities, have been reported.  Hepatic function should be monitored at 
repeated intervals with both clinical and laboratory follow-up for at least 6 months after 
discontinuation of hepatitis B therapy.  If appropriate, resumption of hepatitis B therapy may be 
warranted.  In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 
recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 
 
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease. 
 
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients 
co-infected with hepatitis C or D virus. 
 



86 

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir 
disoproxil should only be used as part of an appropriate antiretroviral combination regimen in 
HIV/HBV co-infected patients.  Patients with pre-existing liver dysfunction, including chronic active 
hepatitis, have an increased frequency of liver function abnormalities during combination 
antiretroviral therapy (CART) and should be monitored according to standard practice.  If there is 
evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must 
be considered.  However, it should be noted that increases of ALT can be part of HBV clearance 
during therapy with tenofovir, see above Exacerbations of hepatitis. 
 
Use with certain hepatitis C virus antiviral agents 
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, 
especially when used together with an HIV regimen containing tenofovir disoproxil and a 
pharmacokinetic enhancer (ritonavir or cobicistat).  The safety of tenofovir disoproxil in the setting of 
ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a 
pharmacokinetic enhancer has not been established.  The potential risks and benefits associated with 
co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV 
protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at 
increased risk of renal dysfunction.  Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV 
protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil. 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Mitochondrial dysfunction following exposure in utero 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such 
neurological disorders are transient or permanent is currently unknown.  These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of institution of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause 
serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed 
within the first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment. 
 



87 

Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
Excipients 
 
Viread 204 mg film-coated tablets contain lactose monohydrate.  Patients with rare hereditary 
problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should 
not take this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the 
potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low. 
 
Concomitant use not recommended 
Viread should not be administered concomitantly with other medicinal products containing tenofovir 
disoproxil or tenofovir alafenamide. 
 
Viread should not be administered concomitantly with adefovir dipivoxil. 
 
Didanosine 
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and 
Table 1). 
 
Renally eliminated medicinal products 
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with 
medicinal products that reduce renal function or compete for active tubular secretion via transport 
proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir 
and/or the co-administered medicinal products. 
 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product.  Some examples include, but are not limited to, aminoglycosides, amphotericin B, 
foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4). 
 
Given that tacrolimus can affect renal function, close monitoring is recommended when it is 
co-administered with tenofovir disoproxil. 
 
Other interactions 
Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily 
as “q.d.”). 
 



88 

Table 1: Interactions between tenofovir disoproxil and other medicinal products 
 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

ANTI-INFECTIVES 
Antiretrovirals 
Protease inhibitors 
Atazanavir/Ritonavir 
(300 q.d./100 q.d.) 

Atazanavir: 
AUC: ↓ 25% 
Cmax: ↓ 28% 
Cmin: ↓ 26% 
Tenofovir: 
AUC: ↑ 37% 
Cmax: ↑ 34% 
Cmin: ↑ 29% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-
associated adverse events, 
including renal disorders.  
Renal function should be 
closely monitored 
(see section 4.4). 

Lopinavir/Ritonavir 
(400 b.i.d./100 b.i.d.) 

Lopinavir/ritonavir: 
No significant effect on lopinavir/ritonavir 
PK parameters. 
Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-
associated adverse events, 
including renal disorders.  
Renal function should be 
closely monitored 
(see section 4.4). 

Darunavir/Ritonavir 
(300/100 b.i.d.) 

Darunavir: 
No significant effect on darunavir/ritonavir 
PK parameters. 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-
associated adverse events, 
including renal disorders.  
Renal function should be 
closely monitored 
(see section 4.4). 



89 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

NRTIs 
Didanosine Co-administration of tenofovir disoproxil 

and didanosine results in a 40-60% increase 
in systemic exposure to didanosine. 

Co-administration of 
tenofovir disoproxil and 
didanosine is not 
recommended 
(see section 4.4). 
 
Increased systemic exposure 
to didanosine may increase 
didanosine related adverse 
reactions.  Rarely, 
pancreatitis and lactic 
acidosis, sometimes fatal, 
have been reported.  
Co-administration of 
tenofovir disoproxil and 
didanosine at a dose of 
400 mg daily has been 
associated with a significant 
decrease in CD4 cell count, 
possibly due to an 
intracellular interaction 
increasing phosphorylated 
(i.e. active) didanosine.  A 
decreased dosage of 250 mg 
didanosine co-administered 
with tenofovir disoproxil 
therapy has been associated 
with reports of high rates of 
virological failure within 
several tested combinations 
for the treatment of 
HIV-1 infection. 

Adefovir dipivoxil AUC: ↔ 
Cmax: ↔ 

Tenofovir disoproxil should 
not be administered 
concurrently with adefovir 
dipivoxil (see section 4.4). 



90 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Hepatitis C virus antiviral agents 
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↑ 96% 
Cmax: ↑ 68% 
Cmin: ↑ 118% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 63% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 45% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 47% 
Cmin: ↑ 47% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
ledipasvir/sofosbuvir and 
atazanavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring, if 
other alternatives are not 
available (see section 4.4). 



91 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↓ 27% 
Cmax: ↓ 37% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 48% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 50% 
Cmax: ↑ 64% 
Cmin: ↑ 59% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
ledipasvir/sofosbuvir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring, if 
other alternatives are not 
available (see section 4.4). 



92 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovi
r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↓ 34% 
Cmax: ↓ 34% 
Cmin: ↓ 34% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 98% 
Cmax: ↑ 79% 
Cmin: ↑ 163% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofo
vir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↔ 
Cmin: ↑ 91% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



93 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Dolutegravir (50 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072 

AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Dolutegravir  
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Tenofovir: 
AUC: ↑ 65% 
Cmax: ↑ 61% 
Cmin: ↑ 115% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



94 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔  
Cmax: ↔  
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Velpatasvir: 
AUC: ↑ 142% 
Cmax: ↑ 55% 
Cmin: ↑ 301% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 39% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 29% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 55% 
Cmin: ↑ 39% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
atazanavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



95 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC:  ↓28% 
Cmax: ↓ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 24% 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 55% 
Cmin: ↑ 52% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



96 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Lopinavir/Ritonavir 
(800 mg/200 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↓ 29% 
Cmax: ↓ 41% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: ↑ 63% 
 
Lopinavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 42% 
Cmin: ↔ 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
lopinavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



97 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Raltegravir 
(400 mg b.i.d) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Raltegravir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 21% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 46% 
Cmin: ↑ 70% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/ 
Tenofovir disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↓ 53% 
Cmax: ↓ 47% 
Cmin: ↓ 57% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 81% 
Cmax: ↑ 77% 
Cmin: ↑ 121% 

Concomitant administration 
of sofosbuvir/velpatasvir and 
efavirenz is expected to 
decrease plasma 
concentrations of velpatasvir.  
Co-administration of 
sofosbuvir/velpatasvir with 
efavirenz-containing 
regimens is not 
recommended. 



98 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Emtricitabine/Rilpivirine/ 
Tenofovir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 44% 
Cmin: ↑ 84% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



99 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir/ 
Voxilaprevir (400 mg/100 mg/ 
100 mg+100 mg q.d.)3 + 
Darunavir (800 mg q.d.) + 
Ritonavir (100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: N/A 
 
GS-3310072: 
AUC: ↔ 
Cmax:↔ 
Cmin: N/A 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Voxilaprevir: 
AUC: ↑ 143% 
Cmax:↑ 72% 
Cmin: ↑ 300% 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 34% 
 
Ritonavir: 
AUC: ↑ 45% 
Cmax: ↑ 60% 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 48% 
Cmin: ↑ 47% 

Increased plasma 
concentrations of tenofovir 
resulting from co-
administration of tenofovir 
disoproxil, 
sofosbuvir/velpatasvir/voxila
previr and darunavir/ritonavir 
may increase adverse 
reactions related to tenofovir 
disoproxil, including renal 
disorders.  
The safety of tenofovir 
disoproxil when used with 
sofosbuvir/velpatasvir/voxila
previr and a pharmacokinetic 
enhancer (e.g. ritonavir or 
cobicistat) has not been 
established.  
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



100 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir 
(400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovi
r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 19% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↓ 23% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 25% 
Cmin: ↔ 

No dose adjustment is 
required. 

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir.  Staggered administration (12 hours apart) provided 
similar results. 
2 The predominant circulating metabolite of sofosbuvir. 
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 
 
Studies conducted with other medicinal products 
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was 
co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir 
boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive 
norgestimate/ethinyl oestradiol. 
 
Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir 
(see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no 
malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.  Animal studies do not 
indicate reproductive toxicity (see section 5.3).  The use of tenofovir disoproxil may be considered 
during pregnancy, if necessary. 
 
In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to 
reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, 
in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.  

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were 
administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 
months postpartum; women and their infants were followed for up to 12 months after delivery.  No 
safety signal has emerged from these data. 

Breastfeeding 
Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with 
hepatitis B may breast-feed her infant. 



101 

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is 
considered negligible. Although long-term data is limited, no adverse reactions have been reported in 
breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed. 
 
As a general rule, it is recommended that HIV infected mothers do not breastfeed their infants in order 
to avoid transmission of HIV to the infant. 
 
Fertility 
There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility.  Animal 
studies do not indicate harmful effects of tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
patients should be informed that dizziness has been reported during treatment with tenofovir 
disoproxil. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, 
renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) 
sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.  
Monitoring of renal function is recommended for patients receiving Viread (see section 4.4). 
 
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following 
treatment with tenofovir disoproxil in combination with other antiretroviral agents.  These reactions 
are usually mild to moderate gastrointestinal events.  Approximately 1% of tenofovir 
disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events. 
 
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions 
following treatment with tenofovir disoproxil, most of which are mild.  In clinical trials of 
HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was 
nausea (5.4%). 
 
Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who 
have discontinued hepatitis B therapy (see section 4.4). 
 
Tabulated summary of adverse reactions 
Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies 
and post-marketing experience.  All adverse reactions are presented in Table 2. 
 
HIV-1 clinical studies:  Assessment of adverse reactions from HIV-1 clinical study data is based on 
experience in two studies in 653 treatment-experienced adult patients receiving treatment with 
tenofovir disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal 
products for 24 weeks and also in a double-blind comparative controlled study in which 600 
treatment-naïve adult patients received treatment with tenofovir disoproxil 245 mg (n = 299) or 
stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks. 
 
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is 
primarily based on experience in two double-blind comparative controlled studies in which 641 adult 
patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir 
disoproxil 245 mg  daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.  The 
adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 
profile of tenofovir disoproxil.  After an initial decline of approximately -4.9 ml/min (using 
Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease 
[MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal 



102 

function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using 
Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation). 
 
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil in patients with 
decompensated liver disease was assessed in a double-blind active controlled study 
(GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n = 45) or 
emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks. 
 
In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse 
event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant 
differences between the combined tenofovir-containing arms and the entecavir arm.  After 168 weeks, 
16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil 
group, and 14% (3/22) of the entecavir group experienced tolerability failure.  Thirteen percent (6/45) 
of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 
9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl. 
 
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 
13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil 
group and 14% (3/22) in the entecavir group.  The rate of hepatocellular carcinoma was 18% (8/45) in 
the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% 
(2/22) in the entecavir group. 
 
Subjects with a high baseline CPT score were at higher risk of developing serious adverse events 
(see section 4.4). 
 
Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir 
disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 
lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or 
emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks. 
 
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by 
body system organ class and frequency.  Within each frequency grouping, undesirable effects are 
presented in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on 
clinical study and post-marketing experience 
 
Frequency Tenofovir disoproxil  
Metabolism and nutrition disorders: 
Very common: hypophosphataemia1 
Uncommon: hypokalaemia1 
Rare: lactic acidosis 

Nervous system disorders: 
Very common: dizziness 
Gastrointestinal disorders: 
Very common: diarrhoea, vomiting, nausea 
Common: flatulence 
Uncommon: pancreatitis 
Hepatobiliary disorders: 
Common: increased transaminases 
Rare: hepatic steatosis, hepatitis 



103 

Frequency Tenofovir disoproxil  
Skin and subcutaneous tissue disorders: 
Very common: rash 
Rare: angioedema 
Musculoskeletal and connective tissue disorders: 
Uncommon: rhabdomyolysis1, muscular weakness1 

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 

2, myopathy1 
Renal and urinary disorders: 
Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconi syndrome) 

Rare: acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute 
interstitial nephritis)2, nephrogenic diabetes insipidus 

General disorders and administration site conditions: 
Very common: asthenia 
1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 
associated with tenofovir disoproxil in the absence of this condition. 
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical 
trials or the tenofovir disoproxil expanded access program.  The frequency category was estimated from a statistical 
calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and 
the expanded access program (n = 7,319). 
 
Description of selected adverse reactions 
HIV-1 and hepatitis B: 
Renal impairment 
As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 
4.8 Summary of the safety profile).  Proximal renal tubulopathy generally resolved or improved after 
tenofovir disoproxil discontinuation.  However, in some patients, declines in creatinine clearance did 
not completely resolve despite tenofovir disoproxil discontinuation.  Patients at risk of renal 
impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients 
receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete 
recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4). 
 
Lactic acidosis 
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with 
other antiretrovirals.  Patients with predisposing factors such as patients with decompensated liver 
disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased 
risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal 
outcomes. 
 
HIV-1: 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune 
disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 
reported time to onset is more variable and these events can occur many months after initiation of 
treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART.  The frequency of this is unknown 
(see section 4.4). 
 



104 

Hepatitis B: 
Exacerbations of hepatitis during treatment 
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit 
of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients.  ALT 
elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a 
majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or 
coincided with the ALT elevation.  Periodic monitoring of hepatic function is recommended during 
treatment (see section 4.4). 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred 
after discontinuation of HBV therapy (see section 4.4). 
 
Paediatric population 
HIV-1: 
Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and 
GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received 
treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with 
other antiretroviral agents for 48 weeks (see section 5.1).  The adverse reactions observed in paediatric 
patients who received treatment with tenofovir disoproxil were consistent with those observed in 
clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse 
reactions and 5.1). 
 
Reductions in BMD have been reported in paediatric patients.  In HIV-1 infected adolescents, the 
BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed 
in subjects who received placebo.  In HIV-1 infected children, the BMD Z-scores observed in subjects 
who switched to tenofovir disoproxil were lower than those observed in subjects who remained on 
their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1). 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse 
events.  Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal 
tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy.  Seven patients had estimated 
glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2.  Among them, 3 patients 
experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of 
tenofovir disoproxil. 
 
Chronic hepatitis B 
Assessment of adverse reactions is based on one randomised study (Study GS-US-174-0115) in 
106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with 
tenofovir disoproxil 245 mg  (n = 52) or placebo (n = 54) for 72 weeks and another randomized study 
(study GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to  < 12 years of age) receiving 
treatment with tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks.  The adverse reactions 
observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with 
those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary 
of adverse reactions and 5.1). 
 
Reductions in BMD have been observed in HBV infected paediatric patients 2 to < 18 years of age.  
The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those 
observed in subjects who received placebo (see sections 4.4 and 5.1). 
 
Other special population(s) 
Patients with renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
sections 4.2 and 4.4). 
 



105 

Exacerbations of hepatitis after discontinuation of treatment 
In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have 
occurred after discontinuation of tenofovir disoproxil (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  
It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), 
and standard supportive treatment applied as necessary. 
 
Management 
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 
134 ml/min.  It is not known whether tenofovir can be removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC code: J05AF07 
 
Mechanism of action and pharmacodynamic effects 
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.  Tenofovir 
disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside 
monophosphate (nucleotide) analogue.  Tenofovir is then converted to the active metabolite, tenofovir 
diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes.  Tenofovir 
diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral 
blood mononuclear cells (PBMCs).  Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and 
the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate 
and, after incorporation into DNA, by DNA chain termination.  Tenofovir diphosphate is a weak 
inhibitor of cellular polymerases α, β, and γ.  At concentrations of up to 300 µmol/l, tenofovir has also 
shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro 
assays. 
 
Data pertaining to HIV 
HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the 
wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against 
primary HIV-1 subtype B isolates in PBMCs.  Tenofovir is also active against HIV-1 subtypes A, C, 
D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells.  Tenofovir shows 
activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells. 
 
Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse 
transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety).  
Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring 
the K65R mutation (see section 4.4).  In addition, a K70E substitution in HIV-1 reverse transcriptase 
has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. 
 
Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir 
disoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors.  The results 
indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations 

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106 

(TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced 
response to tenofovir disoproxil 245 mg therapy. 
 
Clinical efficacy and safety 
The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults 
have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively. 
 
In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir 
disoproxil 245 mg for 24 weeks.  The mean baseline CD4 cell count was 427 cells/mm3, the mean 
baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of 
< 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years.  Baseline genotypic 
analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance 
mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated 
with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase 
inhibitors. 
 
At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels 
(DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 
245 mg recipients (p < 0.0001).  A statistically significant difference in favour of tenofovir disoproxil 
245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 
count (+13 cells/mm3 for tenofovir disoproxil 245 mg versus -11 cells/mm3 for placebo, 
p-value = 0.0008).  The antiviral response to tenofovir disoproxil was durable through 48 weeks 
(DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 
50 copies/ml was 41% and 18% respectively).  Eight (2%) tenofovir disoproxil 245 mg treated patients 
developed the K65R mutation within the first 48 weeks. 
 
The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and 
safety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine and 
efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy.  The mean baseline CD4 cell 
count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of 
patients had symptomatic HIV-1 infection and 18% had AIDS.  Patients were stratified by baseline 
HIV-1 RNA and CD4 count.  Forty-three percent of patients had baseline viral loads 
> 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml. 
 
By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as 
failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 
48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm, 
compared to 84% and 80% in the stavudine arm.  At 144 weeks, the proportion of patients with 
HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir 
disoproxil 245 mg arm, compared to 64% and 63% in the stavudine arm. 
 
The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was 
similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the 
tenofovir disoproxil 245 mg and stavudine groups, respectively).  At 144 weeks of treatment, the 
average change from baseline remained similar in both treatment groups (-3.07 and 
-3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg and stavudine 
groups, respectively).  A consistent response to treatment with tenofovir disoproxil 245 mg was seen 
regardless of baseline HIV-1 RNA and CD4 count. 
 
The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil 
group than the active control group (2.7% versus 0.7%).  Efavirenz or lamivudine resistance either 
preceded or was coincident with the development of K65R in all cases.  Eight patients had HIV that 
expressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks 
of treatment and the last one at week 96.  No further K65R development was observed up to 
week 144.  One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus.  
From both the genotypic and phenotypic analyses there was no evidence for other pathways of 
resistance to tenofovir. 



107 

 
Data pertaining to HBV 
HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessed in 
the HepG2 2.2.15 cell line.  The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l, with 
CC50 (50% cytotoxicity concentration) values > 100 µmol/l. 
 
Resistance: No HBV mutations associated with tenofovir disoproxil resistance have been identified 
(see Clinical efficacy and safety).  In cell based assays, HBV strains expressing the rtV173L, 
rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a 
susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus.  HBV strains 
expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with 
resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-
type virus.  HBV strains expressing the adefovir-associated resistance mutations rtA181V and 
rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.  
Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold 
that of wild-type virus. 
 
Clinical efficacy and safety 
The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is 
based on virological, biochemical and serological responses in adults with HBeAg positive and 
HBeAg negative chronic hepatitis B.  Treated patients included those who were treatment-naïve, 
lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir 
dipivoxil resistance mutations at baseline.  Benefit has also been demonstrated based on histological 
responses in compensated patients. 
 
Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and 
GS-US-174-0103) 
Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir 
disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in 
Table 3 below.  Study GS-US-174-0103 was conducted in 266 (randomised and treated) 
HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) 
patients negative for HBeAg and positive for HBeAb. 
 
In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the 
primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis).  Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater 
proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg 
treatment.  Both treatments produced similar results with regard to histological response (defined as 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis) at week 48 (see Table 3 below). 
 
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil 
group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 
(see Table 3 below). 
 



108 

Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at 
week 48 
 
 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg 
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg 

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 

Complete 
response (%)a 

71* 49 67* 12 

Histology     
Histological response 
(%)b 

72 
 

69 74 68 

Median HBV DNA 
reduction from 
baselinec 
(log10 copies/ml) 

-4.7* -4.0 -6.4* -3.7 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

 
93* 

 
63 

 
76* 

 
13 

ALT (%) 
Normalised ALTd 

 
76 

 
77 

 
68* 

 
54 

Serology (%) 
HBeAg 
loss/seroconversion 

 
n/a 

 
n/a 

 
22/21 

 
18/18 

HBsAg 
loss/seroconversion 

0/0 0/0 3*/1 0/0 

* p-value versus adefovir dipivoxil < 0.05. 
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at 
least 2 points without worsening in Knodell fibrosis. 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 
c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of 
detection (LOD) of the assay. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
n/a = not applicable. 
 
Tenofovir disoproxil was associated with significantly greater proportions of patients with 
undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas 
Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and 
study GS-US-174-0103; 69%, 9%), respectively. 
 
Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) 
and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT 
(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined.  
Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine.  
Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved 
complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients 
achieved HBV DNA suppression < 400 copies/ml.  All patients with normal ALT at baseline and 88% 
of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. 
 
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 
In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 
48 weeks (either tenofovir disoproxil 245 mg  or adefovir dipivoxil 10 mg), patients rolled over with 
no interruption in treatment to open-label tenofovir disoproxil.  In studies GS-US-174-0102 and 
GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively.  
At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses 
were maintained with continued tenofovir disoproxil treatment (see Tables 4 and 5 below). 
 



109 

Table 4: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 

Week 96b 144e 192g 240i 288l 384o 96c 144f 192h 240j 288m 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

90 87 84 83 80 74 89 88 87 84 84 76 

ALT (%) 
Normalised 
ALTd 

72 73 67 70 68 64 68 70 77 76 74 69 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

HBsAg loss/ 
seroconversion 

0/0 0/0 0/0 0/0 0/0 1/1n 0/0 0/0 0/0 0/0k 1/1n 1/1n 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at 
the time of the data cut-off.  However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit. 
l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF). 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
n/a = not applicable. 
 
Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0103 (HBeAg positive) 
Parametera Tenofovir disoproxil 245 mg  

n = 176 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 90 

Week 96b 144e 192h 240j 288m 384o 96c 144f 192i 240k 288n 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

76 72 68 64 61 56 74 71 72 66 65 61 

ALT (%) 
Normalised 
ALTd 

60 55 56 46 47 47 65 61 59 56 57 56 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
26/ 
23 

 
29/ 
23 

 
34/ 
25 

 
38/ 
30 

 
37/ 
25 

 
30/ 
20 

 
24/ 
20 

 
33/ 
26 

 
36/ 
30 

 
38/ 
31 

 
40/ 
31 

 
35/ 
24 

HBsAg loss/ 
seroconversion 

5/ 
4 

8/ 
6g 

11/ 
8g 

11/ 
8l 

12/ 
8l 

15/ 
12l 

6/ 
5 

8/ 
7g 

8/ 
7g 

10/ 
10l 

11/ 
10l 

13/ 
11l 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 



110 

e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT). 
h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF). 
m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
 
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in 
studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below).  Ninety-five percent 
(225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at 
baseline had either no change or an improvement in fibrosis (Ishak fibrosis score).  Of the 94 patients 
with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak 
fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak 
fibrosis score of at least 2 points. 
 
Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects 
at week 240 compared to baseline 
 
 Study 174-0102 

(HBeAg negative) 
Study 174-0103 

(HBeAg positive) 
Tenofovir disoproxil 

245 mg  
n = 250c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 125d 

Tenofovir disoproxil 
245 mg  
n = 176c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 90d 

Histological 
responsea,b (%)  

88 
[130/148] 

85 
[63/74] 

90 
[63/70] 

92 
[36/39] 

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) 
by week 240.  Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).  
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. 
c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label. 
d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil. 
 
Experience in patients with HIV co-infection and prior lamivudine experience 
In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg  in adult 
patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study 
ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir 
arm were 9.45 log10 copies/ml (n = 27).  Treatment with tenofovir disoproxil 245 mg  was associated 
with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week 
data, of -5.74 log10 copies/ml (n = 18).  In addition, 61% of patients had normal ALT at week 48. 
 
Experience in patients with persistent viral replication (study GS-US-174-0106) 
The efficacy and safety of tenofovir disoproxil 245 mg  or tenofovir disoproxil 245 mg  plus 200 mg 
emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in 
HBeAg positive and HBeAg negative adult patients who had persistent viraemia 
(HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks.  At 
baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to 
emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine.  
Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with 
HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine 
plus tenofovir disoproxil (p = 0.672).  In addition 55% (29/53) of patients treated with tenofovir 
disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of 
the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus 
tenofovir disoproxil (p = 0.504).  Comparisons between treatment groups beyond week 24 are difficult 



111 

to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus 
tenofovir disoproxil.  Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine 
plus tenofovir disoproxil in HBV monoinfected patients are ongoing. 
 
Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) 
Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety 
and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and 
entecavir (n = 22), in patients with decompensated liver disease.  In the tenofovir disoproxil treatment 
arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum 
ALT of 61 U/l at baseline.  Forty-two percent (19/45) of patients had at least 6 months of prior 
lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 
45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline.  The 
co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in 
serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. 
 
In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of 
emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 
48 weeks of treatment. 
 
Overall, the data derived from this study are too limited to draw any definitive conclusions on the 
comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 7 below). 
 
Table 7: Safety and efficacy parameters in decompensated patients at week 48 
 
 Study 174-0108 
Parameter Tenofovir disoproxil 

245 mg  
(n = 45) 

Emtricitabine 200 mg/ 
tenofovir disoproxil 

245 mg  
(n = 45) 

Entecavir 
(0.5 mg or 1 mg) 

n = 22 

Tolerability failure 
(permanent 
discontinuation of study 
drug due to a treatment 
emergent AE) 
n (%)a 

3 (7%) 2 (4%) 2 (9%) 

Confirmed increase in 
serum creatinine 
≥ 0.5 mg/dl from 
baseline or confirmed 
serum phosphate of 
< 2 mg/dl 
n (%)b 

4 (9%) 3 (7%) 1 (5%) 

HBV DNA n (%) 
< 400 copies/ml 
n (%) 

31/44 (70%) 36/41 (88%) 16/22 (73%) 

ALT n (%) 
Normal ALT 

25/44 (57%) 31/41 (76%) 12/22 (55%) 

≥ 2 point decrease in 
CPT from baseline 
n (%) 

7/27 (26%) 12/25 (48%) 5/12 (42%) 

Mean change from 
baseline in CPT score 

-0.8 -0.9 -1.3 

Mean change from 
baseline in MELD score 

-1.8 -2.3 -2.6 

a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622, 
b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000. 
 



112 

Experience beyond 48 weeks in study GS-US-174-0108 
Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir 
disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) 
of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. 
 
Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121) 
The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind 
study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with 
compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of 
lamivudine resistance (rtM204I/V +/- rtL180M).  Only five had adefovir-associated resistance 
mutations at baseline.  One hundred forty-one and 139 adult subjects were randomised to a tenofovir 
disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively.  Baseline 
demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were 
HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and 
mean ALT was 79 U/l, respectively. 
 
After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had 
HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation.  After 240 weeks of 
treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had 
HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation.  Among the 
HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced 
HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240.  In 
the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects 
(19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion 
through week 240.  Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by 
Week 240, but not seroconversion to anti-HBs.  Five subjects randomised to emtricitabine plus 
tenofovir disoproxil experienced HBsAg loss, with 2 of these 5 subjects experiencing seroconversion 
to anti-HBs. 
 
Clinical resistance 
Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive 
(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil 
treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic 
changes in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 
(n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive 
(GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment 
and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes 
in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 
(n = 1) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil 
resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks.  Genotypic data 
from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA 
> 400 copies/ml at week 48.  No amino acid substitutions associated with resistance to tenofovir 
disoproxil were identified in these isolates.  Genotypic analysis was conducted for 5 subjects in the 
tenofovir disoproxil arm post week 48.  No amino acid substitutions associated with tenofovir 
disoproxil resistance were detected in any subject. 
 
In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received 
tenofovir disoproxil for up to 240 weeks.  Cumulatively, there were 4 patients who experienced a 
viremic episode (HBV DNA>400 copies/ml) at their last timepoint on TDF.  Among them, sequence 



113 

data from paired baseline and on treatment HBV isolates were available for 2 of 4 patients.  No amino 
acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. 
 
In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance 
mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 
51/52 patients switched to open-label tenofovir disoproxil (TDF-TDF group).  Genotypic evaluations 
were performed on all patients within this group with HBV DNA > 400 copies/ml at week 48 (n = 6), 
week 72 (n = 5), week 96 (n = 4), week 144 (n = 2), and week 192 (n = 3).  Fifty-four patients 
(including 2 patients with lamivudine resistance mutations at baseline) initially received blinded 
placebo treatment for 72 weeks, and 52/54 patients followed with tenofovir disoproxil (PLB-TDF 
group).  Genotypic evaluations were performed on all patients within this group with HBV DNA 
> 400 copies/ml at week 96 (n = 17), week 144 (n = 7), and week 192 (n = 8).  No amino acid 
substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. 
 
In a paediatric study (GS-US-174-0144), genotypic data from paired baseline and on treatment HBV 
isolates from patients who received tenofovir disoproxil were available for 9 of 10 patients who had 
plasma HBV DNA > 400 copies/ml. No amino acid substitutions associated with resistance to 
tenofovir disoproxil were identified in these isolates by week 48. 
 
Paediatric population 
HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years 
of age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an 
optimised background regimen (OBR) for 48 weeks.  Due to limitations of the study, a benefit of 
tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at 
week 24.  However, a benefit is expected for the adolescent population based on extrapolation of adult 
data and comparative pharmacokinetic data (see section 5.2). 
 
In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine 
BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, 
respectively, at baseline.  Mean changes at week 48 (end of double-blind phase) were -0.215 and 
-0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the 
tenofovir disoproxil and placebo groups, respectively.  The mean rate of BMD gain was less in the 
tenofovir disoproxil group compared to the placebo group.  At week 48, six adolescents in the 
tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD 
loss (defined as > 4% loss).  Among 28 patients receiving 96 weeks of treatment with tenofovir 
disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. 
 
In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, 
virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either 
replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original 
regimen (n = 49) for 48 weeks.  At week 48, 83% of patients in the tenofovir disoproxil treatment 
group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA 
concentrations < 400 copies/ml.  The difference in the proportion of patients who maintained 
< 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the 
tenofovir disoproxil treatment group.  When missing data were excluded, 91% of patients in the 
tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment 
group had HIV-1 RNA concentrations < 400 copies/ml at week 48. 
 
Reductions in BMD have been reported in paediatric patients.  In patients who received treatment with 
tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and 
-0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline.  Mean 
changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, 
and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or 
zidovudine groups, respectively.  The mean rate of lumbar spine bone gain at week 48 was similar 
between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group.  
Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine 
or zidovudine treatment group.  One tenofovir disoproxil treated subject and no stavudine or 



114 

zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48.  
BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who 
were treated with tenofovir disoproxil for 96 weeks.  BMD Z-scores were not adjusted for height and 
weight. 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
discontinued study drug due to renal adverse events.  Five subjects (5.6%) had laboratory findings 
clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil 
therapy (median tenofovir disoproxil exposure 331 weeks). 
 
Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients 
aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT 
(≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks.  Subjects must have been naïve 
to tenofovir disoproxil, but could have received interferon based regimens (> 6 months prior to 
screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotide 
therapy (> 16 weeks prior to screening).  At week 72, overall 88% (46/52) of patients in the tenofovir 
disoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA 
< 400 copies/ml.  Seventy-four percent (26/35) of patients in the tenofovir disoproxil group had 
normalised ALT at week 72 compared to 31% (13/42) in the placebo group.  Response to treatment 
with tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-
experienced (n = 32) patients, including lamivudine-resistant patients (n = 6).  Ninety-five percent of 
nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine-
resistant patients achieved HBV DNA < 400 copies/ml at week 72.  Thirty-one of the 32 nucleos(t)ide-
experienced patients had prior lamivudine experience.  At week 72, 96% (27/28) of immune-active 
patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil treatment 
group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml.  Seventy-five 
percent (21/28) of immune-active patients in the tenofovir disoproxil group had normal ALT at 
week 72 compared to 34% (11/32) in the placebo group. 
 
After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir 
disoproxil treatment up to week 192.  After week 72, virologic suppression was maintained for those 
receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (TDF-TDF 
group): 86.5% (45/52) of subjects in the TDF-TDF group had HBV DNA < 400 copies/ml at 
week 192.  Among the subjects who received placebo during the double-blind period, the proportion 
of subjects with HBV DNA < 400 copies/mL rose sharply after they began treatment with open-label 
TDF (PLB-TDF group): 74.1% (40/54) of subjects in the PLB-TDF group had HBV DNA 
< 400 copies/ml at week 192.  The proportion of subjects with ALT normalization at week 192 in the 
TDF-TDF group was 75.8% (25/33) among those who were HBeAg positive at baseline and 100.0% 
(2 of 2 subjects) among those who were HBeAg negative at baseline.  Similar percentages of subjects 
in the TDF-TDF and PLB-TDF groups (37.5% and 41.7%, respectively) experienced seroconversion 
to anti-HBe through week 192. 
 
Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 8: 
 
Table 8: Bone Mineral Density Evaluation at Baseline, Week 72 and 192 
 

 Baseline Week 72 Week 192 
TDF-TDF PLB-TDF TDF-TDF PLB-TDF TDF-TDF PLB-TDF 

Lumbar spine mean 
(SD) BMD Z-scorea 

−0.42  
(0.762) 

-0.26  
(0.806) 

-0.49  
(0.852)  

-0.23 
(0.893)  

-0.37 
(0.946)  

-0.44 
(0.920)  

Lumbar spine mean 
(SD) change from 
baseline 
BMD Z-scorea 

NA NA -0.06  
(0.320) 

0.10  
(0.378) 

0.02  
(0.548) 

-0.10 
(0.543) 

Whole body mean 
(SD) BMD Z-scorea 

−0.19  
(1.110) 

−0.23 
(0.859) 

−0.36 
 (1.077) 

−0.12 
(0.916) 

−0.38 
(0.934) 

−0.42 
 (0.942) 

Whole body mean NA NA −0.16 0.09 -0.16 -0.19  



115 

 Baseline Week 72 Week 192 
TDF-TDF PLB-TDF TDF-TDF PLB-TDF TDF-TDF PLB-TDF 

(SD) change from 
baseline 
BMD Z-scorea 

(0.355) (0.349) (0.521) (0.504) 

Lumbar spine BMD at 
least 6% decreaseb NA NA 1.9% 

(1 subject) 0% 3.8% 
(2 subjects) 

3.7% 
(2 subjects) 

Whole body BMD at 
least 6% decreaseb NA NA 0% 0% 0% 1.9% 

(1 subject) 
Lumbar spine BMD 
mean % increase NA NA 5.14% 8.08% 10.05% 11.21% 

Whole body BMD 
mean % increase NA NA 3.07% 5.39% 6.09% 7.22% 

NA = Not Applicable 
a BMD Z-scores not adjusted for height and weight 
b Primary safety endpoint through week 72 
 
In study GS-US-174-0144, 89 HBeAg-negative and -positive patients aged 2 to < 12 years with 
chronic hepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of 245 mg 
(n = 60) or placebo (n = 29) once daily for 48 weeks. Subjects must have been naïve to tenofovir 
disoproxil, with HBV DNA > 105 copies/mL (~ 4.2 log10 IU/mL) and ALT >1.5 × the upper limit of 
normal (ULN) at screening.  At Week 48, 77% (46 of 60) of patients in the tenofovir disoproxil 
treatment group and 7% (2 of 29) of patients in the placebo group had HBV DNA < 400 copies/mL 
(69 IU/mL). Sixty-six percent (38 of 58) of patients in the tenofovir disoproxil group had normalized 
ALT at week 48 compared with 15% (4 of 27) in the placebo group. Twenty-five percent (14 of 56) of 
patients in the tenofovir disoproxil group and 24% (7 of 29) of patients in the placebo group achieved 
HBeAg seroconversion at Week 48. 

Response to treatment with tenofovir disoproxil was comparable in treatment-naïve and treatment-
experienced subjects with 76% (38/50) of treatment-naïve and 80% (8/10) of treatment-experienced 
subjects achieving HBV DNA < 400 copies/mL (69 IU/ml) at Week 48. Response to treatment with 
tenofovir disoproxil was also similar in subjects who were HBeAg-negative compared with those who 
were HBeAg-positive at baseline with 77% (43/56) HBeAg-positive and 75.0% (3/4) HBeAg-negative 
subjects achieving HBV DNA < 400 copies/mL (69 IU/mL) at Week 48. The distribution of HBV 
genotypes at baseline was similar between the TDF and Placebo groups. The majority of subjects were 
either genotypes C (43.8%) or D (41.6%) with a lower and similar frequency of genotypes A and B 
(6.7% each). Only 1 subject randomized to the TDF group was genotype E at baseline. In general, 
treatment responses to tenofovir disoproxil were similar for genotypes A, B, C and E [75-100% of 
subjects achieved HBV DNA < 400 copies/mL (69 IU/mL) at Week 48] with a lower response rate in 
subjects with genotype D infection (55%). 

Bone Mineral Density (BMD) data from Study GS-US-174-0144 are summarized in Table 9: 
 
Table 9: Bone Mineral Density Evaluation at Baseline and Week 48 
 

 Baseline Week 48 
TDF PLB TDF PLB 

Lumbar spine mean 
(SD) BMD Z-scorea 

0.02  
(0.977) 

-0.29  
(1.229) 

-0.11 
(0.983) 

-0.11 
(1.234) 

Lumbar spine mean 
(SD) change from 
baseline BMD Z-scorea 

NA NA -0.12  
(0.411) 

0.14 
(0.330) 

Whole body mean (SD) 
BMD Z-scorea 

0.11 
(0.743) 

−0.05 
(1.497) 

-0.34 
(0.939) 

0.20 
(1.299) 

Whole body mean (SD) 
change from baseline 
BMD Z-scorea 

NA NA −0.18 
(0.334) 

0.22 
(0.446) 

Lumbar spine BMD at 
least 4% decreaseb NA NA 18.3% 

(11 subjects) 
6.9% 

(2 subjects) 



116 

 Baseline Week 48 
TDF PLB TDF PLB 

Whole body BMD at 
least 4% decrease NA NA 6.7% 

(4 subjects) 0% 

Lumbar spine BMD 
mean % increaseb NA NA 3.8% 7.6% 

Whole body BMD mean 
% increase NA NA 4.5% 8.9% 

NA = Not Applicable 
a BMD Z-scores only available for a limited set of subjects with matched reference data 
b Secondary endpoint through week 48 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Viread in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir 
and formaldehyde. 
 
Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, 
tenofovir diphosphate. 
 
Absorption 
Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is 
rapidly absorbed and converted to tenofovir.  Administration of multiple doses of tenofovir disoproxil 
with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 
326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively.  Maximum tenofovir 
concentrations are observed in serum within one hour of dosing in the fasted state and within two 
hours when taken with food.  The oral bioavailability of tenofovir from tenofovir disoproxil in fasted 
patients was approximately 25%.  Administration of tenofovir disoproxil with a high fat meal 
enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax 
by approximately 14%.  Following the first dose of tenofovir disoproxil in fed patients, the median 
Cmax in serum ranged from 213 to 375 ng/ml.  However, administration of tenofovir disoproxil with a 
light meal did not have a significant effect on the pharmacokinetics of tenofovir. 
 
Distribution 
Following intravenous administration the steady-state volume of distribution of tenofovir was 
estimated to be approximately 800 ml/kg.  After oral administration of tenofovir disoproxil, tenofovir 
is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the 
intestinal contents (preclinical studies).  In vitro protein binding of tenofovir to plasma or serum 
protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 
25 µg/ml. 
 
Biotransformation 
In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 
CYP450 enzymes.  Moreover, at concentrations substantially higher (approximately 300-fold) than 
those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major 
human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, 
CYP2E1, or CYP1A1/2).  Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any 
of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction 
in metabolism of CYP1A1/2 substrate was observed.  Based on these data, it is unlikely that clinically 
significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 
would occur. 
 



117 

Elimination 
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system 
with approximately 70-80% of the dose excreted unchanged in urine following intravenous 
administration.  Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 
300 ml/min).  Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 
210 ml/min), which is in excess of the glomerular filtration rate.  This indicates that active tubular 
secretion is an important part of the elimination of tenofovir.  Following oral administration the 
terminal half-life of tenofovir is approximately 12 to 18 hours. 
 
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal 
tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the 
multidrug resistant protein 4 (MRP 4). 
 
Linearity/non-linearity 
The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 
75 to 600 mg and were not affected by repeated dosing at any dose level. 
 
Gender 
Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. 
 
Ethnicity 
Pharmacokinetics have not been specifically studied in different ethnic groups. 
 
Paediatric population 
HIV-1:  Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent 
patients (aged 12 to < 18 years) with body weight ≥ 35 kg and in 23 HIV-1 infected children aged 
2 to < 12 years (see Table 10 below).  Tenofovir exposure achieved in these paediatric patients 
receiving oral daily doses of tenofovir disoproxil 245 mg or 6.5 mg/kg body weight tenofovir 
disoproxil up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving 
once-daily doses of tenofovir disoproxil 245 mg. 
 
Table 10: Mean (± SD) tenofovir pharmacokinetic parameters by age groups for paediatric 
patients 
 

Dose and formulation 245 mg film-coated tablet 
12 to < 18 years (n = 8) 

6.5 mg/kg granules 
2 to < 12 years (n = 23) 

Cmax (μg/ml) 0.38 ± 0.13 0.24 ± 0.13 
AUCtau (μg·h/ml) 3.39 ± 1.22 2.59 ± 1.06 

 
Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients 
(12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg was similar to 
exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg . 
 
Tenofovir exposure in HBV infected paediatric patients 2 to <12 years of age receiving an oral daily 
dose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of 
245 mg was similar to exposures achieved in HIV-1 infected paediatric patients 2 to <12 years of age 
receiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovir 
disoproxil 245 mg. 
 
Pharmacokinetic studies have not been performed in children under 2 years. 
 
Renal impairment 
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of 
tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of 
renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function 
when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and 
severe with CrCl = 10-29 ml/min).  Compared with patients with normal renal function, the mean 



118 

(%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to 
respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with 
mild, moderate and severe renal impairment. 
 
The pharmacokinetics of tenofovir in non-haemodialysis adult patients with creatinine clearance 
< 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not 
been studied. 
 
The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied.  
No data are available to make dose recommendations (see sections 4.2 and 4.4). 
 
Hepatic impairment 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult 
patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) 
classification.  Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic 
impairment suggesting that no dose adjustment is required in these subjects.  The mean (%CV) 
tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, 
in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with 
moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with 
severe hepatic impairment. 
 
Intracellular pharmacokinetics 
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir 
diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-
stimulated PBMCs was found to be approximately 10 hours. 
 
5.3 Preclinical safety data 
 
Non-clinical safety pharmacology studies reveal no special hazard for humans.  Findings in repeated 
dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical 
exposure levels and with possible relevance to clinical use include renal and bone toxicity and a 
decrease in serum phosphate concentration.  Bone toxicity was diagnosed as osteomalacia (monkeys) 
and reduced bone mineral density (BMD) (rats and dogs).  The bone toxicity in young adult rats and 
dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred 
in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the 
exposure in patients).  Findings in the rat and monkey studies indicated that there was a substance-
related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD. 
 
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results 
in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat 
hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay. 
 
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an 
extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 
 
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal 
parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in peri-
postnatal toxicity studies at maternally toxic doses. 
 
Environmental Risk Assessment (ERA) 
The active substance tenofovir disoproxil and its main transformation products are persistent in the 
environment. 
 
 



119 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate (E572) 
Microcrystalline cellulose (E460) 
Starch pregelatinised 
 
Film-coating 
Glycerol triacetate (E1518) 
Hypromellose (E464) 
Lactose monohydrate 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
30 film-coated tablets and a silica gel desiccant. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/008 
EU/1/01/200/009 
 
 



120 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 February 2002 
Date of latest renewal: 14 December 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



121 

1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 245 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 245 mg of tenofovir disoproxil (as fumarate). 
 
Excipient with known effect 
Each tablet contains 164 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Light blue, almond-shaped, film-coated tablets, of dimensions 16.8 mm x 10.3 mm, debossed on one 
side with “GILEAD” and “4331” and on the other side with “300”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
HIV-1 infection 
Viread 245 mg film-coated tablets are indicated in combination with other antiretroviral medicinal 
products for the treatment of HIV-1 infected adults. 
 
In adults, the demonstration of the benefit of Viread in HIV-1 infection is based on results of one 
study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and 
studies in which Viread was added to stable background therapy (mainly tritherapy) in antiretroviral 
pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of 
patients having < 5,000 copies/ml). 
 
Viread 245 mg film-coated tablets are also indicated for the treatment of HIV-1 infected adolescents, 
with NRTI resistance or toxicities precluding the use of first line agents, aged 12 to < 18 years. 
 
The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based 
on individual viral resistance testing and/or treatment history of patients. 
 
Hepatitis B infection 
Viread 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in adults with: 
 
• compensated liver disease, with evidence of active viral replication, persistently elevated serum 

alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or 
fibrosis (see section 5.1). 

 
• evidence of lamivudine-resistant hepatitis B virus (see sections 4.8 and 5.1). 
 
• decompensated liver disease (see sections 4.4, 4.8 and 5.1). 
 
Viread 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in adolescents 
12 to < 18 years of age with: 
 



122 

• compensated liver disease and evidence of immune active disease, i.e. active viral replication 
and persistently elevated serum ALT levels, or histological evidence of moderate to severe 
inflammation and/or fibrosis.  With respect to the decision to initiate treatment in paediatric 
patients, see sections 4.2, 4.4, 4.8 and 5.1. 

 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection and/or 
treatment of chronic hepatitis B. 
 
Posology 
 
HIV-1 and Chronic hepatitis B 
Adults and adolescents aged 12 to < 18 years and weighing ≥ 35 kg: 
The recommended dose of Viread for the treatment of HIV or for the treatment of chronic hepatitis B 
is 245 mg (one tablet) once daily taken orally with food. 
 
Viread is also available as 33 mg/g granules for the treatment of HIV-1 infection and 
chronic hepatitis B in adults or adolescents for whom a solid dosage form is not appropriate. 
 
The decision to treat paediatric patients (adolescents) should be based on careful consideration of 
individual patient needs and with reference to current paediatric treatment guidelines including the 
value of baseline histological information.  The benefits of long-term virologic suppression with 
continued therapy must be weighed against the risk of prolonged treatment, including the emergence 
of resistant hepatitis B virus and the uncertainties as regards the long term impact of bone and renal 
toxicity (see section 4.4). 
 
Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric 
patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 
months in patients with HBeAg negative disease. 
 
Duration of therapy in adult and adolescent patients with chronic hepatitis B 
 
The optimal duration of treatment is unknown.  Treatment discontinuation may be considered as 
follows: 
 
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 

12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection 
on two consecutive serum samples at least 3-6 months apart) is confirmed or until 
HBs seroconversion or there is loss of efficacy (see section 4.4).  Serum ALT and HBV DNA 
levels should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 

 
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until 

HBs seroconversion or there is evidence of loss of efficacy.  Treatment discontinuation may 
also be considered after stable virological suppression is achieved (i.e. for at least 3 years) 
provided serum ALT and HBV DNA levels are followed regularly after treatment 
discontinuation to detect any late virological relapse.  With prolonged treatment for more than 
2 years, regular reassessment is recommended to confirm that continuing the selected therapy 
remains appropriate for the patient. 

 
In adult patients with decompensated liver disease or cirrhosis, treatment cessation is not 
recommended. 
 
Paediatric population 
Viread is also available as granules for the treatment of HIV-1 infection and chronic hepatitis B in 
paediatric patients aged 2 to < 12 years and as reduced tablet strengths for the treatment of 



123 

HIV-1 infection and chronic hepatitis B in paediatric patients aged 6 to < 12 years (see section 5.1).  
Please refer to the Summaries of Product Characteristics for Viread 33 mg/g granules and Viread 
123 mg, 163 mg and 204 mg film-coated tablets. 
 
The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with 
chronic hepatitis B under 2 years of age have not been established.  No data are available. 
 
Missed dose 
If a patient misses a dose of Viread within 12 hours of the time it is usually taken, the patient should 
take Viread with food as soon as possible and resume their normal dosing schedule.  If a patient 
misses a dose of Viread by more than 12 hours and it is almost time for their next dose, the patient 
should not take the missed dose and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Viread, another tablet should be taken.  If the patient 
vomits more than 1 hour after taking Viread they do not need to take another dose. 
 
Special populations 
Elderly 
No data are available on which to make a dose recommendation for patients over the age of 65 years 
(see section 4.4). 
 
Renal impairment 
Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with 
renal dysfunction. 
 
Adults 
There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients with 
moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data 
has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min).  Therefore, in 
adult patients with renal impairment tenofovir disoproxil should only be used if the potential benefits 
of treatment are considered to outweigh the potential risks.  Administration of Viread 33 mg/g 
granules to provide a reduced daily dose of tenofovir disoproxil is recommended for adult patients 
with creatinine clearance < 50 ml/min, including haemodialysis patients.  Please refer to the Summary 
of Product Characteristics for Viread 33 mg/g granules. 
 
Mild renal impairment (creatinine clearance 50-80 ml/min) 
Limited data from clinical studies support once daily dosing of 245 mg tenofovir disoproxil in patients 
with mild renal impairment. 
 
Moderate renal impairment (creatinine clearance 30-49 ml/min) 
For patients unable to take the granule formulation of tenofovir disoproxil, prolonged dose intervals 
using the 245 mg film-coated tablets may be used.  Administration of 245 mg tenofovir disoproxil 
every 48 hours can be used based on modelling of single-dose pharmacokinetic data in HIV negative 
and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal 
disease requiring haemodialysis, but has not been confirmed in clinical studies.  Therefore, clinical 
response to treatment and renal function should be closely monitored in these patients (see sections 4.4 
and 5.2). 
 
Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients 
For patients unable to take the granule formulation of tenofovir disoproxil and with no alternative 
treatment available, prolonged dose intervals using the 245 mg film-coated tablets may be used as 
follows: 
 
Severe renal impairment: 245 mg tenofovir disoproxil may be administered every 72-96 hours (dosing 
twice a week). 
 



124 

Haemodialysis patients: 245 mg tenofovir disoproxil may be administered every 7 days following 
completion of a haemodialysis session*. 
 
These dose interval adjustments have not been confirmed in clinical studies.  Simulations suggest that 
the prolonged dose interval using Viread 245 mg film-coated tablets is not optimal and could result in 
increased toxicity and possibly inadequate response.  Therefore, clinical response to treatment and 
renal function should be closely monitored (see sections 4.4 and 5.2). 
 
* Generally, once weekly dosing assuming three haemodialysis sessions per week, each of 
approximately 4 hours duration or after 12 hours cumulative haemodialysis. 
 
No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance 
< 10 ml/min. 
 
Paediatrics 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.4). 
 
Hepatic impairment 
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). 
 
If Viread is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these 
patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4). 
 
Method of administration 
Viread tablets should be taken once daily, orally with food. 
 
A granules formulation of tenofovir disoproxil is available for patients having difficulty in swallowing 
film-coated tablets.  However, in exceptional circumstances Viread 245 mg film-coated tablets can be 
administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape 
juice. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
General 
HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir 
disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). 
 
HIV-1 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines. 
 
Hepatitis B 
Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of 
transmission of HBV to others through sexual contact or contamination with blood.  Appropriate 
precautions must continue to be used. 
 
Co-administration of other medicinal products 
- Viread should not be administered concomitantly with other medicinal products containing 

tenofovir disoproxil or tenofovir alafenamide. 
- Viread should not be administered concomitantly with adefovir dipivoxil. 
- Co-administration of tenofovir disoproxil and didanosine is not recommended (see Section 4.5).   



125 

 
Triple therapy with nucleosides/nucleotides 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well 
as with lamivudine and didanosine as a once-daily regimen. 
 
Renal and bone effects in adult population 
Renal effects 
Tenofovir is principally eliminated via the kidney.  Renal failure, renal impairment, elevated 
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been 
reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). 
 
Renal monitoring 
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with 
tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored 
after two to four weeks of treatment, after three months of treatment and every three to six months 
thereafter in patients without renal risk factors.  In patients at risk for renal impairment, a more 
frequent monitoring of renal function is required. 
 
Renal management 
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in 
any adult patient receiving tenofovir disoproxil, renal function should be re-evaluated within one 
week, including measurements of blood glucose, blood potassium and urine glucose concentrations 
(see section 4.8, proximal tubulopathy).  Consideration should also be given to interrupting treatment 
with tenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or 
decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).  Interrupting treatment with tenofovir 
disoproxil should also be considered in case of progressive decline of renal function when no other 
cause has been identified. 
 
Co-administration and risk of renal toxicity 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, 
vancomycin, cidofovir or interleukin-2).  If concomitant use of tenofovir disoproxil and nephrotoxic 
agents is unavoidable, renal function should be monitored weekly. 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If tenofovir disoproxil is co-administered with an NSAID, renal function should 
be monitored adequately. 
 
A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in 
combination with a ritonavir or cobicistat boosted protease inhibitor.  A close monitoring of renal 
function is required in these patients (see section 4.5).  In patients with renal risk factors, the 
co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully 
evaluated. 
 
Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which 
are secreted by the same renal pathway, including the transport proteins human organic anion 
transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product).  These 
renal transport proteins may be responsible for tubular secretion and in part, renal elimination of 
tenofovir and cidofovir.  Consequently, the pharmacokinetics of these medicinal products, which are 
secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be 
modified if they are co-administered.  Unless clearly necessary, concomitant use of these medicinal 
products which are secreted by the same renal pathway is not recommended, but if such use is 
unavoidable, renal function should be monitored weekly (see section 4.5). 
 



126 

Renal impairment 
Renal safety with tenofovir disoproxil has only been studied to a very limited degree in adult patients 
with impaired renal function (creatinine clearance < 80 ml/min). 
 
Adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients: 
There are limited data on the safety and efficacy of tenofovir disoproxil in patients with impaired renal 
function.  Therefore, tenofovir disoproxil should only be used if the potential benefits of treatment are 
considered to outweigh the potential risks.  In patients with severe renal impairment (creatinine 
clearance < 30 ml/min) and in patients who require haemodialysis use of tenofovir disoproxil is not 
recommended.  If no alternative treatment is available, the dosing interval must be adjusted and renal 
function should be closely monitored (see sections 4.2 and 5.2). 
 
Bone effects 
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain 
and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-
induced proximal renal tubulopathy (see section 4.8). 
 
Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).  In HIV infected 
patients, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in 
BMD of the hip and spine were observed in both treatment groups.  Decreases in BMD of spine and 
changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil 
treatment group at 144 weeks.  Decreases in BMD of hip were significantly greater in this group until 
96 weeks.  However, there was no increased risk of fractures or evidence for clinically relevant bone 
abnormalities over 144 weeks in this study. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 
inhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the 
limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, 
alternative treatment regimens should be considered for patients with osteoporosis that are at a high 
risk for fractures. 
 
If bone abnormalities are suspected or detected then appropriate consultation should be obtained. 
 
Renal and bone effects in paediatric population 
There are uncertainties associated with the long term effects of bone and renal toxicity.  Moreover, the 
reversibility of renal toxicity cannot be fully ascertained.  Therefore, a multidisciplinary approach is 
recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide 
the appropriate monitoring during treatment (including decision for treatment withdrawal) and 
consider the need for supplementation. 
 
Renal effects 
Renal adverse reactions consistent with proximal renal tubulopathy have been reported in 
HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see 
sections 4.8 and 5.1). 
 
Renal monitoring 
Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, and 
monitored during treatment as in adults (see above). 
 
Renal management 
If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving 
tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements 
of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal 
tubulopathy).  If renal abnormalities are suspected or detected then consultation with a nephrologist 
should be obtained to consider interruption of tenofovir disoproxil treatment.  Interrupting treatment 



127 

with tenofovir disoproxil should also be considered in case of progressive decline of renal function 
when no other cause has been identified. 
 
Co-administration and risk of renal toxicity 
The same recommendations apply as in adults (see above). 
 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.2).  Tenofovir disoproxil should not be initiated in paediatric patients with renal impairment 
and should be discontinued in paediatric patients who develop renal impairment during tenofovir 
disoproxil therapy. 
 
Bone effects 
Viread may cause a reduction in BMD.  The effects of tenofovir disoproxil-associated changes in 
BMD on long-term bone health and future fracture risk are uncertain (see section 5.1). 
 
If bone abnormalities are detected or suspected in paediatric patients, consultation with an 
endocrinologist and/or nephrologist should be obtained. 
 
Liver disease 
Safety and efficacy data are very limited in liver transplant patients. 
 
There are limited data on the safety and efficacy of tenofovir disoproxil in HBV infected patients with 
decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9.  These patients 
may be at higher risk of experiencing serious hepatic or renal adverse reactions.  Therefore, 
hepatobiliary and renal parameters should be closely monitored in this patient population. 
 
Exacerbations of hepatitis 
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 
characterised by transient increases in serum ALT.  After initiating antiviral therapy, serum ALT may 
increase in some patients (see section 4.8).  In patients with compensated liver disease, these increases 
in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 
hepatic decompensation.  Patients with cirrhosis may be at a higher risk for hepatic decompensation 
following hepatitis exacerbation, and therefore should be monitored closely during therapy. 
 
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in 
patients who have discontinued hepatitis B therapy.  Post-treatment exacerbations are usually 
associated with rising HBV DNA, and the majority appears to be self-limited.  However, severe 
exacerbations, including fatalities, have been reported.  Hepatic function should be monitored at 
repeated intervals with both clinical and laboratory follow-up for at least 6 months after 
discontinuation of hepatitis B therapy.  If appropriate, resumption of hepatitis B therapy may be 
warranted.  In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 
recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 
 
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease. 
 
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients 
co-infected with hepatitis C or D virus. 
 
Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir 
disoproxil should only be used as part of an appropriate antiretroviral combination regimen in 
HIV/HBV co-infected patients.  Patients with pre-existing liver dysfunction, including chronic active 
hepatitis, have an increased frequency of liver function abnormalities during combination 
antiretroviral therapy (CART) and should be monitored according to standard practice.  If there is 
evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must 
be considered.  However, it should be noted that increases of ALT can be part of HBV clearance 
during therapy with tenofovir, see above Exacerbations of hepatitis. 



128 

 
Use with certain hepatitis C virus antiviral agents 
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, 
especially when used together with an HIV regimen containing tenofovir disoproxil and a 
pharmacokinetic enhancer (ritonavir or cobicistat).  The safety of tenofovir disoproxil in the setting of 
ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a 
pharmacokinetic enhancer has not been established.  The potential risks and benefits associated with 
co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV 
protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at 
increased risk of renal dysfunction.  Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV 
protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil. 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Mitochondrial dysfunction following exposure in utero 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such 
neurological disorders are transient or permanent is currently unknown.  These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of institution of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause 
serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed 
within the first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment. 
 
Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 



129 

Elderly 
Tenofovir disoproxil has not been studied in patients over the age of 65.  Elderly patients are more 
likely to have decreased renal function; therefore caution should be exercised when treating elderly 
patients with tenofovir disoproxil. 
 
Excipients 
 
Viread 245 mg film-coated tablets contain lactose monohydrate.  Patients with rare hereditary 
problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should 
not take this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the 
potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low. 
 
Concomitant use not recommended 
Viread should not be administered concomitantly with other medicinal products containing tenofovir 
disoproxil or tenofovir alafenamide. 
 
Viread should not be administered concomitantly with adefovir dipivoxil. 
 
Didanosine 
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and 
Table 1). 
 
Renally eliminated medicinal products 
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with 
medicinal products that reduce renal function or compete for active tubular secretion via transport 
proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir 
and/or the co-administered medicinal products. 
 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product.  Some examples include, but are not limited to, aminoglycosides, amphotericin B, 
foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4). 
 
Given that tacrolimus can affect renal function, close monitoring is recommended when it is 
co-administered with tenofovir disoproxil. 
 
Other interactions 
Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily 
as “q.d.”). 
 



130 

Table 1: Interactions between tenofovir disoproxil and other medicinal products 
 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

ANTI-INFECTIVES 
Antiretrovirals 
Protease inhibitors 
Atazanavir/Ritonavir 
(300 q.d./100 q.d.) 

Atazanavir: 
AUC: ↓ 25% 
Cmax: ↓ 28% 
Cmin: ↓ 26% 
Tenofovir: 
AUC: ↑ 37% 
Cmax: ↑ 34% 
Cmin: ↑ 29% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate 
tenofovir-associated adverse 
events, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Lopinavir/Ritonavir 
(400 b.i.d./100 b.i.d.) 

Lopinavir/ritonavir: 
No significant effect on lopinavir/ritonavir 
PK parameters. 
Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate 
tenofovir-associated adverse 
events, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Darunavir/Ritonavir 
(300/100 b.i.d.) 

Darunavir: 
No significant effect on darunavir/ritonavir 
PK parameters. 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate 
tenofovir-associated adverse 
events, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



131 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

NRTIs 
Didanosine Co-administration of tenofovir disoproxil 

and didanosine results in a 40-60% increase 
in systemic exposure to didanosine. 

Co-administration of 
tenofovir disoproxil and 
didanosine is not 
recommended 
(see section 4.4). 
 
Increased systemic exposure 
to didanosine may increase 
didanosine related adverse 
reactions.  Rarely, 
pancreatitis and lactic 
acidosis, sometimes fatal, 
have been reported.  
Co-administration of 
tenofovir disoproxil and 
didanosine at a dose of 
400 mg daily has been 
associated with a significant 
decrease in CD4 cell count, 
possibly due to an 
intracellular interaction 
increasing phosphorylated 
(i.e. active) didanosine.  A 
decreased dosage of 250 mg 
didanosine co-administered 
with tenofovir disoproxil 
therapy has been associated 
with reports of high rates of 
virological failure within 
several tested combinations 
for the treatment of 
HIV-1 infection. 

Adefovir dipivoxil AUC: ↔ 
Cmax: ↔ 

Tenofovir disoproxil should 
not be administered 
concurrently with adefovir 
dipivoxil (see section 4.4). 



132 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Entecavir AUC: ↔ 
Cmax: ↔ 

No clinically significant 
pharmacokinetic interactions 
when tenofovir disoproxil 
was co-administered with 
entecavir. 

Hepatitis C virus antiviral agents 
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil  
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↑ 96% 
Cmax: ↑ 68% 
Cmin: ↑ 118% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 63% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 45% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 47% 
Cmin: ↑ 47% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
ledipasvir/sofosbuvir and 
atazanavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring, if 
other alternatives are not 
available (see section 4.4). 



133 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↓ 27% 
Cmax: ↓ 37% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 48% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 50% 
Cmax: ↑ 64% 
Cmin: ↑ 59% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
ledipasvir/sofosbuvir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring, if 
other alternatives are not 
available (see section 4.4). 



134 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovi
r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↓ 34% 
Cmax: ↓ 34% 
Cmin: ↓ 34% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 98% 
Cmax: ↑ 79% 
Cmin: ↑ 163% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofo
vir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↔ 
Cmin: ↑ 91% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



135 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Dolutegravir (50 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072 

AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Dolutegravir  
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Tenofovir: 
AUC: ↑ 65% 
Cmax: ↑ 61% 
Cmin: ↑ 115% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



136 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔  
Cmax: ↔  
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Velpatasvir: 
AUC: ↑ 142% 
Cmax: ↑ 55% 
Cmin: ↑ 301% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 39% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 29% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 55% 
Cmin: ↑ 39% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
atazanavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 
 



137 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC:  ↓28% 
Cmax: ↓ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 24% 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 55% 
Cmin: ↑ 52% 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



138 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Lopinavir/Ritonavir 
(800 mg/200 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↓ 29% 
Cmax: ↓ 41% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: ↑ 63% 
 
Lopinavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 42% 
Cmin: ↔ 

Increased plasma 
concentrations of tenofovir 
resulting from 
co-administration of 
tenofovir disoproxil, 
sofosbuvir/velpatasvir and 
lopinavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders.  The safety of 
tenofovir disoproxil when 
used with 
sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) 
has not been established. 
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 



139 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Raltegravir 
(400 mg b.i.d) + 
Emtricitabine/Tenofovir 
disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Raltegravir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 21% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 46% 
Cmin: ↑ 70% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/ 
Tenofovir disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↓ 53% 
Cmax: ↓ 47% 
Cmin: ↓ 57% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 81% 
Cmax: ↑ 77% 
Cmin: ↑ 121% 

Concomitant administration 
of sofosbuvir/velpatasvir and 
efavirenz is expected to 
decrease plasma 
concentrations of velpatasvir.  
Co-administration of 
sofosbuvir/velpatasvir with 
efavirenz-containing 
regimens is not 
recommended. 



140 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Emtricitabine/Rilpivirine/ 
Tenofovir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 44% 
Cmin: ↑ 84% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function 
should be closely monitored 
(see section 4.4). 



141 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir/Velpatasvir/ 
Voxilaprevir (400 mg/100 mg/ 
100 mg+100 mg q.d.)3 + 
Darunavir (800 mg q.d.) + 
Ritonavir (100 mg q.d.) + 
Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: N/A 
 
GS-3310072: 
AUC: ↔ 
Cmax:↔ 
Cmin: N/A 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Voxilaprevir: 
AUC: ↑ 143% 
Cmax:↑ 72% 
Cmin: ↑ 300% 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 34% 
 
Ritonavir: 
AUC: ↑ 45% 
Cmax: ↑ 60% 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 48% 
Cmin: ↑ 47% 

Increased plasma 
concentrations of tenofovir 
resulting from co-
administration of tenofovir 
disoproxil, 
sofosbuvir/velpatasvir/voxila
previr and darunavir/ritonavir 
may increase adverse 
reactions related to tenofovir 
disoproxil, including renal 
disorders.  
The safety of tenofovir 
disoproxil when used with 
sofosbuvir/velpatasvir/voxila
previr and a pharmacokinetic 
enhancer (e.g. ritonavir or 
cobicistat) has not been 
established.  
 
The combination should be 
used with caution with 
frequent renal monitoring 
(see section 4.4). 
 



142 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, Cmax, Cmin 

Recommendation 
concerning 

co-administration with 
245 mg tenofovir disoproxil  

Sofosbuvir 
(400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovi
r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 19% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↓ 23% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 25% 
Cmin: ↔ 

No dose adjustment is 
required. 

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir.  Staggered administration (12 hours apart) provided 
similar results. 
2 The predominant circulating metabolite of sofosbuvir. 
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 
 
Studies conducted with other medicinal products 
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was 
co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir 
boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive 
norgestimate/ethinyl oestradiol. 
 
Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir 
(see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no 
malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.  Animal studies do not 
indicate reproductive toxicity (see section 5.3).  The use of tenofovir disoproxil may be considered 
during pregnancy, if necessary. 
 
In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to 
reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, 
in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.  

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were 
administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 
months postpartum; women and their infants were followed for up to 12 months after delivery.  No 
safety signal has emerged from these data. 

Breastfeeding 
Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with 
hepatitis B may breast-feed her infant. 



143 

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is 
considered negligible. Although long-term data is limited, no adverse reactions have been reported in 
breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed. 
 
As a general rule, it is recommended that HIV infected mothers do not breastfeed their infants in order 
to avoid transmission of HIV to the infant. 
 
Fertility 
There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility.  Animal 
studies do not indicate harmful effects of tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
patients should be informed that dizziness has been reported during treatment with tenofovir 
disoproxil. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, 
renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) 
sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.  
Monitoring of renal function is recommended for patients receiving Viread (see section 4.4). 
 
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following 
treatment with tenofovir disoproxil in combination with other antiretroviral agents.  These reactions 
are usually mild to moderate gastrointestinal events.  Approximately 1% of tenofovir 
disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events. 
 
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions 
following treatment with tenofovir disoproxil, most of which are mild.  In clinical trials of 
HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was 
nausea (5.4%). 
 
Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who 
have discontinued hepatitis B therapy (see section 4.4). 
 
Tabulated summary of adverse reactions 
Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies 
and post-marketing experience.  All adverse reactions are presented in Table 2. 
 
HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on 
experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir 
disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products 
for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve 
patients received treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) in 
combination with lamivudine and efavirenz for 144 weeks. 
 
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is 
primarily based on experience in two double-blind comparative controlled studies in which 641 adult 
patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir 
disoproxil 245 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.  The 
adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 
profile of tenofovir disoproxil.  After an initial decline of approximately -4.9 ml/min (using 
Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease 
[MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal 



144 

function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using 
Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation). 
 
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil in patients with 
decompensated liver disease was assessed in a double-blind active controlled study 
(GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n = 45) or 
emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks. 
 
In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse 
event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant 
differences between the combined tenofovir-containing arms and the entecavir arm.  After 168 weeks, 
16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil 
group, and 14% (3/22) of the entecavir group experienced tolerability failure.  Thirteen percent (6/45) 
of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 
9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl. 
 
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 
13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil 
group and 14% (3/22) in the entecavir group.  The rate of hepatocellular carcinoma was 18% (8/45) in 
the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% 
(2/22) in the entecavir group. 
 
Subjects with a high baseline CPT score were at higher risk of developing serious adverse events 
(see section 4.4). 
 
Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir 
disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 
lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or 
emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks. 
 
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by 
body system organ class and frequency.  Within each frequency grouping, undesirable effects are 
presented in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on 
clinical study and post-marketing experience 
 
Frequency Tenofovir disoproxil  
Metabolism and nutrition disorders: 
Very common: hypophosphataemia1 
Uncommon: hypokalaemia1 
Rare: lactic acidosis 

Nervous system disorders: 
Very common: Dizziness 
Common: Headache 
Gastrointestinal disorders: 
Very common: diarrhoea, vomiting, nausea 
Common: abdominal pain, abdominal distension, flatulence 
Uncommon: Pancreatitis 
Hepatobiliary disorders: 
Common: increased transaminases 
Rare: hepatic steatosis, hepatitis 



145 

Frequency Tenofovir disoproxil  
Skin and subcutaneous tissue disorders: 
Very common: Rash 
Rare: Angioedema 
Musculoskeletal and connective tissue disorders: 
Uncommon: rhabdomyolysis1, muscular weakness1 

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 

2, myopathy1 
Renal and urinary disorders: 
Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconi syndrome) 

Rare: acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute 
interstitial nephritis)2, nephrogenic diabetes insipidus 

General disorders and administration site conditions: 
Very common: Asthenia 
Common: Fatigue 
1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 
associated with tenofovir disoproxil in the absence of this condition. 
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical 
trials or the tenofovir disoproxil expanded access program.  The frequency category was estimated from a statistical 
calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and 
the expanded access program (n = 7,319). 
 
Description of selected adverse reactions 
HIV-1 and hepatitis B: 
Renal impairment 
As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 
4.8 Summary of the safety profile).  Proximal renal tubulopathy generally resolved or improved after 
tenofovir disoproxil discontinuation.  However, in some patients, declines in creatinine clearance did 
not completely resolve despite tenofovir disoproxil discontinuation.  Patients at risk of renal 
impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients 
receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete 
recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4). 
 
Lactic acidosis 
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with 
other antiretrovirals.  Patients with predisposing factors such as patients with decompensated liver 
disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased 
risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal 
outcomes. 
 
HIV-1: 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune 
disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 
reported time to onset is more variable and these events can occur many months after initiation of 
treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART.  The frequency of this is unknown 
(see section 4.4). 
 



146 

Hepatitis B: 
Exacerbations of hepatitis during treatment 
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit 
of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients.  ALT 
elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a 
majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or 
coincided with the ALT elevation.  Periodic monitoring of hepatic function is recommended during 
treatment (see section 4.4). 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred 
after discontinuation of HBV therapy (see section 4.4). 
 
Paediatric population 
HIV-1 
Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and 
GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received 
treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with 
other antiretroviral agents for 48 weeks (see section 5.1).  The adverse reactions observed in paediatric 
patients who received treatment with tenofovir disoproxil were consistent with those observed in 
clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse 
reactions and 5.1). 
 
Reductions in BMD have been reported in paediatric patients.  In HIV-1 infected adolescents, the 
BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed 
in subjects who received placebo.  In HIV-1 infected children, the BMD Z-scores observed in subjects 
who switched to tenofovir disoproxil were lower than those observed in subjects who remained on 
their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1). 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse 
events.  Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal 
tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy.  Seven patients had estimated 
glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2.  Among them, 3 patients 
experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of 
tenofovir disoproxil. 
 
Chronic hepatitis B 
Assessment of adverse reactions is based on a randomised study (study GS-US-174-0115) in 
106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks and a randomised study (Study 
GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to  < 12 years of age) receiving treatment 
with tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks.  The adverse reactions observed in 
paediatric patients who received treatment with tenofovir disoproxil were consistent with those 
observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of 
adverse reactions and 5.1). 
 
Reductions in BMD have been observed in HBV infected paediatric patients 2 to < 18 years of age.  
The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those 
observed in subjects who received placebo (see sections 4.4 and 5.1). 
 
Other special population(s) 
Elderly 
Tenofovir disoproxil has not been studied in patients over the age of 65.  Elderly patients are more 
likely to have decreased renal function, therefore caution should be exercised when treating elderly 
patients with tenofovir disoproxil (see section 4.4). 
 



147 

Patients with renal impairment 
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended 
in adult patients with renal impairment treated with Viread (see sections 4.2, 4.4 and 5.2).  The use of 
tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see sections 4.2 
and 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  
It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), 
and standard supportive treatment applied as necessary. 
 
Management 
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 
134 ml/min.  It is not known whether tenofovir can be removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC code: J05AF07 
 
Mechanism of action and pharmacodynamic effects 
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.  Tenofovir 
disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside 
monophosphate (nucleotide) analogue.  Tenofovir is then converted to the active metabolite, tenofovir 
diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes.  Tenofovir 
diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral 
blood mononuclear cells (PBMCs).  Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and 
the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate 
and, after incorporation into DNA, by DNA chain termination.  Tenofovir diphosphate is a weak 
inhibitor of cellular polymerases α, β, and γ.  At concentrations of up to 300 µmol/l, tenofovir has also 
shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro 
assays. 
 
Data pertaining to HIV 
HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the 
wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against 
primary HIV-1 subtype B isolates in PBMCs.  Tenofovir is also active against HIV-1 subtypes A, C, 
D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells.  Tenofovir shows 
activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells. 
 
Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse 
transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety).  
Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring 
the K65R mutation (see section 4.4).  In addition, a K70E substitution in HIV-1 reverse transcriptase 
has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. 
 

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148 

Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir 
disoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors.  The results 
indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations 
(TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced 
response to tenofovir disoproxil 245 mg therapy. 
 
Clinical efficacy and safety 
The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults 
have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively. 
 
In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir 
disoproxil 245 mg for 24 weeks.  The mean baseline CD4 cell count was 427 cells/mm3, the mean 
baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of 
< 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years.  Baseline genotypic 
analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance 
mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated 
with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase 
inhibitors. 
 
At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels 
(DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 
245 mg recipients (p < 0.0001).  A statistically significant difference in favour of tenofovir disoproxil 
245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 
count (+13 cells/mm3 for tenofovir disoproxil 245 mg versus -11 cells/mm3 for placebo, 
p-value = 0.0008).  The antiviral response to tenofovir disoproxil was durable through 48 weeks 
(DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 
50 copies/ml was 41% and 18% respectively).  Eight (2%) tenofovir disoproxil 245 mg treated patients 
developed the K65R mutation within the first 48 weeks. 
 
The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and 
safety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine and 
efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy.  The mean baseline CD4 cell 
count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of 
patients had symptomatic HIV-1 infection and 18% had AIDS.  Patients were stratified by baseline 
HIV-1 RNA and CD4 count.  Forty-three percent of patients had baseline viral loads 
> 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml. 
 
By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as 
failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 
48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm, 
compared to 84% and 80% in the stavudine arm.  At 144 weeks, the proportion of patients with 
HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir 
disoproxil 245 mg arm, compared to 64% and 63% in the stavudine arm. 
 
The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was 
similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the 
tenofovir disoproxil 245 mg and stavudine groups, respectively).  At 144 weeks of treatment, the 
average change from baseline remained similar in both treatment groups (-3.07 and 
-3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg and stavudine 
groups, respectively).  A consistent response to treatment with tenofovir disoproxil 245 mg was seen 
regardless of baseline HIV-1 RNA and CD4 count. 
 
The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil 
group than the active control group (2.7% versus 0.7%).  Efavirenz or lamivudine resistance either 
preceded or was coincident with the development of K65R in all cases.  Eight patients had HIV that 
expressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks 
of treatment and the last one at week 96.  No further K65R development was observed up to 



149 

week 144.  One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus.  
From both the genotypic and phenotypic analyses there was no evidence for other pathways of 
resistance to tenofovir. 
 
Data pertaining to HBV 
HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessed in 
the HepG2 2.2.15 cell line.  The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l, with 
CC50 (50% cytotoxicity concentration) values > 100 µmol/l. 
 
Resistance: No HBV mutations associated with tenofovir disoproxil resistance have been identified 
(see Clinical efficacy and safety).  In cell based assays, HBV strains expressing the rtV173L, 
rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a 
susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus.  HBV strains 
expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with 
resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-
type virus.  HBV strains expressing the adefovir-associated resistance mutations rtA181V and 
rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.  
Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold 
that of wild-type virus. 
 
Clinical efficacy and safety 
The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is 
based on virological, biochemical and serological responses in adults with HBeAg positive and 
HBeAg negative chronic hepatitis B.  Treated patients included those who were treatment-naïve, 
lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir 
dipivoxil resistance mutations at baseline.  Benefit has also been demonstrated based on histological 
responses in compensated patients. 
 
Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and 
GS-US-174-0103) 
Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir 
disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in 
Table 3 below.  Study GS-US-174-0103 was conducted in 266 (randomised and treated) 
HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) 
patients negative for HBeAg and positive for HBeAb. 
 
In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the 
primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis).  Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater 
proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg 
treatment.  Both treatments produced similar results with regard to histological response (defined as 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis) at week 48 (see Table 3 below). 
 
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil 
group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 
(see Table 3 below). 
 
Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at 
week 48 
 
 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg  
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 



150 

 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg  
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 

Complete 
response (%)a 

71* 49 67* 12 

Histology     
Histological response 
(%)b 

72 
 

69 74 68 

Median HBV DNA 
reduction from 
baselinec 
(log10 copies/ml) 

-4.7* -4.0 -6.4* -3.7 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

 
93* 

 
63 

 
76* 

 
13 

ALT (%) 
Normalised ALTd 

 
76 

 
77 

 
68* 

 
54 

Serology (%) 
HBeAg 
loss/seroconversion 

 
n/a 

 
n/a 

 
22/21 

 
18/18 

HBsAg 
loss/seroconversion 

0/0 0/0 3*/1 0/0 

* p-value versus adefovir dipivoxil < 0.05. 
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at 
least 2 points without worsening in Knodell fibrosis. 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 
c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of 
detection (LOD) of the assay. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
n/a = not applicable. 
 
Tenofovir disoproxil was associated with significantly greater proportions of patients with 
undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas 
Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and 
study GS-US-174-0103; 69%, 9%), respectively. 
 
Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) 
and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT 
(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined.  
Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine.  
Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved 
complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients 
achieved HBV DNA suppression < 400 copies/ml.  All patients with normal ALT at baseline and 88% 
of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. 
 
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 
In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 
48 weeks (either tenofovir disoproxil 245 mg or adefovir dipivoxil 10 mg), patients rolled over with 
no interruption in treatment to open-label tenofovir disoproxil.  In studies GS-US-174-0102 and 
GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively.  
At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses 
were maintained with continued tenofovir disoproxil treatment (see Tables 4 and 5 below). 
 
Table 4: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 



151 

 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 

Week 96b 144e 192g 240i 288l 384o 96c 144f 192h 240j 288m 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

90 87 84 83 80 74 89 88 87 84 84 76 

ALT (%) 
Normalised 
ALTd 

72 73 67 70 68 64 68 70 77 76 74 69 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

HBsAg loss/ 
seroconversion 

0/0 0/0 0/0 0/0 0/0 1/1n 0/0 0/0 0/0 0/0k 1/1n 1/1n 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at 
the time of the data cut-off.  However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit. 
l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil). 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
n/a = not applicable. 
 
Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0103 (HBeAg positive) 
Parametera Tenofovir disoproxil 245 mg  

n = 176 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 90 

Week 96b 144e 192h 240j 288m 384o 96c 144f 192i 240k 288n 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

76 72 68 64 61 56 74 71 72 66 65 61 

ALT (%) 
Normalised 
ALTd 

60 55 56 46 47 47 65 61 59 56 57 56 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
26/ 
23 

 
29/ 
23 

 
34/ 
25 

 
38/ 
30 

 
37/ 
25 

 
30/ 
20 

 
24/ 
20 

 
33/ 
26 

 
36/ 
30 

 
38/ 
31 

 
40/ 
31 

 
35/ 
24 

HBsAg loss/ 
seroconversion 

5/ 
4 

8/ 
6g 

11/ 
8g 

11/ 
8l 

12/ 
8l 

15/ 
12l 

6/ 
5 

8/ 
7g 

8/ 
7g 

10/ 
10l 

11/ 
10l 

13/ 
11l 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT). 



152 

h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil). 
m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
 
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in 
studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below).  Ninety-five percent 
(225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at 
baseline had either no change or an improvement in fibrosis (Ishak fibrosis score).  Of the 94 patients 
with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak 
fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak 
fibrosis score of at least 2 points. 
 
Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects 
at week 240 compared to baseline 
 
 Study 174-0102 

(HBeAg negative) 
Study 174-0103 

(HBeAg positive) 
Tenofovir disoproxil 

245 mg  
n = 250c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 125d 

Tenofovir disoproxil 
245 mg  
n = 176c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 90d 

Histological 
responsea,b (%)  

88 
[130/148] 

85 
[63/74] 

90 
[63/70] 

92 
[36/39] 

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) 
by week 240.  Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).  
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. 
c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label. 
d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil. 
 
Experience in patients with HIV co-infection and prior lamivudine experience 
In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg in adult 
patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study 
ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir 
arm were 9.45 log10 copies/ml (n = 27).  Treatment with tenofovir disoproxil 245 mg  was associated 
with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week 
data, of -5.74 log10 copies/ml (n = 18).  In addition, 61% of patients had normal ALT at week 48. 
 
Experience in patients with persistent viral replication (study GS-US-174-0106) 
The efficacy and safety of tenofovir disoproxil 245 mg or tenofovir disoproxil 245 mg plus 200 mg 
emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in 
HBeAg positive and HBeAg negative adult patients who had persistent viraemia 
(HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks.  At 
baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to 
emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine.  
Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with 
HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine 
plus tenofovir disoproxil (p = 0.672).  In addition 55% (29/53) of patients treated with tenofovir 
disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of 
the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus 
tenofovir disoproxil (p = 0.504).  Comparisons between treatment groups beyond week 24 are difficult 
to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus 
tenofovir disoproxil.  Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine 
plus tenofovir disoproxil in HBV monoinfected patients are ongoing. 



153 

 
Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) 
Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety 
and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and 
entecavir (n = 22), in patients with decompensated liver disease.  In the tenofovir disoproxil treatment 
arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum 
ALT of 61 U/l at baseline.  Forty-two percent (19/45) of patients had at least 6 months of prior 
lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 
45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline.  The 
co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in 
serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. 
 
In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of 
emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 
48 weeks of treatment. 
 
Overall, the data derived from this study are too limited to draw any definitive conclusions on the 
comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 7 below). 
 
Table 7: Safety and efficacy parameters in decompensated patients at week 48 
 
 Study 174-0108 
Parameter Tenofovir disoproxil 

245 mg  
(n = 45) 

Emtricitabine 200 mg/ 
tenofovir disoproxil 

245 mg  
(n = 45) 

Entecavir 
(0.5 mg or 1 mg) 

n = 22 

Tolerability failure 
(permanent 
discontinuation of study 
drug due to a treatment 
emergent AE) 
n (%)a 

3 (7%) 2 (4%) 2 (9%) 

Confirmed increase in 
serum creatinine 
≥ 0.5 mg/dl from 
baseline or confirmed 
serum phosphate of 
< 2 mg/dl 
n (%)b 

4 (9%) 3 (7%) 1 (5%) 

HBV DNA n (%) 
< 400 copies/ml 
n (%) 

31/44 (70%) 36/41 (88%) 16/22 (73%) 

ALT n (%) 
Normal ALT 

25/44 (57%) 31/41 (76%) 12/22 (55%) 

≥ 2 point decrease in 
CPT from baseline 
n (%) 

7/27 (26%) 12/25 (48%) 5/12 (42%) 

Mean change from 
baseline in CPT score 

-0.8 -0.9 -1.3 

Mean change from 
baseline in MELD score 

-1.8 -2.3 -2.6 

a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622, 
b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000. 
 
Experience beyond 48 weeks in study GS-US-174-0108 
Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir 
disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) 
of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. 
 



154 

Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121) 
The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind 
study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with 
compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of 
lamivudine resistance (rtM204I/V +/- rtL180M).  Only five had adefovir-associated resistance 
mutations at baseline.  One hundred forty-one and 139 adult subjects were randomised to a tenofovir 
disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively.  Baseline 
demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were 
HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and 
mean ALT was 79 U/l, respectively. 
 
After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had 
HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation.  After 240 weeks of 
treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had 
HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation.  Among the 
HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced 
HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240.  In 
the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects 
(19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion 
through week 240.  Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by 
Week 240, but not seroconversion to anti-HBs.  Five subjects randomised to emtricitabine plus 
tenofovir disoproxil experienced HBsAg loss, with 2 of these 5 subjects experiencing seroconversion 
to anti-HBs. 
 
Clinical resistance 
Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive 
(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil 
treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic 
changes in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 
(n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive 
(GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment 
and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes 
in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 
(n = 1) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil 
resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks.  Genotypic data 
from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA 
> 400 copies/ml at week 48.  No amino acid substitutions associated with resistance to tenofovir 
disoproxil were identified in these isolates.  Genotypic analysis was conducted for 5 subjects in the 
tenofovir disoproxil arm post week 48.  No amino acid substitutions associated with tenofovir 
disoproxil resistance were detected in any subject. 
 
In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received 
tenofovir disoproxil for up to 240 weeks.  Cumulatively, there were 4 patients who experienced a 
viremic episode (HBV DNA>400 copies/ml) at their last timepoint on tenofovir disoproxil.  Among 
them, sequence data from paired baseline and on treatment HBV isolates were available for 2 of 4 
patients.  No amino acid substitutions associated with resistance to tenofovir disoproxil were identified 
in these isolates. 
 



155 

In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance 
mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 
51/52 patients switched to open-label tenofovir disoproxil (tenofovir disoproxil-tenofovir disoproxil 
group).  Genotypic evaluations were performed on all patients within this group with HBV DNA 
> 400 copies/ml at week 48 (n = 6), week 72 (n = 5), week 96 (n = 4), week 144 (n = 2), and week 192 
(n = 3).  Fifty-four patients (including 2 patients with lamivudine resistance mutations at baseline) 
initially received blinded placebo treatment for 72 weeks, and 52/54 patients followed with tenofovir 
disoproxil (PLB-tenofovir disoproxil group).  Genotypic evaluations were performed on all patients 
within this group with HBV DNA > 400 copies/ml at week 96 (n = 17), week 144 (n = 7), and 
week 192 (n = 8).  No amino acid substitutions associated with resistance to tenofovir disoproxil were 
identified in these isolates. 
 
In a paediatric study (GS-US-174-0144), genotypic data from paired baseline and on treatment HBV 
isolates from patients who received tenofovir disoproxil were available for 9 of 10 patients who had 
plasma HBV DNA > 400 copies/ml. No amino acid substitutions associated with resistance to 
tenofovir disoproxil were identified in these isolates by week 48. 
 
Paediatric population 
HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years 
of age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an 
optimised background regimen (OBR) for 48 weeks.  Due to limitations of the study, a benefit of 
tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at 
week 24.  However, a benefit is expected for the adolescent population based on extrapolation of adult 
data and comparative pharmacokinetic data (see section 5.2). 
 
In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine 
BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, 
respectively, at baseline.  Mean changes at week 48 (end of double-blind phase) were -0.215 and 
-0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the 
tenofovir disoproxil and placebo groups, respectively.  The mean rate of BMD gain was less in the 
tenofovir disoproxil group compared to the placebo group.  At week 48, six adolescents in the 
tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD 
loss (defined as > 4% loss).  Among 28 patients receiving 96 weeks of treatment with tenofovir 
disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. 
 
In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, 
virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either 
replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original 
regimen (n = 49) for 48 weeks.  At week 48, 83% of patients in the tenofovir disoproxil treatment 
group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA 
concentrations < 400 copies/ml.  The difference in the proportion of patients who maintained 
< 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the 
tenofovir disoproxil treatment group.  When missing data were excluded, 91% of patients in the 
tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment 
group had HIV-1 RNA concentrations < 400 copies/ml at week 48. 
 
Reductions in BMD have been reported in paediatric patients.  In patients who received treatment with 
tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and 
-0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline.  Mean 
changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, 
and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or 
zidovudine groups, respectively.  The mean rate of lumbar spine bone gain at week 48 was similar 
between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group.  
Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine 
or zidovudine treatment group.  One tenofovir disoproxil treated subject and no stavudine or 
zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48.  
BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who 



156 

were treated with tenofovir disoproxil for 96 weeks.  BMD Z-scores were not adjusted for height and 
weight. 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
discontinued study drug due to renal adverse events.  Five subjects (5.6%) had laboratory findings 
clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil 
therapy (median tenofovir disoproxil exposure 331 weeks). 
 
Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients 
aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT 
(≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks.  Subjects must have been naïve 
to tenofovir disoproxil, but could have received interferon based regimens (> 6 months prior to 
screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotide 
therapy (> 16 weeks prior to screening).  At week 72, overall 88% (46/52) of patients in the tenofovir 
disoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA 
< 400 copies/ml.  Seventy-four percent (26/35) of patients in the tenofovir disoproxil group had 
normalised ALT at week 72 compared to 31% (13/42) in the placebo group.  Response to treatment 
with tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-
experienced (n = 32) patients, including lamivudine-resistant patients (n = 6).  Ninety-five percent of 
nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine-
resistant patients achieved HBV DNA < 400 copies/ml at week 72.  Thirty-one of the 32 nucleos(t)ide-
experienced patients had prior lamivudine experience.  At week 72, 96% (27/28) of immune-active 
patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil treatment 
group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml.  Seventy-five 
percent (21/28) of immune-active patients in the tenofovir disoproxil group had normal ALT at 
week 72 compared to 34% (11/32) in the placebo group. 
 
After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir 
disoproxil treatment up to week 192.  After week 72, virologic suppression was maintained for those 
receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (tenofovir 
disoproxil-tenofovir disoproxil group): 86.5% (45/52) of subjects in the tenofovir disoproxil-tenofovir 
disoproxil group had HBV DNA < 400 copies/ml at week 192.  Among the subjects who received 
placebo during the double-blind period, the proportion of subjects with HBV DNA < 400 copies/mL 
rose sharply after they began treatment with open-label tenofovir disoproxil (PLB- tenofovir 
disoproxil group): 74.1% (40/54) of subjects in the PLB-tenofovir disoproxil group had HBV DNA 
< 400 copies/ml at week 192.  The proportion of subjects with ALT normalization at week 192 in the 
tenofovir disoproxil-tenofovir disoproxil group was 75.8% (25/33) among those who were HBeAg 
positive at baseline and 100.0% (2 of 2 subjects) among those who were HBeAg negative at baseline.  
Similar percentages of subjects in the tenofovir disoproxil-tenofovir disoproxil and PLB-tenofovir 
disoproxil groups (37.5% and 41.7%, respectively) experienced seroconversion to anti-HBe through 
week 192. 
 
Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 8: 
 
Table 8: Bone Mineral Density Evaluation at Baseline, Week 72 and 192 
 

 

Baseline Week 72 Week 192 
Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Lumbar spine 
mean (SD) 
BMD Z-scorea 

−0.42  
(0.762) 

-0.26  
(0.806) 

-0.49  
(0.852)  

-0.23 
(0.893)  -0.37 (0.946)  -0.44 

(0.920)  



157 

 

Baseline Week 72 Week 192 
Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Lumbar spine 
mean (SD) 
change from 
baseline 
BMD Z-scorea 

NA NA -0.06  
(0.320) 

0.10  
(0.378) 

0.02  
(0.548) 

-0.10 
(0.543) 

Whole body mean 
(SD) 
BMD Z-scorea 

−0.19  
(1.110) 

−0.23 
(0.859) 

−0.36 
 (1.077) 

−0.12 
(0.916) −0.38 (0.934) −0.42 

 (0.942) 

Whole body mean 
(SD) change from 
baseline 
BMD Z-scorea 

NA NA −0.16 (0.355) 0.09 
(0.349) 

-0.16 
(0.521) 

-0.19  
(0.504) 

Lumbar spine 
BMD at least 6% 
decreaseb 

NA NA 1.9% 
(1 subject) 0% 3.8% 

(2 subjects) 
3.7% 

(2 subjects) 

Whole body 
BMD at least 6% 
decreaseb 

NA NA 0% 0% 0% 1.9% 
(1 subject) 

Lumbar spine 
BMD mean % 
increase 

NA NA 5.14% 8.08% 10.05% 11.21% 

Whole body 
BMD mean % 
increase 

NA NA 3.07% 5.39% 6.09% 7.22% 

NA = Not Applicable 
a BMD Z-scores not adjusted for height and weight 
b Primary safety endpoint through week 72 
 
In study GS-US-174-0144, 89 HBeAg-negative and -positive patients aged 2 to < 12 years with 
chronic hepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of 245 mg 
(n = 60) or placebo (n = 29) once daily for 48 weeks. Subjects must have been naïve to tenofovir 
disoproxil, with HBV DNA > 105 copies/mL (~ 4.2 log10 IU/mL) and ALT >1.5 × the upper limit of 
normal (ULN) at screening.  At Week 48, 77% (46 of 60) of patients in the tenofovir disoproxil 
treatment group and 7% (2 of 29) of patients in the placebo group had HBV DNA < 400 copies/mL 
(69 IU/mL). Sixty-six percent (38 of 58) of patients in the tenofovir disoproxil group had normalized 
ALT at week 48 compared with 15% (4 of 27) in the placebo group. Twenty-five percent (14 of 56) of 
patients in the tenofovir disoproxil group and 24% (7 of 29) of patients in the placebo group achieved 
HBeAg seroconversion at Week 48. 

Response to treatment with tenofovir disoproxil was comparable in treatment-naïve and treatment-
experienced subjects with 76% (38/50) of treatment-naïve and 80% (8/10) of treatment-experienced 
subjects achieving HBV DNA < 400 copies/mL (69 IU/ml) at Week 48. Response to treatment with 
tenofovir disoproxil was also similar in subjects who were HBeAg-negative compared with those who 
were HBeAg-positive at baseline with 77% (43/56) HBeAg-positive and 75.0% (3/4) HBeAg-negative 
subjects achieving HBV DNA < 400 copies/mL (69 IU/mL) at Week 48. The distribution of HBV 
genotypes at baseline was similar between the TDF and Placebo groups. The majority of subjects were 
either genotypes C (43.8%) or D (41.6%) with a lower and similar frequency of genotypes A and B 
(6.7% each). Only 1 subject randomized to the TDF group was genotype E at baseline. In general, 
treatment responses to tenofovir disoproxil were similar for genotypes A, B, C and E [75-100% of 
subjects achieved HBV DNA < 400 copies/mL (69 IU/mL) at Week 48] with a lower response rate in 
subjects with genotype D infection (55%). 

Bone Mineral Density (BMD) data from Study GS-US-174-0144 are summarized in Table 9: 
 
Table 9: Bone Mineral Density Evaluation at Baseline and Week 48 



158 

 

 Baseline Week 48 
TDF PLB TDF PLB 

Lumbar spine mean 
(SD) BMD Z-scorea 

0.02  
(0.977) 

-0.29  
(1.229) 

-0.11 
(0.983) 

-0.11 
(1.234) 

Lumbar spine mean 
(SD) change from 
baseline BMD Z-scorea 

NA NA -0.12  
(0.411) 

0.14 
(0.330) 

Whole body mean (SD) 
BMD Z-scorea 

0.11 
(0.743) 

−0.05 
(1.497) 

-0.34 
(0.939) 

0.20 
(1.299) 

Whole body mean (SD) 
change from baseline 
BMD Z-scorea 

NA NA −0.18 
(0.334) 

0.22 
(0.446) 

Lumbar spine BMD at 
least 4% decreaseb NA NA 18.3% 

(11 subjects) 
6.9% 

(2 subjects) 
Whole body BMD at 
least 4% decrease NA NA 6.7% 

(4 subjects) 0% 

Lumbar spine BMD 
mean % increaseb NA NA 3.8% 7.6% 

Whole body BMD mean 
% increase NA NA 4.5% 8.9% 

NA = Not Applicable 
a BMD Z-scores only available for a limited set of subjects with matched reference data 
b Secondary endpoint through week 48 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Viread in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir 
and formaldehyde. 
 
Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, 
tenofovir diphosphate. 
 
Absorption 
Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is 
rapidly absorbed and converted to tenofovir.  Administration of multiple doses of tenofovir disoproxil 
with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 
326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively.  Maximum tenofovir 
concentrations are observed in serum within one hour of dosing in the fasted state and within two 
hours when taken with food.  The oral bioavailability of tenofovir from tenofovir disoproxil in fasted 
patients was approximately 25%.  Administration of tenofovir disoproxil with a high fat meal 
enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax 
by approximately 14%.  Following the first dose of tenofovir disoproxil in fed patients, the median 
Cmax in serum ranged from 213 to 375 ng/ml.  However, administration of tenofovir disoproxil with a 
light meal did not have a significant effect on the pharmacokinetics of tenofovir. 
 
Distribution 
Following intravenous administration the steady-state volume of distribution of tenofovir was 
estimated to be approximately 800 ml/kg.  After oral administration of tenofovir disoproxil, tenofovir 
is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the 
intestinal contents (preclinical studies).  In vitro protein binding of tenofovir to plasma or serum 
protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 
25 µg/ml. 
 



159 

Biotransformation 
In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 
CYP450 enzymes.  Moreover, at concentrations substantially higher (approximately 300-fold) than 
those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major 
human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, 
CYP2E1, or CYP1A1/2).  Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any 
of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction 
in metabolism of CYP1A1/2 substrate was observed.  Based on these data, it is unlikely that clinically 
significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 
would occur. 
 
Elimination 
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system 
with approximately 70-80% of the dose excreted unchanged in urine following intravenous 
administration.  Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 
300 ml/min).  Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 
210 ml/min), which is in excess of the glomerular filtration rate.  This indicates that active tubular 
secretion is an important part of the elimination of tenofovir.  Following oral administration the 
terminal half-life of tenofovir is approximately 12 to 18 hours. 
 
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal 
tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the 
multidrug resistant protein 4 (MRP 4). 
 
Linearity/non-linearity 
The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 
75 to 600 mg and were not affected by repeated dosing at any dose level. 
 
Age 
Pharmacokinetic studies have not been performed in the elderly (over 65 years of age). 
 
Gender 
Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. 
 
Ethnicity 
Pharmacokinetics have not been specifically studied in different ethnic groups. 
 
Paediatric population 
HIV-1: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent 
patients (aged 12 to < 18 years) with body weight ≥ 35 kg.  Mean (± SD) Cmax and AUCtau are 
0.38 ± 0.13 μg/ml and 3.39 ± 1.22 μg·h/ml, respectively.  Tenofovir exposure achieved in adolescent 
patients receiving oral daily doses of tenofovir disoproxil 245 mg was similar to exposures achieved in 
adults receiving once-daily doses of tenofovir disoproxil 245 mg. 
 
Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients 
(12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg was similar to 
exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg. 
 
Tenofovir exposure in HBV infected paediatric patients 2 to <12 years of age receiving an oral daily 
dose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of 
245 mg was similar to exposures achieved in HIV-1 infected paediatric patients 2 to <12 years of age 
receiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovir 
disoproxil 245 mg. 
 
Pharmacokinetic studies have not been performed with tenofovir disoproxil 245 mg tablets in children 
under 12 years or with renal impairment. 
 



160 

Renal impairment 
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of 
tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of 
renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function 
when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and 
severe with CrCl = 10-29 ml/min).  Compared with patients with normal renal function, the mean 
(%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to 
respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with 
mild, moderate and severe renal impairment.  The dosing recommendations in patients with renal 
impairment, with increased dosing interval, are expected to result in higher peak plasma 
concentrations and lower Cmin levels in patients with renal impairment compared with patients with 
normal renal function.  The clinical implications of this are unknown. 
 
In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between 
dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of 
1,032 ng/ml and a mean AUC0-48h of 42,857 ng·h/ml. 
 
It is recommended that the dosing interval for tenofovir disoproxil 245 mg is modified in adult patients 
with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis 
(see section 4.2). 
 
The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance 
< 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not 
been studied. 
 
The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied.  
No data are available to make dose recommendations (see sections 4.2 and 4.4). 
 
Hepatic impairment 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult 
patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) 
classification.  Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic 
impairment suggesting that no dose adjustment is required in these subjects.  The mean (%CV) 
tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, 
in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with 
moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with 
severe hepatic impairment. 
 
Intracellular pharmacokinetics 
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir 
diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-
stimulated PBMCs was found to be approximately 10 hours. 
 
5.3 Preclinical safety data 
 
Non-clinical safety pharmacology studies reveal no special hazard for humans.  Findings in repeated 
dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical 
exposure levels and with possible relevance to clinical use include renal and bone toxicity and a 
decrease in serum phosphate concentration.  Bone toxicity was diagnosed as osteomalacia (monkeys) 
and reduced bone mineral density (BMD) (rats and dogs).  The bone toxicity in young adult rats and 
dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred 
in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the 
exposure in patients).  Findings in the rat and monkey studies indicated that there was a substance-
related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD. 
 



161 

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results 
in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat 
hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay. 
 
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an 
extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 
 
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal 
parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in peri-
postnatal toxicity studies at maternally toxic doses. 
 
Environmental Risk Assessment (ERA) 
The active substance tenofovir disoproxil and its main transformation products are persistent in the 
environment. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate (E572) 
Microcrystalline cellulose (E460) 
Starch pregelatinised 
 
Film-coating 
Glycerol triacetate (E1518) 
Hypromellose (E464) 
Indigo carmine aluminium lake (E132) 
Lactose monohydrate 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
30 film-coated tablets and a silica gel desiccant. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 



162 

6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/001 
EU/1/01/200/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 February 2002 
Date of latest renewal: 14 December 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



163 

1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 33 mg/g granules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each scoop delivers one gram of granules which contains 33 mg of tenofovir disoproxil (as fumarate). 
 
Excipient with known effect 
One gram of granules contains 622 mg mannitol. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Granules. 
 
White, taste masked, coated granules. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
HIV-1 infection 
Viread 33 mg/g granules are indicated in combination with other antiretroviral medicinal products for 
the treatment of HIV-1 infected paediatric patients, with NRTI resistance or toxicities precluding the 
use of first line agents, from 2 to < 6 years of age, and above 6 years of age for whom a solid dosage 
form is not appropriate. 
 
Viread 33 mg/g granules are also indicated in combination with other antiretroviral medicinal products 
for the treatment of HIV-1 infected adults for whom a solid dosage form is not appropriate. 
 
In adults, the demonstration of the benefit of Viread in HIV-1 infection is based on results of one 
study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and 
studies in which Viread was added to stable background therapy (mainly tritherapy) in antiretroviral 
pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of 
patients having < 5,000 copies/ml). 
 
The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based 
on individual viral resistance testing and/or treatment history of patients. 
 
Hepatitis B infection 
Viread 33 mg/g granules are indicated for the treatment of chronic hepatitis B in adults for whom a 
solid dosage form is not appropriate with: 
 
• compensated liver disease, with evidence of active viral replication, persistently elevated serum 

alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or 
fibrosis (see section 5.1). 

 
• evidence of lamivudine-resistant hepatitis B virus (see sections 4.8 and 5.1). 
 
• decompensated liver disease (see sections 4.4, 4.8 and 5.1). 
 



164 

Viread 33 mg/g granules are also indicated for the treatment of chronic hepatitis B in paediatric 
patients2 to < 18 years of age for whom a solid dosage form is not appropriate with: 
 
• compensated liver disease and evidence of immune active disease, i.e. active viral replication, 

and persistently elevated serum ALT levels, or histological evidence of moderate to severe 
inflammation and/or fibrosis.  With respect to the decision to initiate treatment in paediatric 
patients, see sections 4.2, 4.4, 4.8 and 5.1. 

 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection and/or 
treatment of chronic hepatitis B. 
 
Posology 
 
HIV-1 and Chronic hepatitis B 
 
Adults and adolescents aged 12 to < 18 years and weighing ≥ 35 kg: 
The recommended dose of Viread for the treatment of HIV or for the treatment of chronic hepatitis B 
is 245 mg, equivalent to 7.5 scoops of granules, once daily taken orally with food. 
 
Viread is also available as 245 mg film-coated tablets for the treatment of HIV-1 infection and 
chronic hepatitis B in adults and adolescents aged 12 to < 18 years who weigh ≥ 35 kg. 
 
Children aged 2 to < 12 years: 
The recommended dose is 6.5 mg of tenofovir disoproxil per kilogram of body weight once daily 
taken with food.  Refer to Table 1. 
 
Limited clinical data are available at the 6.5 mg/kg dose of the granules.  Therefore, close monitoring 
of efficacy and safety is needed. 
 
Table 1: Dosing for children aged 2 to < 12 years 
 

Body weight (kg) Once daily 
Scoops of granules 

Total dose (mg) tenofovir 
disoproxil  

10 to < 12 2 65 
12 to < 14 2.5 82 
14 to < 17 3 98 
17 to < 19 3.5 114 
19 to < 22 4 131 
22 to < 24 4.5 147 
24 to < 27 5 163 
27 to < 29 5.5 180 
29 to < 32 6 196 
32 to < 34 6.5 212 
34 to < 35 7 229 

≥ 35 7.5 245 
 
Viread is also available as 123 mg, 163 mg, 204 mg film-coated tablets for the treatment of 
HIV-1 infection and chronic hepatitis B in paediatric patients aged 6 to < 12 years who weigh ≥ 17 
and < 35 kg for whom a solid dosage form is appropriate.  Please refer to the Summaries of Product 
Characteristics for these medicinal products. 
 



165 

The decision to treat paediatric patients (adolescents and children) should be based on careful 
consideration of individual patient needs and with reference to current paediatric treatment guidelines 
including the value of baseline histological information.  The benefits of long-term virologic 
suppression with continued therapy must be weighed against the risk of prolonged treatment, including 
the emergence of resistant hepatitis B virus and the uncertainties as regards the long term impact of 
bone and renal toxicity (see section 4.4). 
 
Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric 
patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 
months in patients with HBeAg negative disease. 
 
Duration of therapy in adults and paediatric patients with chronic hepatitis B 
 
The optimal duration of treatment is unknown.  Treatment discontinuation may be considered as 
follows: 
 
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 

12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection 
on two consecutive serum samples at least 3-6 months apart) is confirmed or until 
HBs seroconversion or there is loss of efficacy (see section 4.4).  Serum ALT and HBV DNA 
levels should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 

 
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until 

HBs seroconversion or there is evidence of loss of efficacy.  Treatment discontinuation may 
also be considered after stable virological suppression is achieved (i.e. for at least 3 years) 
provided serum ALT and HBV DNA levels are followed regularly after treatment 
discontinuation to detect any late virological relapse. With prolonged treatment for more than 
2 years, regular reassessment is recommended to confirm that continuing the selected therapy 
remains appropriate for the patient. 

 
In adult patients with decompensated liver disease or cirrhosis, treatment cessation is not 
recommended. 
 
Missed dose 
If a patient misses a dose of Viread within 12 hours of the time it is usually taken, the patient should 
take Viread with food as soon as possible and resume their normal dosing schedule.  If a patient 
misses a dose of Viread by more than 12 hours and it is almost time for their next dose, the patient 
should not take the missed dose and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Viread, another dose should be taken.  If the patient 
vomits more than 1 hour after taking Viread they do not need to take another dose. 
 
Special populations 
Elderly 
No data are available on which to make a dose recommendation for patients over the age of 65 years 
(see section 4.4). 
 
Renal impairment 
Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with 
renal dysfunction. 
 
Adults 
There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients with 
moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data 
has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min).  Therefore, in 
adult patients with renal impairment tenofovir disoproxil should only be used if the potential benefits 



166 

of treatment are considered to outweigh the potential risks.  Dose adjustments using tenofovir 
disoproxil 33 mg/g granules are recommended for patients with creatinine clearance < 50 ml/min. 
 
Mild renal impairment (creatinine clearance 50-80 ml/min) 
Limited data from clinical studies support once daily dosing of 245 mg tenofovir disoproxil, 
equivalent to 7.5 scoops of granules, in patients with mild renal impairment. 
 
Adjustments of the daily dose of tenofovir disoproxil 33 mg/g granules are recommended in patients 
with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance < 30 ml/min) renal 
impairment based on modelling of single-dose pharmacokinetic data in HIV negative and 
non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal 
disease requiring haemodialysis.  These pharmacokinetic modelling data have not been confirmed in 
clinical studies.  Therefore, clinical response to treatment and renal function should be closely 
monitored in these patients (see sections 4.4 and 5.2). 
 
Moderate renal impairment (creatinine clearance 30-49 ml/min) 
Administration of 132 mg (4 scoops) tenofovir disoproxil 33 mg/g granules once daily is 
recommended. 
 
Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients 
For patients with creatinine clearance 20-29 ml/min: Administration of 65 mg (2 scoops) tenofovir 
disoproxil 33 mg/g granules once daily is recommended. 
 
For patients with creatinine clearance 10-19 ml/min: Administration of 33 mg (1 scoop) tenofovir 
disoproxil 33 mg/g granules once daily is recommended. 
 
Haemodialysis patients: 16.5 mg (0.5 scoop) tenofovir disoproxil 33 mg/g granules may be 
administered following completion of each 4-hour haemodialysis session. 
 
These dose adjustments have not been confirmed in clinical studies.  Therefore, clinical response to 
treatment and renal function should be closely monitored (see sections 4.4 and 5.2). 
 
No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance 
< 10 ml/min. 
 
Paediatric patients 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.4). 
 
Hepatic impairment 
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). 
 
If Viread is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these 
patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4). 
 
Paediatric population 
The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with 
chronic hepatitis B under 2 years of age have not been established.  No data are available. 
 
Method of administration 
Viread granules should be measured with the supplied dosing scoop.  One level scoop delivers 1 g of 
granules which contains 33 mg of tenofovir disoproxil.  Viread granules should be mixed in a 
container with soft food not requiring chewing, for example yoghurt, applesauce or baby food.  One 
tablespoon (15 ml) of soft food per one level scoop of granules is required.  The entire mixture should 
be ingested immediately.  Viread granules must not be mixed with liquids. 
 
Viread should be taken once daily, orally with food. 



167 

 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
General 
HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir 
disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). 
 
HIV-1 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines. 
 
Hepatitis B 
Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of 
transmission of HBV to others through sexual contact or contamination with blood.  Appropriate 
precautions must continue to be used. 
 
Co-administration of other medicinal products 
- Viread should not be administered concomitantly with other medicinal products containing 

tenofovir disoproxil or tenofovir alafenamide. 
- Viread should not be administered concomitantly with adefovir dipivoxil. 
- Co-administration of tenofovir disoproxil and didanosine is not recommended (see Section 4.5).   
 
Triple therapy with nucleosides/nucleotides 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well 
as with lamivudine and didanosine as a once-daily regimen. 
 
Renal and bone effects in adult population 
Renal effects 
Tenofovir is principally eliminated via the kidney.  Renal failure, renal impairment, elevated 
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been 
reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). 
 
Renal monitoring 
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with 
tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored 
after two to four weeks of treatment, after three months of treatment and every three to six months 
thereafter in patients without renal risk factors.  In patients at risk for renal impairment, a more 
frequent monitoring of renal function is required. 
 
Renal management 
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in 
any adult patient receiving tenofovir disoproxil, renal function should be re-evaluated within one 
week, including measurements of blood glucose, blood potassium and urine glucose concentrations 
(see section 4.8, proximal tubulopathy).  Consideration should also be given to interrupting treatment 
with tenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or 
decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).  Interrupting treatment with tenofovir 
disoproxil should also be considered in case of progressive decline of renal function when no other 
cause has been identified. 
 



168 

Co-administration and risk of renal toxicity 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, 
vancomycin, cidofovir or interleukin-2).  If concomitant use of tenofovir disoproxil and nephrotoxic 
agents is unavoidable, renal function should be monitored weekly. 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If tenofovir disoproxil is co-administered with an NSAID, renal function should 
be monitored adequately. 
 
A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in 
combination with a ritonavir or cobicistat boosted protease inhibitor.  A close monitoring of renal 
function is required in these patients (see section 4.5).  In patients with renal risk factors, the 
co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully 
evaluated. 
 
Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which 
are secreted by the same renal pathway, including the transport proteins human organic anion 
transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product).  These 
renal transport proteins may be responsible for tubular secretion and in part, renal elimination of 
tenofovir and cidofovir.  Consequently, the pharmacokinetics of these medicinal products, which are 
secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be 
modified if they are co-administered.  Unless clearly necessary, concomitant use of these medicinal 
products which are secreted by the same renal pathway is not recommended, but if such use is 
unavoidable, renal function should be monitored weekly (see section 4.5). 
 
Renal impairment 
Renal safety with tenofovir disoproxil has only been studied to a very limited degree in adult patients 
with impaired renal function (creatinine clearance < 80 ml/min). 
 
Adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients 
There are limited data on the safety and efficacy of tenofovir disoproxil in patients with impaired renal 
function.  Therefore, tenofovir disoproxil should only be used if the potential benefits of treatment are 
considered to outweigh the potential risks.  In patients with moderate or severe renal impairment 
(creatinine clearance < 50 ml/min) the daily dose must be adjusted and renal function should be 
closely monitored (see sections 4.2 and 5.2). 
 
Bone effects 
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain 
and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-
induced proximal renal tubulopathy (see section 4.8). 
 
Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).  In HIV infected 
patients, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in 
BMD of the hip and spine were observed in both treatment groups.  Decreases in BMD of spine and 
changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil 
treatment group at 144 weeks.  Decreases in BMD of hip were significantly greater in this group until 
96 weeks.  However, there was no increased risk of fractures or evidence for clinically relevant bone 
abnormalities over 144 weeks in this study. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 
inhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the 
limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, 



169 

alternative treatment regimens should be considered for patients with osteoporosis that are at a high 
risk for fractures. 
 
If bone abnormalities are suspected or detected then appropriate consultation should be obtained. 
 
Renal and bone effects in paediatric population 
There are uncertainties associated with the long term effects of bone and renal toxicity.  Moreover, the 
reversibility of renal toxicity cannot be fully ascertained.  Therefore, a multidisciplinary approach is 
recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide 
the appropriate monitoring during treatment (including decision for treatment withdrawal) and 
consider the need for supplementation. 
 
Renal effects 
Renal adverse reactions consistent with proximal renal tubulopathy have been reported in 
HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see 
sections 4.8 and 5.1). 
 
Renal monitoring 
Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, and 
monitored during treatment as in adults (see above). 
 
Renal management 
If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving 
tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements 
of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal 
tubulopathy).  If renal abnormalities are suspected or detected then consultation with a nephrologist 
should be obtained to consider interruption of tenofovir disoproxil treatment.  Interrupting treatment 
with tenofovir disoproxil should also be considered in case of progressive decline of renal function 
when no other cause has been identified. 
 
Co-administration and risk of renal toxicity 
The same recommendations apply as in adults (see above). 
 
Renal impairment 
The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 
section 4.2).  Tenofovir disoproxil should not be initiated in paediatric patients with renal impairment 
and should be discontinued in paediatric patients who develop renal impairment during tenofovir 
disoproxil therapy. 
 
Bone effects 
Viread may cause a reduction in BMD.  The effects of tenofovir disoproxil-associated changes in 
BMD on long-term bone health and future fracture risk are uncertain (see section 5.1). 
 
If bone abnormalities are detected or suspected in paediatric patients, consultation with an 
endocrinologist and/or nephrologist should be obtained. 
 
Liver disease 
Safety and efficacy data are very limited in liver transplant patients. 
 
There are limited data on the safety and efficacy of tenofovir disoproxil in HBV infected patients with 
decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9.  These patients 
may be at higher risk of experiencing serious hepatic or renal adverse reactions.  Therefore, 
hepatobiliary and renal parameters should be closely monitored in this patient population. 
 
Exacerbations of hepatitis 
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 
characterised by transient increases in serum ALT.  After initiating antiviral therapy, serum ALT may 



170 

increase in some patients (see section 4.8).  In patients with compensated liver disease, these increases 
in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 
hepatic decompensation.  Patients with cirrhosis may be at a higher risk for hepatic decompensation 
following hepatitis exacerbation, and therefore should be monitored closely during therapy. 
 
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in 
patients who have discontinued hepatitis B therapy.  Post-treatment exacerbations are usually 
associated with rising HBV DNA, and the majority appears to be self-limited.  However, severe 
exacerbations, including fatalities, have been reported.  Hepatic function should be monitored at 
repeated intervals with both clinical and laboratory follow-up for at least 6 months after 
discontinuation of hepatitis B therapy.  If appropriate, resumption of hepatitis B therapy may be 
warranted.  In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 
recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 
 
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease. 
 
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients 
co-infected with hepatitis C or D virus. 
 
Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir 
disoproxil should only be used as part of an appropriate antiretroviral combination regimen in 
HIV/HBV co-infected patients.  Patients with pre-existing liver dysfunction, including chronic active 
hepatitis, have an increased frequency of liver function abnormalities during combination 
antiretroviral therapy (CART) and should be monitored according to standard practice.  If there is 
evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must 
be considered.  However, it should be noted that increases of ALT can be part of HBV clearance 
during therapy with tenofovir, see above Exacerbations of hepatitis. 
 
Use with certain hepatitis C virus antiviral agents 
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, 
especially when used together with an HIV regimen containing tenofovir disoproxil and a 
pharmacokinetic enhancer (ritonavir or cobicistat).  The safety of tenofovir disoproxil in the setting of 
ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a 
pharmacokinetic enhancer has not been established.  The potential risks and benefits associated with 
co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV 
protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at 
increased risk of renal dysfunction.  Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV 
protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil. 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Mitochondrial dysfunction following exposure in utero 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such 



171 

neurological disorders are transient or permanent is currently unknown.  These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of institution of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause 
serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed 
within the first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment. 
 
Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
Elderly 
Tenofovir disoproxil has not been studied in patients over the age of 65.  Elderly patients are more 
likely to have decreased renal function; therefore caution should be exercised when treating elderly 
patients with tenofovir disoproxil. 
 
Viread granules contain mannitol which may have a mild laxative effect. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the 
potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low. 
 
Concomitant use not recommended 
Viread should not be administered concomitantly with other medicinal products containing tenofovir 
disoproxil or tenofovir alafenamide. 
 
Viread should not be administered concomitantly with adefovir dipivoxil. 
 
Didanosine 
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and 
Table 2). 
 
Renally eliminated medicinal products 
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with 
medicinal products that reduce renal function or compete for active tubular secretion via transport 
proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir 
and/or the co-administered medicinal products. 
 



172 

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 
medicinal product.  Some examples include, but are not limited to, aminoglycosides, amphotericin B, 
foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4). 
 
Given that tacrolimus can affect renal function, close monitoring is recommended when it is 
co-administered with tenofovir disoproxil. 
 
Other interactions 
Interactions between tenofovir disoproxil and other medicinal products are listed in Table 2 below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily 
as “q.d.”). 
 
Table 2: Interactions between tenofovir disoproxil and other medicinal products 
 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
ANTI-INFECTIVES 
Antiretrovirals 
Protease inhibitors 
Atazanavir/Ritonavir 
(300 q.d./100 q.d.) 

Atazanavir: 
AUC: ↓ 25% 
Cmax: ↓ 28% 
Cmin: ↓ 26% 
Tenofovir: 
AUC: ↑ 37% 
Cmax: ↑ 34% 
Cmin: ↑ 29% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders.  Renal function should 
be closely monitored 
(see section 4.4). 

Lopinavir/Ritonavir 
(400 b.i.d./100 b.i.d.) 

Lopinavir/ritonavir: 
No significant effect on 
lopinavir/ritonavir PK parameters. 
Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders.  Renal function should 
be closely monitored 
(see section 4.4). 

Darunavir/Ritonavir 
(300/100 b.i.d.) 

Darunavir: 
No significant effect on 
darunavir/ritonavir PK parameters. 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders.  Renal function should 
be closely monitored 
(see section 4.4). 



173 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
NRTIs 
Didanosine Co-administration of tenofovir 

disoproxil and didanosine results in 
a 40-60% increase in systemic 
exposure to didanosine. 

Co-administration of tenofovir 
disoproxil and didanosine is not 
recommended (see section 4.4). 
 
Increased systemic exposure to 
didanosine may increase 
didanosine related adverse 
reactions.  Rarely, pancreatitis and 
lactic acidosis, sometimes fatal, 
have been reported.  
Co-administration of tenofovir 
disoproxil and didanosine at a 
dose of 400 mg daily has been 
associated with a significant 
decrease in CD4 cell count, 
possibly due to an intracellular 
interaction increasing 
phosphorylated (i.e. active) 
didanosine.  A decreased dosage 
of 250 mg didanosine 
co-administered with tenofovir 
disoproxil therapy has been 
associated with reports of high 
rates of virological failure within 
several tested combinations for the 
treatment of HIV-1 infection. 

Adefovir dipivoxil AUC: ↔ 
Cmax: ↔ 

Tenofovir disoproxil should not be 
administered concurrently with 
adefovir dipivoxil 
(see section 4.4). 

Entecavir AUC: ↔ 
Cmax: ↔ 

No clinically significant 
pharmacokinetic interactions when 
tenofovir disoproxil was 
co-administered with entecavir. 

Hepatitis C virus antiviral agents 
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↑ 96% 
Cmax: ↑ 68% 
Cmin: ↑ 118% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 63% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 45% 
 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, ledipasvir/sofosbuvir 
and atazanavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring, if other alternatives 
are not available (see section 4.4). 



174 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 47% 
Cmin: ↑ 47% 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.)1 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↓ 27% 
Cmax: ↓ 37% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 48% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 50% 
Cmax: ↑ 64% 
Cmin: ↑ 59% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, ledipasvir/sofosbuvir 
and darunavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with ledipasvir/sofosbuvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring, if other alternatives 
are not available (see section 4.4). 



175 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↓ 34% 
Cmax: ↓ 34% 
Cmin: ↓ 34% 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 98% 
Cmax: ↑ 79% 
Cmin: ↑ 163% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofovir 
disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↔ 
Cmin: ↑ 91% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



176 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Dolutegravir (50 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072 

AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Dolutegravir  
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

 
Tenofovir: 
AUC: ↑ 65% 
Cmax: ↑ 61% 
Cmin: ↑ 115% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see section 
4.4). 



177 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Atazanavir/Ritonavir 
(300 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔  
Cmax: ↔  
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 42% 
 
Velpatasvir: 
AUC: ↑ 142% 
Cmax: ↑ 55% 
Cmin: ↑ 301% 
 
Atazanavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 39% 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↑ 29% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 55% 
Cmin: ↑ 39% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, sofosbuvir/velpatasvir 
and atazanavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 
 



178 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Darunavir/Ritonavir 
(800 mg q.d./100 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC:  ↓28% 
Cmax: ↓ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 24% 
Cmin: ↔ 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 55% 
Cmin: ↑ 52% 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, sofosbuvir/velpatasvir 
and darunavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 



179 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Lopinavir/Ritonavir 
(800 mg/200 mg q.d.) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↓ 29% 
Cmax: ↓ 41% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: ↑ 63% 
 
Lopinavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 42% 
Cmin: ↔ 

Increased plasma concentrations 
of tenofovir resulting from 
co-administration of tenofovir 
disoproxil, sofosbuvir/velpatasvir 
and lopinavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  The safety of 
tenofovir disoproxil when used 
with sofosbuvir/velpatasvir and a 
pharmacokinetic enhancer (e.g. 
ritonavir or cobicistat) has not 
been established. 
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 



180 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Raltegravir 
(400 mg b.i.d) + 
Emtricitabine/Tenofovir disoproxil 
(200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Raltegravir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 21% 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 46% 
Cmin: ↑ 70% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 

Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 38% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↓ 53% 
Cmax: ↓ 47% 
Cmin: ↓ 57% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 81% 
Cmax: ↑ 77% 
Cmin: ↑ 121% 

Concomitant administration of 
sofosbuvir/velpatasvir and 
efavirenz is expected to decrease 
plasma concentrations of 
velpatasvir.  Co-administration of 
sofosbuvir/velpatasvir with 
efavirenz-containing regimens is 
not recommended. 



181 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenofovir 
disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 44% 
Cmin: ↑ 84% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



182 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir/Velpatasvir/ 
Voxilaprevir (400 mg/100 mg/ 
100 mg+100 mg q.d.)3 + Darunavir 
(800 mg q.d.) + Ritonavir (100 mg 
q.d.) + Emtricitabine/Tenofovir 
disoproxil (200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 30% 
Cmin: N/A 
 
GS-3310072: 
AUC: ↔ 
Cmax:↔ 
Cmin: N/A 

 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Voxilaprevir: 
AUC: ↑ 143% 
Cmax:↑ 72% 
Cmin: ↑ 300% 
 
Darunavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 34% 
 
Ritonavir: 
AUC: ↑ 45% 
Cmax: ↑ 60% 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 39% 
Cmax: ↑ 48% 
Cmin: ↑ 47% 

Increased plasma concentrations 
of tenofovir resulting from co-
administration of tenofovir 
disoproxil, 
sofosbuvir/velpatasvir/voxilaprevir 
and darunavir/ritonavir may 
increase adverse reactions related 
to tenofovir disoproxil, including 
renal disorders.  
The safety of tenofovir disoproxil 
when used with 
sofosbuvir/velpatasvir/voxilaprevir 
and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has 
not been established.  
 
The combination should be used 
with caution with frequent renal 
monitoring (see section 4.4). 



183 

Medicinal product by 
therapeutic areas 

(dose in mg) 

Effects on drug levels 
Mean percent change in AUC, 

Cmax, Cmin 

Recommendation concerning 
co-administration with 245 mg 

tenofovir disoproxil  
Sofosbuvir 
(400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 19% 
 
GS-3310072: 
AUC: ↔ 
Cmax: ↓ 23% 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 25% 
Cmin: ↔ 

No dose adjustment is required. 

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir.  Staggered administration (12 hours apart) provided 
similar results. 
2 The predominant circulating metabolite of sofosbuvir. 
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 
 
Studies conducted with other medicinal products 
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was 
co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir 
boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive 
norgestimate/ethinyl oestradiol. 
 
Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir 
(see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no 
malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.  Animal studies do not 
indicate reproductive toxicity (see section 5.3).  The use of tenofovir disoproxil may be considered 
during pregnancy, if necessary. 
 
In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to 
reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, 
in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.  

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were 
administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 
months postpartum; women and their infants were followed for up to 12 months after delivery.  No 
safety signal has emerged from these data. 

Breastfeeding 
Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with 
hepatitis B may breast-feed her infant. 



184 

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is 
considered negligible. Although long-term data is limited, no adverse reactions have been reported in 
breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed. 
 
As a general rule, it is recommended that HIV infected mothers do not breastfeed their infants in order 
to avoid transmission of HIV to the infant. 
 
Fertility 
There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility.  Animal 
studies do not indicate harmful effects of tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
patients should be informed that dizziness has been reported during treatment with tenofovir 
disoproxil. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, 
renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) 
sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.  
Monitoring of renal function is recommended for patients receiving Viread (see section 4.4). 
 
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following 
treatment with tenofovir disoproxil in combination with other antiretroviral agents.  These reactions 
are usually mild to moderate gastrointestinal events.  Approximately 1% of tenofovir 
disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events. 
 
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions 
following treatment with tenofovir disoproxil, most of which are mild.  In clinical trials of 
HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was 
nausea (5.4%). 
 
Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who 
have discontinued hepatitis B therapy (see section 4.4). 
 
Tabulated summary of adverse reactions 
Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies 
and post-marketing experience.  All adverse reactions are presented in Table 3. 
 
HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on 
experience in two studies in 653 treatment-experienced adult patients receiving treatment with 
tenofovir disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal 
products for 24 weeks and also in a double-blind comparative controlled study in which 600 
treatment-naïve adult patients received treatment with tenofovir disoproxil 245 mg (n = 299) or 
stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks. 
 
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is 
primarily based on experience in two double-blind comparative controlled studies in which 641 adult 
patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir 
disoproxil 245 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.  The 
adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 
profile of tenofovir disoproxil.  After an initial decline of approximately -4.9 ml/min (using Cockcroft-
Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease [MDRD] equation) 
after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported 



185 

in tenofovir disoproxil treated patients was -1.41 ml/min per year (using Cockcroft-Gault equation) 
and -0.74 ml/min/1.73 m2 per year (using MDRD equation). 
 
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil in patients with 
decompensated liver disease was assessed in a double-blind active controlled study 
(GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n = 45) or 
emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks. 
 
In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse 
event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant 
differences between the combined tenofovir-containing arms and the entecavir arm.  After 168 weeks, 
16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil 
group, and 14% (3/22) of the entecavir group experienced tolerability failure.  Thirteen percent (6/45) 
of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 
9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or 
confirmed serum phosphate of < 2 mg/dl. 
 
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 
13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil 
group and 14% (3/22) in the entecavir group.  The rate of hepatocellular carcinoma was 18% (8/45) in 
the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% 
(2/22) in the entecavir group. 
 
Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see 
section 4.4). 
 
Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir 
disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 
lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or 
emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks. 
 
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by 
body system organ class and frequency.  Within each frequency grouping, undesirable effects are 
presented in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Table 3: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on 
clinical study and post-marketing experience 
 
Frequency Tenofovir disoproxil  
Metabolism and nutrition disorders: 
Very common: hypophosphataemia1 
Uncommon: hypokalaemia1 
Rare: lactic acidosis 

Nervous system disorders: 
Very common: dizziness 
Common: headache 
Gastrointestinal disorders: 
Very common: diarrhoea, vomiting, nausea 
Common: abdominal pain, abdominal distension, flatulence 
Uncommon: pancreatitis 
Hepatobiliary disorders: 
Common: increased transaminases 
Rare: hepatic steatosis, hepatitis 



186 

Frequency Tenofovir disoproxil  
Skin and subcutaneous tissue disorders: 
Very common: rash 
Rare: angioedema 
Musculoskeletal and connective tissue disorders: 
Uncommon: rhabdomyolysis1, muscular weakness1 

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 

2, myopathy1 
Renal and urinary disorders: 
Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconi syndrome) 

Rare: acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute 
interstitial nephritis)2, nephrogenic diabetes insipidus 

General disorders and administration site conditions: 
Very common: asthenia 
Common: fatigue 
1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 
associated with tenofovir disoproxil in the absence of this condition. 
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical 
trials or the tenofovir disoproxil expanded access program.  The frequency category was estimated from a statistical 
calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and 
the expanded access program (n = 7,319). 
 
Description of selected adverse reactions 
HIV-1 and hepatitis B: 
Renal impairment 
As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 
4.8 Summary of the safety profile).  Proximal renal tubulopathy generally resolved or improved after 
tenofovir disoproxil discontinuation.  However, in some patients, declines in creatinine clearance did 
not completely resolve despite tenofovir disoproxil discontinuation.  Patients at risk of renal 
impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients 
receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete 
recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4). 
 
Lactic acidosis 
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with 
other antiretrovirals.  Patients with predisposing factors such as patients with decompensated liver 
disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased 
risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal 
outcomes. 
 
HIV-1: 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
Immune reactivation syndrome 
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune 
disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 
reported time to onset is more variable and these events can occur many months after initiation of 
treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART.  The frequency of this is unknown 
(see section 4.4). 
 



187 

Hepatitis B: 
Exacerbations of hepatitis during treatment 
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit 
of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients.  ALT 
elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a 
majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or 
coincided with the ALT elevation.  Periodic monitoring of hepatic function is recommended during 
treatment (see section 4.4). 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred 
after discontinuation of HBV therapy (see section 4.4). 
 
Paediatric population 
HIV-1 
Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and 
GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received 
treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with 
other antiretroviral agents for 48 weeks (see section 5.1).  The adverse reactions observed in paediatric 
patients who received treatment with tenofovir disoproxil were consistent with those observed in 
clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse 
reactions and 5.1). 
 
Reductions in BMD have been reported in paediatric patients.  In HIV-1 infected adolescents, the 
BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed 
in subjects who received placebo.  In HIV-1 infected children, the BMD Z-scores observed in subjects 
who switched to tenofovir disoproxil were lower than those observed in subjects who remained on 
their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1). 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse 
events.  Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal 
tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy.  Seven patients had estimated 
glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2.  Among them, 3 patients 
experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of 
tenofovir disoproxil. 
 
Chronic hepatitis B 
Assessment of adverse reactions is based on a randomised study (study GS-US-174-0115) in 106 
adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks and on a randomised study 
(study GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to  < 12 years of age) receiving 
treatment with tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks.  The adverse reactions 
observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with 
those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary 
of adverse reactions and 5.1). 
 
Reductions in BMD have been observed in HBV infected  paediatric patients 2 to < 18 years of age.  
The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those 
observed in subjects who received placebo (see sections 4.4 and 5.1). 
 
Other special population(s) 
Elderly 
Tenofovir disoproxil has not been studied in patients over the age of 65.  Elderly patients are more 
likely to have decreased renal function, therefore caution should be exercised when treating elderly 
patients with tenofovir disoproxil (see section 4.4). 
 



188 

Patients with renal impairment 
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended 
in adult patients with renal impairment treated with Viread (see sections 4.2, 4.4 and 5.2).  The use of 
tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see sections 4.2 
and 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  
It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), 
and standard supportive treatment applied as necessary. 
 
Management 
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 
134 ml/min.  It is not known whether tenofovir can be removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC code: J05AF07 
 
Mechanism of action and pharmacodynamic effects 
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.  Tenofovir 
disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside 
monophosphate (nucleotide) analogue.  Tenofovir is then converted to the active metabolite, tenofovir 
diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes.  Tenofovir 
diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral 
blood mononuclear cells (PBMCs).  Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and 
the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate 
and, after incorporation into DNA, by DNA chain termination.  Tenofovir diphosphate is a weak 
inhibitor of cellular polymerases α, β, and γ.  At concentrations of up to 300 µmol/l, tenofovir has also 
shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro 
assays. 
 
Data pertaining to HIV 
HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the 
wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against 
primary HIV-1 subtype B isolates in PBMCs.  Tenofovir is also active against HIV-1 subtypes A, C, 
D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells.  Tenofovir shows 
activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells. 
 
Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse 
transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety).  
Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring 
the K65R mutation (see section 4.4).  In addition, a K70E substitution in HIV-1 reverse transcriptase 
has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. 
 

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189 

Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir 
disoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors.  The results 
indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations 
(TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced 
response to tenofovir disoproxil 245 mg therapy. 
 
Clinical efficacy and safety 
The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults 
have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively. 
 
In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir 
disoproxil 245 mg for 24 weeks.  The mean baseline CD4 cell count was 427 cells/mm3, the mean 
baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of 
< 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years.  Baseline genotypic 
analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance 
mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated 
with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase 
inhibitors. 
 
At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels 
(DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 
245 mg recipients (p < 0.0001).  A statistically significant difference in favour of tenofovir disoproxil 
245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 
count (+13 cells/mm3 for tenofovir disoproxil 245 mg versus -11 cells/mm3 for placebo, 
p-value = 0.0008).  The antiviral response to tenofovir disoproxil was durable through 48 weeks 
(DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 
50 copies/ml was 41% and 18% respectively).  Eight (2%) tenofovir disoproxil 245 mg treated patients 
developed the K65R mutation within the first 48 weeks. 
 
The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and 
safety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine and 
efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy.  The mean baseline CD4 cell 
count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of 
patients had symptomatic HIV-1 infection and 18% had AIDS.  Patients were stratified by baseline 
HIV-1 RNA and CD4 count.  Forty-three percent of patients had baseline viral loads 
> 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml. 
 
By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as 
failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 
48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm, 
compared to 84% and 80% in the stavudine arm.  At 144 weeks, the proportion of patients with 
HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir 
disoproxil 245 mg arm, compared to 64% and 63% in the stavudine arm. 
 
The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was 
similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the 
tenofovir disoproxil 245 mg and stavudine groups, respectively).  At 144 weeks of treatment, the 
average change from baseline remained similar in both treatment groups (-3.07 and 
-3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg and stavudine 
groups, respectively).  A consistent response to treatment with tenofovir disoproxil 245 mg was seen 
regardless of baseline HIV-1 RNA and CD4 count. 
 
The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil 
group than the active control group (2.7% versus 0.7%).  Efavirenz or lamivudine resistance either 
preceded or was coincident with the development of K65R in all cases.  Eight patients had HIV that 
expressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks 
of treatment and the last one at week 96.  No further K65R development was observed up to 



190 

week 144.  One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus.  
From both the genotypic and phenotypic analyses there was no evidence for other pathways of 
resistance to tenofovir. 
 
Data pertaining to HBV 
HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessed in 
the HepG2 2.2.15 cell line.  The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l, with 
CC50 (50% cytotoxicity concentration) values > 100 µmol/l. 
 
Resistance: No HBV mutations associated with tenofovir disoproxil resistance have been identified 
(see Clinical efficacy and safety).  In cell based assays, HBV strains expressing the rtV173L, 
rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a 
susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus.  HBV strains 
expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with 
resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-
type virus.  HBV strains expressing the adefovir-associated resistance mutations rtA181V and 
rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.  
Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold 
that of wild-type virus. 
 
Clinical efficacy and safety 
The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is 
based on virological, biochemical and serological responses in adults with HBeAg positive and 
HBeAg negative chronic hepatitis B.  Treated patients included those who were treatment-naïve, 
lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir 
dipivoxil resistance mutations at baseline.  Benefit has also been demonstrated based on histological 
responses in compensated patients. 
 
Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and 
GS-US-174-0103) 
Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir 
disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in 
Table 4 below.  Study GS-US-174-0103 was conducted in 266 (randomised and treated) 
HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) 
patients negative for HBeAg and positive for HBeAb. 
 
In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the 
primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis).  Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater 
proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg 
treatment.  Both treatments produced similar results with regard to histological response (defined as 
Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 
fibrosis) at week 48 (see Table 4 below). 
 
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil 
group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 
(see Table 4 below). 
 
Table 4: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at 
week 48 
 
 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg  
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 



191 

 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 
Parameter Tenofovir 

disoproxil 245 mg  
n = 250 

Adefovir dipivoxil 
10 mg 

n = 125 

Tenofovir 
disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 
10 mg 
n = 90 

Complete 
response (%)a 

71* 49 67* 12 

Histology     
Histological response 
(%)b 

72 
 

69 74 68 

Median HBV DNA 
reduction from 
baselinec 
(log10 copies/ml) 

-4.7* -4.0 -6.4* -3.7 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

 
93* 

 
63 

 
76* 

 
13 

ALT (%) 
Normalised ALTd 

 
76 

 
77 

 
68* 

 
54 

Serology (%) 
HBeAg 
loss/seroconversion 

 
n/a 

 
n/a 

 
22/21 

 
18/18 

HBsAg 
loss/seroconversion 

0/0 0/0 3*/1 0/0 

* p-value versus adefovir dipivoxil < 0.05. 
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at 
least 2 points without worsening in Knodell fibrosis. 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 
c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of 
detection (LOD) of the assay. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
n/a = not applicable. 
 
Tenofovir disoproxil was associated with significantly greater proportions of patients with 
undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas 
Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and 
study GS-US-174-0103; 69%, 9%), respectively. 
 
Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) 
and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT 
(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined.  
Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine.  
Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved 
complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients 
achieved HBV DNA suppression < 400 copies/ml.  All patients with normal ALT at baseline and 88% 
of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. 
 
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 
In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 
48 weeks (either tenofovir disoproxil 245 mg or adefovir dipivoxil 10 mg), patients rolled over with 
no interruption in treatment to open-label tenofovir disoproxil.  In studies GS-US-174-0102 and 
GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively.  
At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses 
were maintained with continued tenofovir disoproxil treatment (see Tables 5 and 6 below). 
 
Table 5: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 



192 

 Study 174-0102 (HBeAg negative) 
Parametera Tenofovir disoproxil 245 mg  

n = 250 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 125 

Week 96b 144e 192g 240i 288l 384o 96c 144f 192h 240j 288m 384p 

HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

90 87 84 83 80 74 89 88 87 84 84 76 

ALT (%) 
Normalised 
ALTd 

72 73 67 70 68 64 68 70 77 76 74 69 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

 
n/a 

HBsAg loss/ 
seroconversion 

0/0 0/0 0/0 0/0 0/0 1/1n 0/0 0/0 0/0 0/0k 1/1n 1/1n 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at 
the time of the data cut-off.  However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit. 
l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil). 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
n/a = not applicable. 
 
Table 6: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 
288 and 384 open-label treatment 
 
 Study 174-0103 (HBeAg positive) 
Parametera Tenofovir disoproxil 245 mg  

n = 176 
Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
n = 90 

Week 96b 144e 192h 240j 288m 384o 96c 144f 192i 240k 288n 384p 
HBV DNA (%) 
< 400 copies/ml 
(< 69 IU/ml) 

76 72 68 64 61 56 74 71 72 66 65 61 

ALT (%) 
Normalised 
ALTd 

60 55 56 46 47 47 65 61 59 56 57 56 

Serology (%) 
HBeAg loss/ 
seroconversion 

 
26/ 
23 

 
29/ 
23 

 
34/ 
25 

 
38/ 
30 

 
37/ 
25 

 
30/ 
20 

 
24/ 
20 

 
33/ 
26 

 
36/ 
30 

 
38/ 
31 

 
40/ 
31 

 
35/ 
24 

HBsAg loss/ 
seroconversion 

5/ 
4 

8/ 
6g 

11/ 
8g 

11/ 
8l 

12/ 
8l 

15/ 
12l 

6/ 
5 

8/ 
7g 

8/ 
7g 

10/ 
10l 

11/ 
10l 

13/ 
11l 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to 
week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT). 



193 

h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the 
addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil). 
m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 
 
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in 
studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 7 below).  Ninety-five percent 
(225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at 
baseline had either no change or an improvement in fibrosis (Ishak fibrosis score).  Of the 94 patients 
with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak 
fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak 
fibrosis score of at least 2 points. 
 
Table 7: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects 
at week 240 compared to baseline 
 
 Study 174-0102 

(HBeAg negative) 
Study 174-0103 

(HBeAg positive) 
Tenofovir disoproxil 

245 mg  
n = 250c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 125d 

Tenofovir disoproxil 
245 mg  
n = 176c 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  
n = 90d 

Histological 
responsea,b (%)  

88 
[130/148] 

85 
[63/74] 

90 
[63/70] 

92 
[36/39] 

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) 
by week 240.  Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).  
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. 
c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label. 
d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil. 
 
Experience in patients with HIV co-infection and prior lamivudine experience 
In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg in adult 
patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study 
ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir 
arm were 9.45 log10 copies/ml (n = 27).  Treatment with tenofovir disoproxil 245 mg was associated 
with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week 
data, of -5.74 log10 copies/ml (n = 18).  In addition, 61% of patients had normal ALT at week 48. 
 
Experience in patients with persistent viral replication (study GS-US-174-0106) 
The efficacy and safety of tenofovir disoproxil 245 mg or tenofovir disoproxil 245 mg plus 200 mg 
emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in 
HBeAg positive and HBeAg negative adult patients who had persistent viraemia 
(HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks.  At 
baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to 
emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine.  
Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with 
HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine 
plus tenofovir disoproxil (p = 0.672).  In addition 55% (29/53) of patients treated with tenofovir 
disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of 
the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus 
tenofovir disoproxil (p = 0.504).  Comparisons between treatment groups beyond week 24 are difficult 
to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus 
tenofovir disoproxil.  Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine 
plus tenofovir disoproxil in HBV monoinfected patients are ongoing. 



194 

 
Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) 
Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety 
and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and 
entecavir (n = 22), in patients with decompensated liver disease.  In the tenofovir disoproxil treatment 
arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum 
ALT of 61 U/l at baseline.  Forty-two percent (19/45) of patients had at least 6 months of prior 
lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 
45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline.  The 
co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in 
serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. 
 
In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of 
emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 
48 weeks of treatment. 
 
Overall, the data derived from this study are too limited to draw any definitive conclusions on the 
comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 8 below). 
 
Table 8: Safety and efficacy parameters in decompensated patients at week 48 
 
 Study 174-0108 
Parameter Tenofovir disoproxil 

245 mg  
(n = 45) 

Emtricitabine 200 mg/ 
tenofovir disoproxil 

245 mg  
(n = 45) 

Entecavir 
(0.5 mg or 1 mg) 

n = 22 

Tolerability failure 
(permanent 
discontinuation of study 
drug due to a treatment 
emergent AE) 
n (%)a 

3 (7%) 2 (4%) 2 (9%) 

Confirmed increase in 
serum creatinine 
≥ 0.5 mg/dl from 
baseline or confirmed 
serum phosphate of 
< 2 mg/dl 
n (%)b 

4 (9%) 3 (7%) 1 (5%) 

HBV DNA n (%) 
< 400 copies/ml 
n (%) 

31/44 (70%) 36/41 (88%) 16/22 (73%) 

ALT n (%) 
Normal ALT 

25/44 (57%) 31/41 (76%) 12/22 (55%) 

≥ 2 point decrease in 
CPT from baseline 
n (%) 

7/27 (26%) 12/25 (48%) 5/12 (42%) 

Mean change from 
baseline in CPT score 

-0.8 -0.9 -1.3 

Mean change from 
baseline in MELD score 

-1.8 -2.3 -2.6 

a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622, 
b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000. 
 
Experience beyond 48 weeks in study GS-US-174-0108 
Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir 
disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) 
of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. 
 



195 

Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121) 
The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind 
study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with 
compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of 
lamivudine resistance (rtM204I/V +/- rtL180M).  Only five had adefovir-associated resistance 
mutations at baseline.  One hundred forty-one and 139 adult subjects were randomised to a tenofovir 
disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively.  Baseline 
demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were 
HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and 
mean ALT was 79 U/l, respectively. 
 
After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had 
HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation.  After 240 weeks of 
treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had 
HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation.  Among the 
HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced 
HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240.  In 
the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects 
(19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion 
through week 240.  Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by 
Week 240, but not seroconversion to anti-HBs.  Five subjects randomised to emtricitabine plus 
tenofovir disoproxil experienced HBsAg loss, with 2 of these 5 subjects experiencing seroconversion 
to anti-HBs. 
 
Clinical resistance 
Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive 
(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil 
treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic 
changes in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 
(n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with 
tenofovir disoproxil resistance have developed. 
 
Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive 
(GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment 
and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes 
in HBV polymerase from baseline.  Genotypic evaluations performed on all patients with 
HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 
288 (n = 1) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated 
with tenofovir disoproxil resistance have developed. 
 
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil 
resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks.  Genotypic data 
from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA 
> 400 copies/ml at week 48.  No amino acid substitutions associated with resistance to tenofovir 
disoproxil were identified in these isolates.  Genotypic analysis was conducted for 5 subjects in the 
tenofovir disoproxil arm post week 48.  No amino acid substitutions associated with tenofovir 
disoproxil resistance were detected in any subject. 
 
In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received 
tenofovir disoproxil for up to 240 weeks.  Cumulatively, there were 4 patients who experienced a 
viremic episode (HBV DNA>400 copies/ml) at their last timepoint on tenofovir disoproxil.  Among 
them, sequence data from paired baseline and on treatment HBV isolates were available for 2 of 4 
patients.  No amino acid substitutions associated with resistance to tenofovir disoproxil were identified 
in these isolates. 
 



196 

In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance 
mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 
51/52 patients switched to open-label tenofovir disoproxil (tenofovir disoproxil-tenofovir disoproxil 
group).  Genotypic evaluations were performed on all patients within this group with HBV DNA 
> 400 copies/ml at week 48 (n = 6), week 72 (n = 5), week 96 (n = 4), week 144 (n = 2), and week 
192 (n = 3).  Fifty-four patients (including 2 patients with lamivudine resistance mutations at baseline) 
initially received blinded placebo treatment for 72 weeks, and 52/54 patients followed with tenofovir 
disoproxil (PLB-tenofovir disoproxil group).  Genotypic evaluations were performed on all patients 
within this group with HBV DNA > 400 copies/ml at week 96 (n = 17), week 144 (n = 7), and 
week 192 (n = 8).  No amino acid substitutions associated with resistance to tenofovir disoproxil were 
identified in these isolates. 
 
In a paediatric study (GS-US-174-0144), genotypic data from paired baseline and on treatment HBV 
isolates from patients who received tenofovir disoproxil were available for 9 of 10 patients who had 
plasma HBV DNA > 400 copies/ml.  No amino acid substitutions associated with resistance to 
tenofovir disoproxil were identified in these isolates by Week 48. 
 
Paediatric population 
HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years 
of age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an 
optimised background regimen (OBR) for 48 weeks.  Due to limitations of the study, a benefit of 
tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at 
week 24.  However, a benefit is expected for the adolescent population based on extrapolation of adult 
data and comparative pharmacokinetic data (see section 5.2). 
 
In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine 
BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, 
respectively, at baseline.  Mean changes at week 48 (end of double-blind phase) were -0.215 and 
-0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the 
tenofovir disoproxil and placebo groups, respectively.  The mean rate of BMD gain was less in the 
tenofovir disoproxil group compared to the placebo group.  At week 48, six adolescents in the 
tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD 
loss (defined as > 4% loss).  Among 28 patients receiving 96 weeks of treatment with tenofovir 
disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. 
 
In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, 
virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either 
replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original 
regimen (n = 49) for 48 weeks.  At week 48, 83% of patients in the tenofovir disoproxil treatment 
group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA 
concentrations < 400 copies/ml.  The difference in the proportion of patients who maintained 
< 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the 
tenofovir disoproxil treatment group.  When missing data were excluded, 91% of patients in the 
tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment 
group had HIV-1 RNA concentrations < 400 copies/ml at week 48. 
 
Reductions in BMD have been reported in paediatric patients.  In patients who received treatment with 
tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and 
-0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline.  Mean 
changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, 
and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or 
zidovudine groups, respectively.  The mean rate of lumbar spine bone gain at week 48 was similar 
between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group.  
Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine 
or zidovudine treatment group.  One tenofovir disoproxil treated subject and no stavudine or 
zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48.  
BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who 



197 

were treated with tenofovir disoproxil for 96 weeks.  BMD Z-scores were not adjusted for height and 
weight. 
 
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil 
discontinued study drug due to renal adverse events.  Five subjects (5.6%) had laboratory findings 
clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil 
therapy (median tenofovir disoproxil exposure 331 weeks). 
 
Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients 
aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT 
(≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with 
tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks.  Subjects must have been naïve 
to tenofovir disoproxil, but could have received interferon based regimens (> 6 months prior to 
screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotide 
therapy (> 16 weeks prior to screening).  At week 72, overall 88% (46/52) of patients in the tenofovir 
disoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA 
< 400 copies/ml.  Seventy-four percent (26/35) of patients in the tenofovir disoproxil group had 
normalised ALT at week 72 compared to 31% (13/42) in the placebo group.  Response to treatment 
with tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-
experienced (n = 32) patients, including lamivudine-resistant patients (n = 6).  Ninety-five percent of 
nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine-
resistant patients achieved HBV DNA < 400 copies/ml at week 72.  Thirty-one of the 32 nucleos(t)ide-
experienced patients had prior lamivudine experience.  At week 72, 96% (27/28) of immune-active 
patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil treatment 
group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml.  Seventy-five 
percent (21/28) of immune-active patients in the tenofovir disoproxil group had normal ALT at 
week 72 compared to 34% (11/32) in the placebo group. 
 
After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir 
disoproxil treatment up to week 192.  After week 72, virologic suppression was maintained for those 
receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (tenofovir 
disoproxil-tenofovir disoproxil group): 86.5% (45/52) of subjects in the tenofovir disoproxil-tenofovir 
disoproxil group had HBV DNA < 400 copies/ml at week 192.  Among the subjects who received 
placebo during the double-blind period, the proportion of subjects with HBV DNA < 400 copies/mL 
rose sharply after they began treatment with open-label tenofovir disoproxil (PLB-tenofovir disoproxil 
group): 74.1% (40/54) of subjects in the PLB-tenofovir disoproxil group had HBV DNA 
< 400 copies/ml at week 192.  The proportion of subjects with ALT normalization at week 192 in the 
tenofovir disoproxil-tenofovir disoproxil group was 75.8% (25/33) among those who were HBeAg 
positive at baseline and 100.0% (2 of 2 subjects) among those who were HBeAg negative at baseline.  
Similar percentages of subjects in the tenofovir disoproxil-tenofovir disoproxil and PLB-tenofovir 
disoproxil groups (37.5% and 41.7%, respectively) experienced seroconversion to anti-HBe through 
week 192. 
 
Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 9: 
 
Table 9: Bone Mineral Density Evaluation at Baseline, Week 72 and 192 
 

 

Baseline Week 72 Week 192 
Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Lumbar spine 
mean (SD) 
BMD Z-scorea 

−0.42  
(0.762) 

-0.26  
(0.806) 

-0.49  
(0.852)  -0.23 (0.893)  -0.37 (0.946)  -0.44 

(0.920)  



198 

 

Baseline Week 72 Week 192 
Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Tenofovir 
disoproxil-
tenofovir 
disoproxil 

PLB-
tenofovir 
disoproxil 

Lumbar spine 
mean (SD) 
change from 
baseline 
BMD Z-scorea 

NA NA -0.06  
(0.320) 

0.10  
(0.378) 

0.02  
(0.548) 

-0.10 
(0.543) 

Whole body 
mean (SD) 
BMD Z-scorea 

−0.19  
(1.110) 

−0.23 
(0.859) 

−0.36 
 (1.077) −0.12 (0.916) −0.38 (0.934) −0.42 

 (0.942) 

Whole body 
mean (SD) 
change from 
baseline 
BMD Z-scorea 

NA NA −0.16 (0.355) 0.09 
(0.349) 

-0.16 
(0.521) 

-0.19  
(0.504) 

Lumbar spine 
BMD at least 
6% decreaseb 

NA NA 1.9% 
(1 subject) 0% 3.8% 

(2 subjects) 
3.7% 

(2 subjects) 

Whole body 
BMD at least 
6% decreaseb 

NA NA 0% 0% 0% 1.9% 
(1 subject) 

Lumbar spine 
BMD mean % 
increase 

NA NA 5.14% 8.08% 10.05% 11.21% 

Whole body 
BMD mean % 
increase 

NA NA 3.07% 5.39% 6.09% 7.22% 

NA = Not Applicable 
a BMD Z-scores not adjusted for height and weight 
b Primary safety endpoint through week 72 
 
In study GS-US-174-0144, 89 HBeAg-negative and -positive patients aged 2 to < 12 years with 
chronic hepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of 245 mg 
(n = 60) or placebo (n = 29) once daily for 48 weeks.  Subjects must have been naïve to tenofovir 
disoproxil, with HBV DNA > 105 copies/mL (~ 4.2 log10 IU/mL) and ALT >1.5 × the upper limit of 
normal (ULN) at screening.  At week 48, 77% (46 of 60) of patients in the tenofovir disoproxil 
treatment group and 7% (2 of 29) of patients in the placebo group had HBV DNA < 400 copies/mL 
(69 IU/mL). Sixty-six percent (38 of 58) of patients in the tenofovir disoproxil group had normalized 
ALT at week 48 compared with 15% (4 of 27) in the placebo group. .Twenty-five percent(14 of 56) of 
patients in the tenofovir disoproxil group and 24% (7 of 29) of patients in the placebo group achieved 
HBeAg seroconversion at Week 48. 

Response to treatment with tenofovir disoproxil was comparable in treatment-naïve and treatment-
experienced subjects with 76% (38/50) of treatment-naïve and 80% (8/10) of treatment-experienced 
subjects achieving HBV DNA < 400 copies/mL (69 IU/ml) at Week 48. Response to treatment with 
tenofovir disoproxil was also similar in subjects who were HBeAg-negative compared with those who 
were HBeAg-positive at baseline with 77% (43/56) HBeAg-positive and 75.0% (3/4) HBeAg-negative 
subjects achieving HBV DNA < 400 copies/mL (69 IU/mL) at Week 48. The distribution of HBV 
genotypes at baseline was similar between the TDF and Placebo groups. The majority of subjects were 
either genotypes C (43.8%) or D (41.6%) with a lower and similar frequency of genotypes A and B 
(6.7% each). Only 1 subject randomized to the TDF group was genotype E at baseline. In general, 
treatment responses to tenofovir disoproxil were similar for genotypes A, B, C and E [75-100% of 
subjects achieved HBV DNA < 400 copies/mL (69 IU/mL) at Week 48] with a lower response rate in 
subjects with genotype D infection (55%). 

Bone Mineral Density (BMD) data from Study GS-US-174-0144 are summarized in Table 10: 
 



199 

Table 10: Bone Mineral Density Evaluation at Baseline and Week 48 
 

 Baseline Week 48 
TDF PLB TDF PLB 

Lumbar spine mean 
(SD) BMD Z-scorea 

0.02  
(0.977) 

-0.29  
(1.229) 

-0.11 
(0.983) 

-0.11 
(1.234) 

Lumbar spine mean 
(SD) change from 
baseline BMD Z-scorea 

NA NA -0.12  
(0.411) 

0.14 
(0.330) 

Whole body mean (SD) 
BMD Z-scorea 

0.11 
(0.743) 

−0.05 
(1.497) 

-0.34 
(0.939) 

0.20 
(1.299) 

Whole body mean (SD) 
change from baseline 
BMD Z-scorea 

NA NA −0.18 
(0.334) 

0.22 
(0.446) 

Lumbar spine BMD at 
least 4% decreaseb NA NA 18.3% 

(11 subjects) 
6.9% 

(2 subjects) 
Whole body BMD at 
least 4% decrease NA NA 6.7% 

(4 subjects) 0% 

Lumbar spine BMD 
mean % increaseb NA NA 3.8% 7.6% 

Whole body BMD mean 
% increase NA NA 4.5% 8.9% 

NA = Not Applicable 
a BMD Z-scores only available for a limited set of subjects with matched reference data 
b Secondary endpoint through week 48 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Viread in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir 
and formaldehyde. 
 
Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, 
tenofovir diphosphate. 
 
Absorption 
Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is 
rapidly absorbed and converted to tenofovir.  Administration of multiple doses of tenofovir disoproxil 
with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 
326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively.  Maximum tenofovir 
concentrations are observed in serum within one hour of dosing in the fasted state and within two 
hours when taken with food.  The oral bioavailability of tenofovir from tenofovir disoproxil in fasted 
patients was approximately 25%.  Administration of tenofovir disoproxil with a high fat meal 
enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax 
by approximately 14%.  Following the first dose of tenofovir disoproxil in fed patients, the median 
Cmax in serum ranged from 213 to 375 ng/ml.  However, administration of tenofovir disoproxil with a 
light meal did not have a significant effect on the pharmacokinetics of tenofovir. 
 
Distribution 
Following intravenous administration the steady-state volume of distribution of tenofovir was 
estimated to be approximately 800 ml/kg.  After oral administration of tenofovir disoproxil, tenofovir 
is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the 
intestinal contents (preclinical studies).  In vitro protein binding of tenofovir to plasma or serum 
protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 
25 µg/ml. 
 



200 

Biotransformation 
In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 
CYP450 enzymes.  Moreover, at concentrations substantially higher (approximately 300-fold) than 
those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major 
human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, 
CYP2E1, or CYP1A1/2).  Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any 
of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction 
in metabolism of CYP1A1/2 substrate was observed.  Based on these data, it is unlikely that clinically 
significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 
would occur. 
 
Elimination 
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system 
with approximately 70-80% of the dose excreted unchanged in urine following intravenous 
administration.  Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 
300 ml/min).  Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 
210 ml/min), which is in excess of the glomerular filtration rate.  This indicates that active tubular 
secretion is an important part of the elimination of tenofovir.  Following oral administration the 
terminal half-life of tenofovir is approximately 12 to 18 hours. 
 
Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal 
tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the 
multidrug resistant protein 4 (MRP 4). 
 
Linearity/non-linearity 
The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 
75 to 600 mg and were not affected by repeated dosing at any dose level. 
 
Age 
Pharmacokinetic studies have not been performed in the elderly (over 65 years of age). 
 
Gender 
Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. 
 
Ethnicity 
Pharmacokinetics have not been specifically studied in different ethnic groups. 
 
Paediatric population 
HIV-1: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent 
patients (aged 12 to < 18 years) with body weight ≥ 35 kg and in 23 HIV-1 infected children aged 
2 to < 12 years (see Table 11 below).  Tenofovir exposure achieved in these paediatric patients 
receiving oral daily doses of tenofovir disoproxil 245 mg or 6.5 mg/kg body weight tenofovir 
disoproxil up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving 
once-daily doses of tenofovir disoproxil 245 mg. 
 
Table 11: Mean (± SD) tenofovir pharmacokinetic parameters by age groups for paediatric 
patients 
 

Dose and formulation 245 mg film-coated tablet 
12 to < 18 years (n = 8) 

6.5 mg/kg granules 
2 to < 12 years (n = 23) 

Cmax (μg/ml) 0.38 ± 0.13 0.24 ± 0.13 
AUCtau (μg·h/ml) 3.39 ± 1.22 2.59 ± 1.06 

 
Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients 
(12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg was similar to 
exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg. 
 



201 

Tenofovir exposure in HBV infected paediatric patients 2 to < 12 years of age receiving an oral daily 
dose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of 
245 mg was similar to exposures achieved in HIV-1 infected paediatric patients 2 to <12 years of age 
receiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovir 
disoproxil 245 mg. 
 
Pharmacokinetic studies have not been performed in children under 2 years. 
 
Renal impairment 
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of 
tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of 
renal impairment defined according to baseline adult creatinine clearance (CrCl) (normal renal 
function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with 
CrCl = 30-49 ml/min and severe with CrCl = 10-29 ml/min).  Compared with patients with normal 
renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects 
with CrCl > 80 ml/min to respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 
(45%) ng·h/ml in patients with mild, moderate and severe renal impairment. 
 
Pharmacokinetic modelling of single-dose pharmacokinetic data in non-HIV and non-HBV infected 
adult subjects with varying degrees of renal impairment was used to determine dose and dosing 
interval recommendations for adult subjects with varying degrees of renal impairment (see 
section 4.2). 
 
Doses of 132 mg, 65 mg and 33 mg tenofovir disoproxil granules once daily are recommended in adult 
patients with calculated creatinine clearance (CrCl) of 30 to 49 ml/min, 20 to 29 ml/min or 10 to 
19 ml/min, respectively.  Although these doses are not expected to exactly reproduce the 
pharmacokinetic profile of tenofovir in patients with normal renal function receiving tenofovir 
disoproxil 245 mg film-coated tablets, they are considered to represent the best balance of benefit and 
risk for patients with renal impairment. 
 
In subjects with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, a dose 
of 16.5 mg tenofovir disoproxil following completion of haemodialysis is predicted to limit tenofovir 
systemic accumulation to exposures approximately 2-fold compared to those observed in patients with 
normal renal function receiving tenofovir disoproxil 245 mg film-coated tablets.  This dosing 
recommendation balances the need to limit drug accumulation while attempting to maintain sufficient 
tenofovir concentrations over the dosing interval similar to trough concentrations observed in patients 
with normal renal function receiving tenofovir disoproxil 245 mg film-coated tablets. 
 
The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance 
< 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not 
been studied. 
 
The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied.  
No data are available to make dose recommendations (see sections 4.2 and 4.4). 
 
Hepatic impairment 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult 
patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) 
classification.  Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic 
impairment suggesting that no dose adjustment is required in these subjects.  The mean (%CV) 
tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, 
in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with 
moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with 
severe hepatic impairment. 
 



202 

Intracellular pharmacokinetics 
In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir 
diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-
stimulated PBMCs was found to be approximately 10 hours. 
 
5.3 Preclinical safety data 
 
Non-clinical safety pharmacology studies reveal no special hazard for humans.  Findings in repeated 
dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical 
exposure levels and with possible relevance to clinical use include renal and bone toxicity and a 
decrease in serum phosphate concentration.  Bone toxicity was diagnosed as osteomalacia (monkeys) 
and reduced bone mineral density (BMD) (rats and dogs).  The bone toxicity in young adult rats and 
dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred 
in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the 
exposure in patients).  Findings in the rat and monkey studies indicated that there was a substance-
related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD. 
 
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results 
in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat 
hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay. 
 
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an 
extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 
 
Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal 
parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in peri-
postnatal toxicity studies at maternally toxic doses. 
 
Environmental Risk Assessment (ERA) 
The active substance tenofovir disoproxil and its main transformation products are persistent in the 
environment. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Ethylcellulose (E462) 
Hydroxypropyl cellulose (E463) 
Mannitol (E421) 
Silicon dioxide (E551) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 



203 

6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 60 g 
of granules and a dosing scoop. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 February 2002 
Date of latest renewal: 14 December 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

http://www.ema.europa.eu/


204 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



205 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Takeda GmbH 
Lehnitzstrasse 70-98 
D-16515 Oranienburg 
Germany 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing 
Authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 
The marketing authorisation holder (MAH) shall ensure that all physicians who are expected to 
prescribe/use Viread in paediatric patients are provided with a physician educational pack containing 
the Summary of Product Characteristics and an appropriate educational brochure, as detailed below: 
 
• HIV paediatric educational brochure 



206 

• HBV paediatric educational brochure 
 
The HIV and HBV paediatric educational brochures should contain the following key messages: 
 
• That a multidisciplinary approach is recommended for the management of paediatric patients 
• That there is an increased risk of renal disease in HIV and HBV infected patients associated 

with tenofovir disoproxil fumarate-containing products such as Viread 
• That Viread is not recommended for use in paediatric patients with renal impairment 
• That use of Viread should be avoided with concomitant or recent use of nephrotoxic medicinal 

products.  If Viread is used with nephrotoxic medicinal products, renal function should be 
closely monitored according to the recommended schedule 

• That patients should have their baseline renal function assessed prior to initiating Viread therapy 
• The importance of regular monitoring of renal function during Viread therapy 
• Recommended schedule for monitoring renal function considering the presence or absence of 

additional risk factors for renal impairment 
• That if serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient 

receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week.  
If renal abnormalities are detected or suspected then consultation with a nephrologist should be 
obtained to consider interruption of Viread treatment.  Interrupting treatment with Viread should 
also be considered in case of progressive decline of renal function when no other cause has been 
identified. 

• That Viread may cause a reduction in BMD and the effects of Viread associated changes in 
BMD on long term bone health and future fracture risk are uncertain in paediatric patients 

• That if bone abnormalities are detected or suspected then consultation with an endocrinologist 
and/or nephrologist should be obtained 

 
 



207 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



208 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



209 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 123 mg film-coated tablets 
tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 123 mg of tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets. 
30 tablets. 
 
90 (3 bottles of 30) film-coated tablets. 
90 (3 bottles of 30) tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



210 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/004 30 film-coated tablets 
EU/1/01/200/005 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Viread 123 mg [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC {number} 
SN {number} 
NN {number} 
[Outer packaging only] 
 



211 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 163 mg film-coated tablets 
tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 163 mg of tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets. 
30 tablets. 
 
90 (3 bottles of 30) film-coated tablets. 
90 (3 bottles of 30) tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



212 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, 
IF APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/006 30 film-coated tablets 
EU/1/01/200/007 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Viread 163 mg [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC {number} 
SN {number} 
NN {number} 
[Outer packaging only] 



213 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 204 mg film-coated tablets 
tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 204 mg of tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets. 
30 tablets. 
 
90 (3 bottles of 30) film-coated tablets. 
90 (3 bottles of 30) tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



214 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, 
IF APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/008 30 film-coated tablets 
EU/1/01/200/009 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Viread 204 mg [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC {number} 
SN {number} 
NN {number} 
[Outer packaging only] 



215 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 245 mg film-coated tablets 
tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 245 mg of tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets. 
30 tablets. 
 
90 (3 bottles of 30) film-coated tablets. 
90 (3 bottles of 30) tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



216 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, 
IF APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/001 30 film-coated tablets 
EU/1/01/200/002 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Viread 245 mg [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC {number} 
SN {number} 
NN {number} 
[Outer packaging only] 



217 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Viread 33 mg/g granules 
tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each scoop delivers one gram of granules which contains 33 mg of tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 g granules. 
 
Use with the supplied dosing scoop. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
 
 



218 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/200/003 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Viread granules [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC {number} 
SN {number} 
NN {number} 
[Outer packaging only] 



219 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



220 

Package leaflet: Information for the user 
 

Viread 123 mg film-coated tablets 
tenofovir disoproxil 

 
Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your child’s doctor or pharmacist. 
- This medicine has been prescribed for your child only.  Do not pass it on to others.  It may harm 

them, even if their signs of illness are the same as your child’s. 
- If your child gets any side effects, talk to your child’s doctor or pharmacist.  This includes any 

possible side effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
1. What Viread is and what it is used for 
2. What you need to know before your child takes Viread 
3. How to take Viread 
4. Possible side effects 
5. How to store Viread 
6. Contents of the pack and other information 
 
 
1. What Viread is and what it is used for 
 
Viread contains the active substance tenofovir disoproxil.  This active substance is an antiretroviral or 
antiviral medicine which is used to treat HIV or HBV infection or both.  Tenofovir is a nucleotide 
reverse transcriptase inhibitor, generally known as an NRTI and works by interfering with the normal 
working of an enzyme (in HIV reverse transcriptase, in hepatitis B DNA polymerase) that are 
essential for the viruses to reproduce themselves.  In HIV Viread should always be used combined 
with other medicines to treat HIV infection. 
 
Viread 123 mg tablets are a treatment for HIV (Human Immunodeficiency Virus) infection. 
 
Viread 123 mg tablets are for use in children.  They are only suitable for: 
• children aged 6 to less than 12 years 
• who weigh from 17 kg to less than 22 kg 
• who have already been treated with other HIV medicines which are no longer fully effective 

due to development of resistance, or have caused side effects. 
 
Viread 123 mg tablets are also a treatment for chronic hepatitis B, an infection with HBV 
(hepatitis B virus). 
 
Viread 123 mg tablets are for use in children.  They are only suitable for: 
• children aged 6 to less than 12 years 
• who weigh from 17 kg to less than 22 kg 
 
Your child does not have to have HIV to be treated with Viread for HBV. 
 
This medicine is not a cure for HIV infection.  While taking Viread your child may still develop 
infections or other illnesses associated with HIV infection.  Your child can also pass on HIV or HBV 
to others, so it is important to take precautions to avoid infecting other people. 
 
 



221 

2. What you need to know before your child takes Viread 
 
Do not give Viread 
 
• If your child is allergic to tenofovir, tenofovir disoproxil or any of the other ingredients of this 

medicine listed in section 6. 
 

 If this applies to your child, tell their doctor immediately and don’t give Viread. 
 
Warnings and precautions 
 
• For HIV, Viread 123 mg tablets are only suitable for children who have already been treated 

with other HIV medicines which are no longer fully effective due to development of resistance, 
or have caused side effects. 

 
• Check your child’s age and weight to see if Viread 123 mg tablets are suitable, see Children 

and adolescents. 
 
Talk to your child’s doctor or pharmacist before giving Viread. 
 
• Take care not to infect other people.  Your child can still pass on HIV when taking this 

medicine, although the risk is lowered by effective antiretroviral therapy.  Viread does not 
reduce the risk of passing on HBV to others through sexual contact or blood contamination. 
Discuss with your child’s doctor the precautions needed to avoid infecting other people. 

 
• Talk to your child’s doctor or pharmacist if your child has had kidney disease or if tests 

have shown problems with their kidneys.  Viread should not be given to children with 
existing kidney problems.  Viread may affect your child’s kidneys during treatment.  Before 
starting treatment, your child’s doctor may order blood tests to assess your child’s kidney 
function.  Your child’s doctor may also order blood tests during treatment to monitor how your 
child’s kidneys work. 

 
Viread is not usually taken with other medicines that can damage your child’s kidneys (see 
Other medicines and Viread).  If this is unavoidable, your child’s doctor will monitor your 
child’s kidney function once a week. 
 

• Bone problems.  Some adult patients with HIV taking combination antiretroviral therapy may 
develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply 
to the bone).  The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be some 
of the many risk factors for developing this disease.  Signs of osteonecrosis are joint stiffness, 
aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If you 
notice any of these symptoms tell your child’s doctor. 

 
Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in 
fractures) may also occur due to damage to kidney tubule cells (see section 4, Possible side 
effects). Tell your child’s doctor if your child has bone pain or fractures. 
 
Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss was 
seen in clinical studies when patients were treated with tenofovir disoproxil in combination with 
a boosted protease inhibitor. 
 
Overall, the effects of tenofovir disoproxil on long term bone health and future fracture risk in 
adult and paediatric patients are uncertain.  
 
Tell your child’s doctor if your child suffers from osteoporosis. Patients with osteoporosis are at 
a higher risk for fractures. 



222 

 
• Talk to your child’s doctor if your child has a history of liver disease, including hepatitis.  

Patients with liver disease including chronic hepatitis B or C, who are treated with 
antiretrovirals, have a higher risk of severe and potentially fatal liver complications.  If your 
child has hepatitis B infection, your child’s doctor will carefully consider the best treatment for 
them.  If your child has a history of liver disease or chronic hepatitis B infection your child’s 
doctor may conduct blood tests to monitor their liver function. 

 
• Look out for infections.  If your child has advanced HIV infection (AIDS) and has an 

infection, they may develop symptoms of infection and inflammation or worsening of the 
symptoms of an existing infection once treatment with Viread is started.  These symptoms may 
indicate that your child’s body’s improved immune system is fighting infection.  Look out for 
signs of inflammation or infection soon after your child starts taking Viread.  If you notice signs 
of inflammation or infection, tell your child’s doctor at once. 

 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after your child starts taking 
medicines for the treatment of their HIV infection.  Autoimmune disorders may occur many 
months after the start of treatment.  If you notice that your child has any symptoms of infection 
or other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform 
your child’s doctor immediately to seek necessary treatment. 

 
Children and adolescents 
 
Viread 123 mg tablets are only suitable for: 
• HIV-1 infected children aged 6 to less than 12 years who weigh from 17 kg to less than 

22 kg who have already been treated with other HIV medicines which are no longer fully 
effective due to development of resistance, or have caused side effects. 
 

• HBV infected children aged 6 to less than 12 years who weigh from 17 kg to less than 
22 kg 

 
Viread 123 mg tablets are not suitable for the following groups: 
• Not for children who weigh under 17 kg or 22 kg and over.  Contact your child’s doctor if your 

child is outside the permitted weight. 
• Not for children and adolescents under 6 years or 12 years and over. 

 
For dosage see section 3, How to take Viread. 
 
Other medicines and Viread 
 
Tell your child’s doctor or pharmacist if they are taking, have recently taken or might take any other 
medicines. 
 
• Don’t stop any anti-HIV medicines prescribed by your child’s doctor when they start Viread if 

they have both HBV and HIV. 
 
• Do not give Viread if your child is already taking other medicines containing tenofovir 

disoproxil or tenofovir alafenamide.  Do not give Viread together with medicines containing 
adefovir dipivoxil (a medicine used to treat chronic hepatitis B). 

 



223 

• It is very important to tell your child’s doctor if your child is taking other medicines that 
may damage their kidneys. 

 
These include: 

 
• aminoglycosides, pentamidine or vancomycin (for bacterial infection), 
• amphotericin B (for fungal infection), 
• foscarnet, ganciclovir, or cidofovir (for viral infection), 
• interleukin-2 (to treat cancer), 
• adefovir dipivoxil (for HBV), 
• tacrolimus (for suppression of the immune system), 
• non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains). 

 
• Other medicines containing didanosine (for HIV infection): Taking Viread with other 

antiviral medicines that contain didanosine can raise the levels of didanosine in the blood and 
may reduce CD4 cell counts.  Rarely, inflammation of the pancreas and lactic acidosis (excess 
lactic acid in the blood), which sometimes caused death, have been reported when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your child’s doctor will 
carefully consider whether to treat your child with combinations of tenofovir and didanosine. 
 

• It is also important to tell your doctor if your child is taking ledipasvir/sofosbuvir, 
sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir to treat hepatitis C infection. 

 
Viread with food and drink 
 
Give Viread with food (for example, a meal or a snack). 
 
Pregnancy and breastfeeding 
 
If your child is pregnant or breastfeeding, or they think they may be pregnant, ask your child’s doctor 
or pharmacist for advice before they take this medicine. 
 
• If your child has taken Viread during their pregnancy, your child’s doctor may request regular 

blood tests and other diagnostic tests to monitor the development of the baby.  In children 
whose mothers took medicines like Viread (NRTIs) during pregnancy, the benefit from the 
protection against the virus outweighed the risk of side effects. 

 
• If your child has HBV, and their baby has been given treatment to prevent hepatitis B 

transmission at birth, your child may be able to breast-feed their infant, but first talk to your 
child’s doctor to get more information. 

 
• If your child has HIV they must not breastfeed, to avoid passing the virus to the baby in breast 

milk. 
 
Driving and using machines 
 
Viread can cause dizziness.  If your child feels dizzy while taking Viread, they must not drive or ride 
a bicycle and must not use any tools or machines. 
 
Viread contains lactose 
 
Tell your child’s doctor before giving Viread.  If you have been told by your child’s doctor that 
your child has an intolerance to some sugars, contact your child’s doctor before they take this 
medicinal product. 
 
Viread contains sodium 



224 

 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
3. How to take Viread 
 
Your child must always take this medicine exactly as their doctor or pharmacist has told you.  
Check with your child’s doctor or pharmacist if you are not sure. 
 
The recommended dose is: 
• Children aged 6 to less than 12 years who weigh from 17 kg to less than 22 kg: 

1 tablet each day with food (for example, a meal or a snack). 
 
Your child’s doctor will monitor their weight. 
 
Your child must always take the dose recommended by their doctor.  This is to make sure that 
their medicine is fully effective, and to reduce the risk of developing resistance to the treatment.  Do 
not change the dose unless your child’s doctor tells you to. 
 
For HIV, your child’s doctor will prescribe Viread with other antiretroviral medicines. 
 
Refer to the patient information leaflets of the other antiretrovirals for guidance on how to take those 
medicines. 
 
If your child takes more Viread than they should 
 
If your child accidentally takes too many Viread tablets, they may be at increased risk of experiencing 
possible side effects with this medicine (see section 4, Possible side effects).  Contact your child’s 
doctor or nearest emergency department for advice.  Keep the tablet bottle with you so that you can 
easily describe what your child has taken. 
 
If your child forgets to take Viread 
 
It is important not to miss a dose of Viread.  If your child misses a dose, work out how long since they 
should have taken it. 
 
• If it is less than 12 hours after it is usually taken, they should take it as soon as they can, and 

then take their next dose at its regular time. 
 
• If it is more than 12 hours since your child should have taken it, forget about the missed dose.  

Wait and give the next dose at the regular time.  Do not give a double dose to make up for a 
forgotten tablet. 

 
If your child throws up less than 1 hour after taking Viread, give your child another tablet.  Your 
child does not need to take another tablet if they were sick more than 1 hour after taking Viread. 
 
If your child stops taking Viread 
 
Your child must not stop taking Viread without their doctor’s advice.  Stopping treatment with Viread 
may reduce the effectiveness of the treatment recommended by your child’s doctor. 
 
If your child has hepatitis B or HIV and hepatitis B together (co-infection), it is very important 
not to stop their Viread treatment without talking to your child’s doctor first.  Some patients have had 
blood tests or symptoms indicating that their hepatitis has got worse after stopping Viread.  Your child 
may require blood tests for several months after stopping treatment.  In some patients with advanced 
liver disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of 
your child’s hepatitis. 



225 

 
• Talk to your child’s doctor before your child stops taking Viread for any reason, particularly if 

your child is experiencing any side effects or they have another illness. 
 
• Tell your child’s doctor immediately about new or unusual symptoms after your child stops 

treatment, particularly symptoms you associate with hepatitis B infection. 
 
• Contact your child’s doctor before your child restarts taking Viread tablets. 
 
If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your child’s doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Possible serious side effects: tell your child’s doctor immediately 
 
• Lactic acidosis (excess lactic acid in the blood) is a rare (can affect up to 1 in every 

1,000 patients) but serious side effect that can be fatal.  The following side effects may be signs 
of lactic acidosis: 

 
• deep, rapid breathing 
• drowsiness 
• feeling sick (nausea), being sick (vomiting) and stomach pain 

 
 If you think that your child may have lactic acidosis, contact your child’s doctor immediately. 
 
Other possible serious side effects 
 
The following side effects are uncommon (this can affect up to 1 in every 100 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the pancreas 
 
• damage to kidney tubule cells 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• inflammation of the kidney, passing a lot of urine and feeling thirsty 
 
• changes to your child’s urine and back pain caused by kidney problems, including kidney 

failure 
 
• softening of the bones (with bone pain and sometimes resulting in fractures), which may occur 

due to damage to kidney tubule cells 
 
• fatty liver 
 
 If you think that your child may have any of these serious side effects, talk to your child’s 

doctor. 
 



226 

Most frequent side effects 
 
The following side effects are very common (these can affect at least 10 in every 100 patients): 
 
• diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, rash, feeling weak 
 
Tests may also show: 
 
• decreases in phosphate in the blood 
 
Other possible side effects 
 
The following side effects are common (these can affect up to 10 in every 100 patients): 
 
• flatulence 
 
Tests may also show: 
 
• liver problems 
 
The following side effects are uncommon (these can affect up to 1 in every 100 patients): 
 
• breakdown of muscle, muscle pain or weakness 
 
Tests may also show: 
 
• decreases in potassium in the blood 
 
• increased creatinine in your child’s blood 
 
• pancreas problems 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the liver 
 
• swelling of the face, lips, tongue or throat 
 
Reporting of side effects 
If your child gets any side effects, talk to your child’s doctor or pharmacist.  This includes any 
possible side effects not listed in this leaflet.  You can also report side effects directly via the national 
reporting system listed in Appendix V.  By reporting side effects you can help provide more 
information on the safety of this medicine. 
 
 
5. How to store Viread 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


227 

This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Viread contains 
 
- The active substance is tenofovir.  Each Viread tablet contains 123 mg of tenofovir disoproxil 

(as fumarate). 
 
- The other ingredients are microcrystalline cellulose (E460), starch pregelatinised, 

croscarmellose sodium, lactose monohydrate, and magnesium stearate (E572) which make up 
the tablet core, and lactose monohydrate, hypromellose (E464), titanium dioxide (E171) and 
glycerol triacetate (E1518) which make up the tablet coating.  Refer to section 2 “Viread 
contains lactose”. 

 
What Viread looks like and contents of the pack 
 
Viread 123 mg film-coated tablets are white, triangle-shaped, film-coated tablets, 8.5 mm in diameter, 
debossed on one side with “GSI” and on the other side with “150”.  Viread 123 mg film-coated tablets 
are supplied in bottles containing 30 tablets.  Each bottle contains a silica gel desiccant that must be 
kept in the bottle to help protect your tablets.  The silica gel desiccant is contained in a separate sachet 
or canister and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
3 bottles of 30 film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer: 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 



228 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



229 

Package leaflet: Information for the user 
 

Viread 163 mg film-coated tablets 
tenofovir disoproxil 

 
Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your child’s doctor or pharmacist. 
- This medicine has been prescribed for your child only.  Do not pass it on to others.  It may harm 

them, even if their signs of illness are the same as your child’s. 
- If your child gets any side effects, talk to your child’s doctor or pharmacist.  This includes any 

possible side effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
1. What Viread is and what it is used for 
2. What you need to know before your child takes Viread 
3. How to take Viread 
4. Possible side effects 
5. How to store Viread 
6. Contents of the pack and other information 
 
 
1. What Viread is and what it is used for 
 
Viread contains the active substance tenofovir disoproxil.  This active substance is an antiretroviral or 
antiviral medicine which is used to treat HIV or HBV infection or both.  Tenofovir is a nucleotide 
reverse transcriptase inhibitor, generally known as an NRTI and works by interfering with the normal 
working of an enzyme (in HIV reverse transcriptase, in hepatitis B DNA polymerase) that are 
essential for the viruses to reproduce themselves.  In HIV Viread should always be used combined 
with other medicines to treat HIV infection. 
 
Viread 163 mg tablets are a treatment for HIV (Human Immunodeficiency Virus) infection. 
 
Viread 163 mg tablets are for use in children.  They are only suitable for: 
• children aged 6 to less than 12 years 
• who weigh from 22 kg to less than 28 kg 
• who have already been treated with other HIV medicines which are no longer fully effective 

due to development of resistance, or have caused side effects. 
 
Viread 163 mg tablets are also a treatment for chronic hepatitis B, an infection with HBV 
(hepatitis B virus). 
 
Viread 163 mg tablets are for use in children.  They are only suitable for: 
• children aged 6 to less than 12 years 
• who weigh from 22 kg to less than 28 kg 
 
Your child does not have to have HIV to be treated with Viread for HBV. 
 
This medicine is not a cure for HIV infection.  While taking Viread your child may still develop 
infections or other illnesses associated with HIV infection.  Your child can also pass on HIV or HBV 
to others, so it is important to take precautions to avoid infecting other people. 
 
 



230 

2. What you need to know before your child takes Viread 
 
Do not give Viread 
 
• If your child is allergic to tenofovir, tenofovir disoproxil or any of the other ingredients of this 

medicine listed in section 6. 
 

 If this applies to your child, tell their doctor immediately and don’t give Viread. 
 
Warnings and precautions 
 
• For HIV, Viread 163 mg tablets are only suitable for children who have already been treated 

with other HIV medicines which are no longer fully effective due to development of resistance, 
or have caused side effects. 

 
• Check your child’s age and weight to see if Viread 163 mg tablets are suitable, see Children 

and adolescents. 
 
Talk to your child’s doctor or pharmacist before giving Viread. 
 
• Take care not to infect other people.  Your child can still pass on HIV when taking this 

medicine, although the risk is lowered by effective antiretroviral therapy.  Viread does not 
reduce the risk of passing on HBV to others through sexual contact or blood contamination. 
Discuss with your child’s doctor the precautions needed to avoid infecting other people. 

 
• Talk to your child’s doctor or pharmacist if your child has had kidney disease or if tests 

have shown problems with their kidneys.  Viread should not be given to children with 
existing kidney problems.  Viread may affect your child’s kidneys during treatment.  Before 
starting treatment, your child’s doctor may order blood tests to assess your child’s kidney 
function.  Your child’s doctor may also order blood tests during treatment to monitor how your 
child’s kidneys work. 

 
Viread is not usually taken with other medicines that can damage your child’s kidneys (see 
Other medicines and Viread).  If this is unavoidable, your child’s doctor will monitor your 
child’s kidney function once a week. 
 

• Bone problems.  Some adult patients with HIV taking combination antiretroviral therapy may 
develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply 
to the bone).  The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be some 
of the many risk factors for developing this disease.  Signs of osteonecrosis are joint stiffness, 
aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If you 
notice any of these symptoms tell your child’s doctor. 

 
Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in 
fractures) may also occur due to damage to kidney tubule cells (see section 4, Possible side 
effects). Tell your child’s doctor if your child has bone pain or fractures. 
 
Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss was 
seen in clinical studies when patients were treated with tenofovir disoproxil in combination with 
a boosted protease inhibitor. 
 
Overall, the effects of tenofovir disoproxil on long term bone health and future fracture risk in 
adult and paediatric patients are uncertain.  
 
Tell your child’s doctor if your child suffers from osteoporosis. Patients with osteoporosis are at 
a higher risk for fractures. 



231 

 
• Talk to your child’s doctor if your child has a history of liver disease, including hepatitis.  

Patients with liver disease including chronic hepatitis B or C, who are treated with 
antiretrovirals, have a higher risk of severe and potentially fatal liver complications.  If your 
child has hepatitis B infection, your child’s doctor will carefully consider the best treatment for 
them.  If your child has a history of liver disease or chronic hepatitis B infection your child’s 
doctor may conduct blood tests to monitor their liver function. 

 
• Look out for infections.  If your child has advanced HIV infection (AIDS) and has an 

infection, they may develop symptoms of infection and inflammation or worsening of the 
symptoms of an existing infection once treatment with Viread is started.  These symptoms may 
indicate that your child’s body’s improved immune system is fighting infection.  Look out for 
signs of inflammation or infection soon after your child starts taking Viread.  If you notice signs 
of inflammation or infection, tell your child’s doctor at once. 

 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after your child starts taking 
medicines for the treatment of their HIV infection.  Autoimmune disorders may occur many 
months after the start of treatment.  If you notice that your child has any symptoms of infection 
or other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform 
your child’s doctor immediately to seek necessary treatment. 

 
Children and adolescents 
 
Viread 163 mg tablets are only suitable for: 
• HIV-1 infected children aged 6 to less than 12 years who weigh from 22 kg to less than 

28 kg who have already been treated with other HIV medicines which are no longer fully 
effective due to development of resistance, or have caused side effects. 

• HBV infected children aged 6 to less than 12 years who weigh from 22 kg to less than 28 kg 
 
Viread 163 mg tablets are not suitable for the following groups: 
• Not for children who weigh under 22 kg or 28 kg and over.  Contact your child’s doctor if your 

child is outside the permitted weight. 
• Not for children and adolescents under 6 years or 12 years and over. 
 
For dosage see section 3, How to take Viread. 
 
Other medicines and Viread 
 
Tell your child’s doctor or pharmacist if they are taking, have recently taken or might take any other 
medicines. 
 
• Don’t stop any anti-HIV medicines prescribed by your child’s doctor when they start Viread if 

they have both HBV and HIV. 
 

• Do not give Viread if your child is already taking other medicines containing tenofovir 
disoproxil or tenofovir alafenamide.  Do not give Viread together with medicines containing 
adefovir dipivoxil (a medicine used to treat chronic hepatitis B). 

 
• It is very important to tell your child’s doctor if your child is taking other medicines that 

may damage their kidneys. 
 

These include: 
 

• aminoglycosides, pentamidine or vancomycin (for bacterial infection), 



232 

• amphotericin B (for fungal infection), 
• foscarnet, ganciclovir, or cidofovir (for viral infection), 
• interleukin-2 (to treat cancer), 
• adefovir dipivoxil (for HBV), 
• tacrolimus (for suppression of the immune system), 
• non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains). 

 
• Other medicines containing didanosine (for HIV infection): Taking Viread with other 

antiviral medicines that contain didanosine can raise the levels of didanosine in the blood and 
may reduce CD4 cell counts.  Rarely, inflammation of the pancreas and lactic acidosis (excess 
lactic acid in the blood), which sometimes caused death, have been reported when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your child’s doctor will 
carefully consider whether to treat your child with combinations of tenofovir and didanosine. 
 

• It is also important to tell your doctor if your child is taking ledipasvir/sofosbuvir, 
sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir to treat hepatitis C infection. 

 
Viread with food and drink 
 
Give Viread with food (for example, a meal or a snack). 
 
Pregnancy and breastfeeding 
 
If your child is pregnant or breastfeeding, or they think they may be pregnant, ask your child’s doctor 
or pharmacist for advice before they take this medicine. 
 
• If your child has taken Viread during their pregnancy, your child’s doctor may request regular 

blood tests and other diagnostic tests to monitor the development of the baby.  In children 
whose mothers took medicines like Viread (NRTIs) during pregnancy, the benefit from the 
protection against the virus outweighed the risk of side effects. 

 
• If your child has HBV, and their baby has been given treatment to prevent hepatitis B 

transmission at birth, your child may be able to breast-feed their infant, but first talk to your 
child’s doctor to get more information. 

 
• If your child has HIV they must not breastfeed, to avoid passing the virus to the baby in breast 

milk. 
 
Driving and using machines 
 
Viread can cause dizziness.  If your child feels dizzy while taking Viread, they must not drive or ride 
a bicycle and must not use any tools or machines. 
 
Viread contains lactose 
 
Tell your child’s doctor before giving Viread.  If you have been told by your child’s doctor that 
your child has an intolerance to some sugars, contact your child’s doctor before they take this 
medicinal product. 
 
Viread contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 



233 

3. How to take Viread 
 
Your child must always take this medicine exactly as their doctor or pharmacist has told you.  
Check with your child’s doctor or pharmacist if you are not sure. 
 
The recommended dose is: 
• Children aged 6 to less than 12 years who weigh from 22 kg to less than 28 kg: 

1 tablet each day with food (for example, a meal or a snack). 
 
Your child’s doctor will monitor their weight. 
 
Your child must always take the dose recommended by their doctor.  This is to make sure that 
their medicine is fully effective, and to reduce the risk of developing resistance to the treatment.  Do 
not change the dose unless your child’s doctor tells you to. 
 
For HIV, your child’s doctor will prescribe Viread with other antiretroviral medicines. 
 
Refer to the patient information leaflets of the other antiretrovirals for guidance on how to take those 
medicines. 
 
If your child takes more Viread than they should 
 
If your child accidentally takes too many Viread tablets, they may be at increased risk of experiencing 
possible side effects with this medicine (see section 4, Possible side effects).  Contact your child’s 
doctor or nearest emergency department for advice.  Keep the tablet bottle with you so that you can 
easily describe what your child has taken. 
 
If your child forgets to take Viread 
 
It is important not to miss a dose of Viread.  If your child misses a dose, work out how long since they 
should have taken it. 
 
• If it is less than 12 hours after it is usually taken, they should take it as soon as they can, and 

then take their next dose at its regular time. 
 
• If it is more than 12 hours since your child should have taken it, forget about the missed dose.  

Wait and give the next dose at the regular time.  Do not give a double dose to make up for a 
forgotten tablet. 

 
If your child throws up less than 1 hour after taking Viread, give your child another tablet.  Your 
child does not need to take another tablet if they were sick more than 1 hour after taking Viread. 
 
If your child stops taking Viread 
 
Your child must not stop taking Viread without their doctor’s advice.  Stopping treatment with Viread 
may reduce the effectiveness of the treatment recommended by your child’s doctor. 
 
If your child has hepatitis B or HIV and hepatitis B together (co-infection),it is very important not 
to stop their Viread treatment without talking to your child’s doctor first.  Some patients have had 
blood tests or symptoms indicating that their hepatitis has got worse after stopping Viread.  Your child 
may require blood tests for several months after stopping treatment.  In some patients with advanced 
liver disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of 
your child’s hepatitis. 
 
• Talk to your child’s doctor before your child stops taking Viread for any reason, particularly if 

your child is experiencing any side effects or they have another illness. 
 



234 

• Tell your child’s doctor immediately about new or unusual symptoms after your child stops 
treatment, particularly symptoms you associate with hepatitis B infection. 

 
• Contact your child’s doctor before your child restarts taking Viread tablets. 
 
If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your child’s doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Possible serious side effects: tell your child’s doctor immediately 
 
• Lactic acidosis (excess lactic acid in the blood) is a rare (can affect up to 1 in every 

1,000 patients) but serious side effect that can be fatal.  The following side effects may be signs 
of lactic acidosis: 

 
• deep, rapid breathing 
• drowsiness 
• feeling sick (nausea), being sick (vomiting) and stomach pain 

 
 If you think that your child may have lactic acidosis, contact your child’s doctor immediately. 
 
Other possible serious side effects 
 
The following side effects are uncommon (this can affect up to 1 in every 100 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the pancreas 
 
• damage to kidney tubule cells 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• inflammation of the kidney, passing a lot of urine and feeling thirsty 
 
• changes to your child’s urine and back pain caused by kidney problems, including kidney 

failure 
 
• softening of the bones (with bone pain and sometimes resulting in fractures), which may occur 

due to damage to kidney tubule cells 
 
• fatty liver 
 
 If you think that your child may have any of these serious side effects, talk to your child’s 

doctor. 
 
Most frequent side effects 
 
The following side effects are very common (these can affect at least 10 in every 100 patients): 
 
• diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, rash, feeling weak 



235 

 
Tests may also show: 
 
• decreases in phosphate in the blood 
 
Other possible side effects 
 
The following side effects are common (these can affect up to 10 in every 100 patients): 
 
• flatulence 
 
Tests may also show: 
 
• liver problems 
 
The following side effects are uncommon (these can affect up to 1 in every 100 patients): 
 
• breakdown of muscle, muscle pain or weakness 
 
Tests may also show: 
 
• decreases in potassium in the blood 
 
• increased creatinine in your child’s blood 
 
• pancreas problems 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the liver 
 
• swelling of the face, lips, tongue or throat 
 
Reporting of side effects 
If your child gets any side effects, talk to your child’s doctor or pharmacist.  This includes any 
possible side effects not listed in this leaflet.  You can also report side effects directly via the national 
reporting system listed in Appendix V.  By reporting side effects you can help provide more 
information on the safety of this medicine. 
 
 
5. How to store Viread 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


236 

6. Contents of the pack and other information 
 
What Viread contains 
 
- The active substance is tenofovir.  Each Viread tablet contains 163 mg of tenofovir disoproxil 

(as fumarate). 
 
- The other ingredients are microcrystalline cellulose (E460), starch pregelatinised, 

croscarmellose sodium, lactose monohydrate, and magnesium stearate (E572) which make up 
the tablet core, and lactose monohydrate, hypromellose (E464), titanium dioxide (E171) and 
glycerol triacetate (E1518) which make up the tablet coating.  Refer to section 2 “Viread 
contains lactose”. 

 
What Viread looks like and contents of the pack 
 
Viread 163 mg film-coated tablets are white, round-shaped, film-coated tablets, 10.7 mm in diameter, 
debossed on one side with “GSI” and on the other side with “200”.  Viread 163 mg film-coated tablets 
are supplied in bottles containing 30 tablets.  Each bottle contains a silica gel desiccant that must be 
kept in the bottle to help protect your tablets.  The silica gel desiccant is contained in a separate sachet 
or canister and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
3 bottles of 30 film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer: 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 



237 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
 



238 

Package leaflet: Information for the user 
 

Viread 204 mg film-coated tablets 
tenofovir disoproxil 

 
Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your child’s doctor or pharmacist. 
- This medicine has been prescribed for your child only.  Do not pass it on to others.  It may harm 

them, even if their signs of illness are the same as your child’s. 
- If your child gets any side effects, talk to your child’s doctor or pharmacist.  This includes any 

possible side effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
1. What Viread is and what it is used for 
2. What you need to know before your child takes Viread 
3. How to take Viread 
4. Possible side effects 
5. How to store Viread 
6. Contents of the pack and other information 
 
 
1. What Viread is and what it is used for 
 
Viread contains the active substance tenofovir disoproxil.  This active substance is an antiretroviral or 
antiviral medicine which is used to treat HIV or HBV infection or both.  Tenofovir is a nucleotide 
reverse transcriptase inhibitor, generally known as an NRTI and works by interfering with the normal 
working of an enzyme (in HIV reverse transcriptase, in hepatitis B DNA polymerase) that are 
essential for the viruses to reproduce themselves.  In HIV Viread should always be used combined 
with other medicines to treat HIV infection. 
 
Viread 204 mg tablets are a treatment for HIV (Human Immunodeficiency Virus) infection. 
 
Viread 204 mg tablets are for use in children.  They are only suitable for: 
• children aged 6 to less than 12 years  
• who weigh from 28 kg to less than 35 kg 
• who have already been treated with other HIV medicines which are no longer fully effective 

due to development of resistance, or have caused side effects. 
 
Viread 204 mg tablets are also a treatment for chronic hepatitis B, an infection with HBV 
(hepatitis B virus). 
 
Viread 204 mg tablets are for use in children.  They are only suitable for: 
• children aged 6 to less than 12 years 
• who weigh from 28 kg to less than 35 kg 
 
Your child does not have to have HIV to be treated with Viread for HBV. 
 
This medicine is not a cure for HIV infection.  While taking Viread your child may still develop 
infections or other illnesses associated with HIV infection.  Your child can also pass on HIV or HBV 
to others, so it is important to take precautions to avoid infecting other people. 
 
 



239 

2. What you need to know before your child takes Viread 
 
Do not give Viread 
 
• If your child is allergic to tenofovir, tenofovir disoproxil or any of the other ingredients of this 

medicine listed in section 6. 
 

 If this applies to your child, tell their doctor immediately and don’t give Viread. 
 
Warnings and precautions 
 
• For HIV, Viread 204 mg tablets are only suitable for children who have already been treated 

with other HIV medicines which are no longer fully effective due to development of resistance, 
or have caused side effects. 

 
• Check your child’s age and weight to see if Viread 204 mg tablets are suitable, see Children 

and adolescents. 
 
Talk to your child’s doctor or pharmacist before giving Viread. 
 
• Take care not to infect other people.  Your child can still pass on HIV when taking this 

medicine, although the risk is lowered by effective antiretroviral therapy.  Viread does not 
reduce the risk of passing on HBV to others through sexual contact or blood contamination. 
Discuss with your child’s doctor the precautions needed to avoid infecting other people. 

 
• Talk to your child’s doctor or pharmacist if your child has had kidney disease or if tests 

have shown problems with their kidneys.  Viread should not be given to children with 
existing kidney problems.  Viread may affect your child’s kidneys during treatment.  Before 
starting treatment, your child’s doctor may order blood tests to assess your child’s kidney 
function.  Your child’s doctor may also order blood tests during treatment to monitor how your 
child’s kidneys work. 

 
Viread is not usually taken with other medicines that can damage your child’s kidneys (see 
Other medicines and Viread).  If this is unavoidable, your child’s doctor will monitor your 
child’s kidney function once a week. 
 

• Bone problems.  Some adult patients with HIV taking combination antiretroviral therapy may 
develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply 
to the bone).  The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be some 
of the many risk factors for developing this disease.  Signs of osteonecrosis are joint stiffness, 
aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If you 
notice any of these symptoms tell your child’s doctor. 

 
Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in 
fractures) may also occur due to damage to kidney tubule cells (see section 4, Possible side 
effects). Tell your child’s doctor if your child has bone pain or fractures. 
 
Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss was 
seen in clinical studies when patients were treated with tenofovir disoproxil in combination with 
a boosted protease inhibitor. 
 
Overall, the effects of tenofovir disoproxil on long term bone health and future fracture risk in 
adult and paediatric patients are uncertain.  
 
Tell your child’s doctor if your child suffers from osteoporosis. Patients with osteoporosis are at 
a higher risk for fractures. 



240 

 
• Talk to your child’s doctor if your child has a history of liver disease, including hepatitis.  

Patients with liver disease including chronic hepatitis B or C, who are treated with 
antiretrovirals, have a higher risk of severe and potentially fatal liver complications.  If your 
child has hepatitis B infection, your child’s doctor will carefully consider the best treatment for 
them.  If your child has a history of liver disease or chronic hepatitis B infection your child’s 
doctor may conduct blood tests to monitor their liver function. 

 
• Look out for infections.  If your child has advanced HIV infection (AIDS) and has an 

infection, they may develop symptoms of infection and inflammation or worsening of the 
symptoms of an existing infection once treatment with Viread is started.  These symptoms may 
indicate that your child’s body’s improved immune system is fighting infection.  Look out for 
signs of inflammation or infection soon after your child starts taking Viread.  If you notice signs 
of inflammation or infection, tell your child’s doctor at once. 

 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after your child starts taking 
medicines for the treatment of their HIV infection.  Autoimmune disorders may occur many 
months after the start of treatment.  If you notice that your child has any symptoms of infection 
or other symptoms such as muscle weakness, weakness beginning in the hands and feet and 
moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform 
your child’s doctor immediately to seek necessary treatment. 

 
Children and adolescents 
 
Viread 204 mg tablets are only suitable for: 
• HIV-1 infected children aged 6 to less than 12 years who weigh from 28 kg to less than 

35 kg who have already been treated with other HIV medicines which are no longer fully 
effective due to development of resistance, or have caused side effects 

• HBV infected children aged 6 to less than 12 years who weigh from 28 kg to less than 35 kg 
 
Viread 204 mg tablets are not suitable for the following groups: 
• Not for children who weigh under 28 kg or 35 kg and over.  Contact your child’s doctor if your 

child is outside the permitted weight. 
• Not for children and adolescents under 6 years or 12 years and over. 
 
For dosage see section 3, How to take Viread. 
 
Other medicines and Viread 
 
Tell your child’s doctor or pharmacist if they are taking, have recently taken or might take any other 
medicines. 
 
• Don’t stop any anti-HIV medicines prescribed by your child’s doctor when they start Viread if 

they have both HBV and HIV. 
 
• Do not give Viread if your child is already taking other medicines containing tenofovir 

disoproxil or tenofovir alafenamide.  Do not give Viread together with medicines containing 
adefovir dipivoxil (a medicine used to treat chronic hepatitis B). 

 
• It is very important to tell your child’s doctor if your child is taking other medicines that 

may damage their kidneys. 
 

These include: 
 

• aminoglycosides, pentamidine or vancomycin (for bacterial infection), 



241 

• amphotericin B (for fungal infection), 
• foscarnet, ganciclovir, or cidofovir (for viral infection), 
• interleukin-2 (to treat cancer), 
• adefovir dipivoxil (for HBV), 
• tacrolimus (for suppression of the immune system), 
• non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains). 

 
• Other medicines containing didanosine (for HIV infection): Taking Viread with other 

antiviral medicines that contain didanosine can raise the levels of didanosine in the blood and 
may reduce CD4 cell counts.  Rarely, inflammation of the pancreas and lactic acidosis (excess 
lactic acid in the blood), which sometimes caused death, have been reported when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your child’s doctor will 
carefully consider whether to treat your child with combinations of tenofovir and didanosine. 
 

• It is also important to tell your doctor if your child is taking ledipasvir/sofosbuvir, 
sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir to treat hepatitis C infection. 

 
Viread with food and drink 
 
Give Viread with food (for example, a meal or a snack). 
 
Pregnancy and breastfeeding 
 
If your child is pregnant or breastfeeding, or they think they may be pregnant, ask your child’s doctor 
or pharmacist for advice before they take this medicine. 
 
• If your child has taken Viread during their pregnancy, your child’s doctor may request regular 

blood tests and other diagnostic tests to monitor the development of the baby.  In children 
whose mothers took medicines like Viread (NRTIs) during pregnancy, the benefit from the 
protection against the virus outweighed the risk of side effects. 

 
• If your child has HBV, and their baby has been given treatment to prevent hepatitis B 

transmission at birth, your child may be able to breast-feed their infant, but first talk to your 
child’s doctor to get more information. 

 
• If your child has HIV they must not breastfeed, to avoid passing the virus to the baby in breast 

milk. 
 
Driving and using machines 
 
Viread can cause dizziness.  If your child feels dizzy while taking Viread, they must not drive or ride 
a bicycle and must not use any tools or machines. 
 
Viread contains lactose 
 
Tell your child’s doctor before giving Viread.  If you have been told by your child’s doctor that 
your child has an intolerance to some sugars, contact your child’s doctor before they take this 
medicinal product. 
 
Viread contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 



242 

3. How to take Viread 
 
Your child must always take this medicine exactly as their doctor or pharmacist has told you.  
Check with your child’s doctor or pharmacist if you are not sure. 
 
The recommended dose is: 
• Children aged 6 to less than 12 years who weigh from 28 kg to less than 35 kg: 

1 tablet each day with food (for example, a meal or a snack). 
 
Your child’s doctor will monitor their weight. 
 
Your child must always take the dose recommended by their doctor.  This is to make sure that 
their medicine is fully effective, and to reduce the risk of developing resistance to the treatment.  Do 
not change the dose unless your child’s doctor tells you to. 
 
For HIV, your child’s doctor will prescribe Viread with other antiretroviral medicines. 
 
Refer to the patient information leaflets of the other antiretrovirals for guidance on how to take those 
medicines. 
 
If your child takes more Viread than they should 
 
If your child accidentally takes too many Viread tablets, they may be at increased risk of experiencing 
possible side effects with this medicine (see section 4, Possible side effects).  Contact your child’s 
doctor or nearest emergency department for advice.  Keep the tablet bottle with you so that you can 
easily describe what your child has taken. 
 
If your child forgets to take Viread 
 
It is important not to miss a dose of Viread.  If your child misses a dose, work out how long since they 
should have taken it. 
 
• If it is less than 12 hours after it is usually taken, they should take it as soon as they can, and 

then take their next dose at its regular time. 
 
• If it is more than 12 hours since your child should have taken it, forget about the missed dose.  

Wait and give the next dose at the regular time.  Do not give a double dose to make up for a 
forgotten tablet. 

 
If your child throws up less than 1 hour after taking Viread, give your child another tablet.  Your 
child does not need to take another tablet if they were sick more than 1 hour after taking Viread. 
 
If your child stops taking Viread 
 
Your child must not stop taking Viread without their doctor’s advice.  Stopping treatment with Viread 
may reduce the effectiveness of the treatment recommended by your child’s doctor. 
 
If your child has hepatitis B or HIV and hepatitis B together (co-infection),it is very important not 
to stop their Viread treatment without talking to your child’s doctor first.  Some patients have had 
blood tests or symptoms indicating that their hepatitis has got worse after stopping Viread.  Your child 
may require blood tests for several months after stopping treatment.  In some patients with advanced 
liver disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of 
your child’s hepatitis. 
 
• Talk to your child’s doctor before your child stops taking Viread for any reason, particularly if 

your child is experiencing any side effects or they have another illness. 
 



243 

• Tell your child’s doctor immediately about new or unusual symptoms after your child stops 
treatment, particularly symptoms you associate with hepatitis B infection. 

 
• Contact your child’s doctor before your child restarts taking Viread tablets. 
 
If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your child’s doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Possible serious side effects: tell your child’s doctor immediately 
 
• Lactic acidosis (excess lactic acid in the blood) is a rare (can affect up to 1 in every 

1,000 patients) but serious side effect that can be fatal.  The following side effects may be signs 
of lactic acidosis: 

 
• deep, rapid breathing 
• drowsiness 
• feeling sick (nausea), being sick (vomiting) and stomach pain 

 
 If you think that your child may have lactic acidosis, contact your child’s doctor immediately. 
 
Other possible serious side effects 
 
The following side effects are uncommon (this can affect up to 1 in every 100 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the pancreas 
 
• damage to kidney tubule cells 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• inflammation of the kidney, passing a lot of urine and feeling thirsty 
 
• changes to your child’s urine and back pain caused by kidney problems, including kidney 

failure 
 
• softening of the bones (with bone pain and sometimes resulting in fractures), which may occur 

due to damage to kidney tubule cells 
 
• fatty liver 
 
 If you think that your child may have any of these serious side effects, talk to your child’s 

doctor. 
 
Most frequent side effects 
 
The following side effects are very common (these can affect at least 10 in every 100 patients): 
 
• diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, rash, feeling weak 



244 

 
Tests may also show: 
 
• decreases in phosphate in the blood 
 
Other possible side effects 
 
The following side effects are common (these can affect up to 10 in every 100 patients): 
 
• flatulence 
 
Tests may also show: 
 
• liver problems 
 
The following side effects are uncommon (these can affect up to 1 in every 100 patients): 
 
• breakdown of muscle, muscle pain or weakness 
 
Tests may also show: 
 
• decreases in potassium in the blood 
 
• increased creatinine in your child’s blood 
 
• pancreas problems 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the liver 
 
• swelling of the face, lips, tongue or throat 
 
Reporting of side effects 
If your child gets any side effects, talk to your child’s doctor or pharmacist.  This includes any 
possible side effects not listed in this leaflet.  You can also report side effects directly via the national 
reporting system listed in Appendix V.  By reporting side effects you can help provide more 
information on the safety of this medicine. 
 
 
5. How to store Viread 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


245 

6. Contents of the pack and other information 
 
What Viread contains 
 
- The active substance is tenofovir.  Each Viread tablet contains 204 mg of tenofovir disoproxil 

(as fumarate). 
 
- The other ingredients are microcrystalline cellulose (E460), starch pregelatinised, 

croscarmellose sodium, lactose monohydrate, and magnesium stearate (E572) which make up 
the tablet core, and lactose monohydrate, hypromellose (E464), titanium dioxide (E171) and 
glycerol triacetate (E1518) which make up the tablet coating.  Refer to section 2 “Viread 
contains lactose”. 

 
What Viread looks like and contents of the pack 
 
Viread 204 mg film-coated tablets are white, capsule-shaped, film-coated tablets, of dimensions 
15.4 mm x 7.3 mm, debossed on one side with “GSI” and on the other side with “250”.  Viread 
204 mg film-coated tablets are supplied in bottles containing 30 tablets.  Each bottle contains a silica 
gel desiccant that must be kept in the bottle to help protect your tablets.  The silica gel desiccant is 
contained in a separate sachet or canister and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
3 bottles of 30 film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer: 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 



246 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 



247 

Package leaflet: Information for the patient 
 

Viread 245 mg film-coated tablets 
tenofovir disoproxil 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
1. What Viread is and what it is used for 
2. What you need to know before you take Viread 
3. How to take Viread 
4. Possible side effects 
5. How to store Viread 
6. Contents of the pack and other information 
 
If Viread has been prescribed for your child, please note that all the information in this leaflet is 
addressed to your child (in this case please read “your child” instead of “you”). 
 
 
1. What Viread is and what it is used for 
 
Viread contains the active substance tenofovir disoproxil.  This active substance is an antiretroviral or 
antiviral medicine which is used to treat HIV or HBV infection or both.  Tenofovir is a nucleotide 
reverse transcriptase inhibitor, generally known as an NRTI and works by interfering with the normal 
working of enzymes (in HIV reverse transcriptase; in hepatitis B DNA polymerase) that are essential 
for the viruses to reproduce themselves.  In HIV Viread should always be used combined with other 
medicines to treat HIV infection. 
 
Viread 245 mg tablets are a treatment for HIV (Human Immunodeficiency Virus) infection.  The 
tablets are suitable for: 
• adults 
• adolescents aged 12 to less than 18 years who have already been treated with other HIV 

medicines which are no longer fully effective due to development of resistance, or have caused 
side effects. 

 
Viread 245 mg tablets are also a treatment for chronic hepatitis B, an infection with HBV 
(hepatitis B virus).  The tablets are suitable for: 
• adults 
• adolescents aged 12 to less than 18 years. 
 
You do not have to have HIV to be treated with Viread for HBV. 
 
This medicine is not a cure for HIV infection.  While taking Viread you may still develop infections or 
other illnesses associated with HIV infection.  You can also pass on HIV or HBV to others, so it is 
important to take precautions to avoid infecting other people. 
 
 



248 

2. What you need to know before you take Viread 
 
Do not take Viread 
 
• If you are allergic to tenofovir, tenofovir disoproxil or any of the other ingredients of this 

medicine listed in section 6. 
 

 If this applies to you, tell your doctor immediately and don’t take Viread. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Viread. 
 
• Take care not to infect other people.  You can still pass on HIV when taking this medicine, 

although the risk is lowered by effective antiretroviral therapy.  Discuss with your doctor the 
precautions needed to avoid infecting other people.  Viread does not reduce the risk of passing 
on HBV to others through sexual contact or blood contamination.  You must continue to take 
precautions to avoid this. 

 
• Talk to your doctor or pharmacist if you have had kidney disease or if tests have shown 

problems with your kidneys.  Viread should not be given to adolescents with existing kidney 
problems.  Before starting treatment, your doctor may order blood tests to assess your kidney 
function.  Viread may affect your kidneys during treatment.  Your doctor may order blood tests 
during treatment to monitor how your kidneys work.  If you are an adult, your doctor may 
advise you to take the tablets less often.  Do not reduce the prescribed dose, unless your doctor 
has told you to do so. 

 
Viread is not usually taken with other medicines that can damage your kidneys (see Other 
medicines and Viread).  If this is unavoidable, your doctor will monitor your kidney function 
once a week. 
 

• Bone problems.  Some adult patients with HIV taking combination antiretroviral therapy may 
develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply 
to the bone).  The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be some 
of the many risk factors for developing this disease.  Signs of osteonecrosis are joint stiffness, 
aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If you 
notice any of these symptoms tell your doctor. 

 
Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in 
fractures) may also occur due to damage to kidney tubule cells (see section 4, Possible side 
effects). Tell your doctor if you have bone pain or fractures. 
 
Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss was 
seen in clinical studies when patients were treated with tenofovir disoproxil in combination with 
a boosted protease inhibitor. 
 
Overall, the effects of tenofovir disoproxil on long term bone health and future fracture risk in 
adult and paediatric patients are uncertain.  
 
Tell your doctor if you know you suffer from osteoporosis. Patients with osteoporosis are at a 
higher risk for fractures. 

 
• Talk to your doctor if you have a history of liver disease, including hepatitis.  Patients with 

liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a 
higher risk of severe and potentially fatal liver complications.  If you have hepatitis B infection, 
your doctor will carefully consider the best treatment for you.  If you have a history of liver 



249 

disease or chronic hepatitis B infection your doctor may conduct blood tests to monitor your 
liver function. 

 
• Look out for infections.  If you have advanced HIV infection (AIDS) and have an infection, 

you may develop symptoms of infection and inflammation or worsening of the symptoms of an 
existing infection once treatment with Viread is started.  These symptoms may indicate that 
your body’s improved immune system is fighting infection.  Look out for signs of inflammation 
or infection soon after you start taking Viread.  If you notice signs of inflammation or infection, 
tell your doctor at once. 

 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection.  Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

 
• Talk to your doctor or pharmacist if you are over 65.  Viread has not been studied in patients 

over 65 years of age.  If you are older than this and are prescribed Viread, your doctor will 
monitor you carefully. 

 
Children and adolescents 
 
Viread 245 mg tablets are suitable for: 
• HIV-1 infected adolescents aged 12 to less than 18 years who weigh at least 35 kg and who 

have already been treated with other HIV medicines which are no longer fully effective due to 
development of resistance, or have caused side effects 

• HBV infected adolescents aged 12 to less than 18 years who weigh at least 35 kg. 
 
Viread 245 mg tablets are not suitable for the following groups: 
• Not for HIV-1 infected children under 12 years of age 
• Not for HBV infected children under 12 years of age. 
 
For dosage see section 3, How to take Viread. 
 
Other medicines and Viread 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
• Don’t stop any anti-HIV medicines prescribed by your doctor when you start Viread if you 

have both HBV and HIV. 
 
• Do not take Viread if you are already taking other medicines containing tenofovir disoproxil or 

tenofovir alafenamide.  Do not take Viread together with medicines containing adefovir 
dipivoxil (a medicine used to treat chronic hepatitis B). 

 
• It is very important to tell your doctor if you are taking other medicines that may damage 

your kidneys. 
 

These include: 
 

• aminoglycosides, pentamidine or vancomycin (for bacterial infection), 
• amphotericin B (for fungal infection), 
• foscarnet, ganciclovir, or cidofovir (for viral infection), 



250 

• interleukin-2 (to treat cancer), 
• adefovir dipivoxil (for HBV), 
• tacrolimus (for suppression of the immune system), 
• non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains). 

 
• Other medicines containing didanosine (for HIV infection): Taking Viread with other 

antiviral medicines that contain didanosine can raise the levels of didanosine in your blood and 
may reduce CD4 cell counts.  Rarely, inflammation of the pancreas and lactic acidosis (excess 
lactic acid in the blood), which sometimes caused death, have been reported when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your doctor will carefully 
consider whether to treat you with combinations of tenofovir and didanosine. 
 

• It is also important to tell your doctor if you are taking ledipasvir/sofosbuvir, 
sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir to treat hepatitis C infection. 

 
Viread with food and drink 
 
Take Viread with food (for example, a meal or a snack). 
 
Pregnancy and breastfeeding 
 
If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
• If you have taken Viread during your pregnancy, your doctor may request regular blood tests 

and other diagnostic tests to monitor the development of your child.  In children whose mothers 
took NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk 
of side effects. 

 
•  If you are a mother with HBV, and your baby has been given treatment to prevent hepatitis B 

transmission at birth, you may be able to breastfeed your infant, but first talk to your doctor to 
get more information. 

 
• If you are a mother with HIV do not breastfeed, to avoid passing the virus to the baby in breast 

milk. 
 
Driving and using machines 
 
Viread can cause dizziness.  If you feel dizzy while taking Viread, do not drive or ride a bicycle and 
do not use any tools or machines. 
 
Viread contains lactose 
 
Tell your doctor before taking Viread.  If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
Viread contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
3. How to take Viread 
 
Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your 
doctor or pharmacist if you are not sure. 
 



251 

The recommended dose is: 
• Adults: 1 tablet each day with food (for example, a meal or a snack). 
• Adolescents aged 12 to less than 18 years who weigh at least 35 kg: 1 tablet each day with 

food (for example, a meal or a snack). 
 
If you have particular difficulty swallowing, you can use the tip of a spoon to crush the tablet.  Then 
mix the powder with about 100 ml (half a glass) of water, orange juice or grape juice and drink 
immediately. 
 
• Always take the dose recommended by your doctor.  This is to make sure that your medicine 

is fully effective, and to reduce the risk of developing resistance to the treatment.  Do not 
change the dose unless your doctor tells you to. 

 
• If you are an adult and have problems with your kidneys, your doctor may advise you to 

take Viread less frequently. 
 
• If you have HBV your doctor may offer you an HIV test to see if you have both HBV and HIV. 
 
Refer to the patient information leaflets of the other antiretrovirals for guidance on how to take those 
medicines. 
 
If you take more Viread than you should 
 
If you accidentally take too many Viread tablets, you may be at increased risk of experiencing possible 
side effects with this medicine (see section 4, Possible side effects).  Contact your doctor or nearest 
emergency department for advice.  Keep the tablet bottle with you so that you can easily describe what 
you have taken. 
 
If you forget to take Viread 
 
It is important not to miss a dose of Viread.  If you miss a dose, work out how long since you should 
have taken it. 
 
• If it is less than 12 hours after it is usually taken, take it as soon as you can, and then take your 

next dose at its regular time. 
 
• If it is more than 12 hours since you should have taken it, forget about the missed dose.  Wait 

and take the next dose at the regular time.  Do not take a double dose to make up for a forgotten 
tablet. 

 
If you throw up less than 1 hour after taking Viread, take another tablet.  You do not need to take 
another tablet if you were sick more than 1 hour after taking Viread. 
 
If you stop taking Viread 
 
Don’t stop taking Viread without your doctor’s advice.  Stopping treatment with Viread may reduce 
the effectiveness of the treatment recommended by your doctor. 
 
If you have hepatitis B or HIV and hepatitis B together (co-infection), it is very important not to 
stop your Viread treatment without talking to your doctor first.  Some patients have had blood tests or 
symptoms indicating that their hepatitis has got worse after stopping Viread.  You may require blood 
tests for several months after stopping treatment.  In some patients with advanced liver disease or 
cirrhosis, stopping treatment is not recommended as this may lead to worsening of your hepatitis. 
 
• Talk to your doctor before you stop taking Viread for any reason, particularly if you are 

experiencing any side effects or you have another illness. 
 



252 

• Tell your doctor immediately about new or unusual symptoms after you stop treatment, 
particularly symptoms you associate with hepatitis B infection. 

 
• Contact your doctor before you restart taking Viread tablets. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Possible serious side effects: tell your doctor immediately 
 
• Lactic acidosis (excess lactic acid in the blood) is a rare (can affect up to 1 in every 

1,000 patients) but serious side effect that can be fatal.  The following side effects may be signs 
of lactic acidosis: 

 
• deep, rapid breathing 
• drowsiness 
• feeling sick (nausea), being sick (vomiting) and stomach pain 

 
 If you think that you may have lactic acidosis, contact your doctor immediately. 
 
Other possible serious side effects 
 
The following side effects are uncommon (this can affect up to 1 in every 100 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the pancreas 
 
• damage to kidney tubule cells 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• inflammation of the kidney, passing a lot of urine and feeling thirsty 
 
• changes to your urine and back pain caused by kidney problems, including kidney failure 
 
• softening of the bones (with bone pain and sometimes resulting in fractures), which may occur 

due to damage to kidney tubule cells 
 
• fatty liver 
 
 If you think that you may have any of these serious side effects, talk to your doctor. 
 
Most frequent side effects 
 
The following side effects are very common (these can affect at least 10 in every 100 patients): 
 
• diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, rash, feeling weak 
 



253 

Tests may also show: 
 
• decreases in phosphate in the blood 
 
Other possible side effects 
 
The following side effects are common (these can affect up to 10 in every 100 patients): 
 
• headache, stomach pain, feeling tired, feeling bloated, flatulence 
 
Tests may also show: 
 
• liver problems 
 
The following side effects are uncommon (these can affect up to 1 in every 100 patients): 
 
• breakdown of muscle, muscle pain or weakness 
 
Tests may also show: 
 
• decreases in potassium in the blood 
 
• increased creatinine in your blood 
 
• pancreas problems 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the liver 
 
• swelling of the face, lips, tongue or throat 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 
effects not listed in this leaflet.  You can also report side effects directly via the national reporting 
system listed in Appendix V.  By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Viread 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 

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254 

6. Contents of the pack and other information 
 
What Viread contains 
 
- The active substance is tenofovir.  Each Viread tablet contains 245 mg of tenofovir disoproxil 

(as fumarate). 
 
- The other ingredients are microcrystalline cellulose (E460), starch pregelatinised, 

croscarmellose sodium, lactose monohydrate, and magnesium stearate (E572) which make up 
the tablet core, and lactose monohydrate, hypromellose (E464), titanium dioxide (E171), 
glycerol triacetate (E1518) and indigo carmine aluminium lake (E132) which make up the tablet 
coating.  Refer to section 2 “Viread contains lactose”. 

 
What Viread looks like and contents of the pack 
 
Viread 245 mg film-coated tablets are light blue, almond-shaped, film-coated tablets, of dimensions 
16.8 mm x 10.3 mm, debossed on one side with “GILEAD” and “4331” and on the other side with 
“300”.  Viread 245 mg film-coated tablets are supplied in bottles containing 30 tablets.  Each bottle 
contains a silica gel desiccant that must be kept in the bottle to help protect your tablets.  The silica gel 
desiccant is contained in a separate sachet or canister and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
3 bottles of 30 film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer: 
Takeda GmbH 
Lehnitzstrasse 70-98 
D-16515 Oranienburg 
Germany 
 
or 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 



255 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. Z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. Z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



256 

Package leaflet: Information for the patient 
 

Viread 33 mg/g granules 
tenofovir disoproxil 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
1. What Viread is and what it is used for 
2. What you need to know before you take Viread 
3. How to take Viread 
4. Possible side effects 
5. How to store Viread 
6. Contents of the pack and other information 
 
If Viread has been prescribed for your child, please note that all the information in this leaflet is 
addressed to your child (in this case please read “your child” instead of “you”). 
 
 
1. What Viread is and what it is used for 
 
Viread contains the active substance tenofovir disoproxil.  This active substance is an antiretroviral or 
antiviral medicine which is used to treat HIV or HBV infection or both.  Tenofovir is a nucleotide 
reverse transcriptase inhibitor, generally known as an NRTI and works by interfering with the normal 
working of enzymes (in HIV reverse transcriptase; in hepatitis B DNA polymerase) that are essential 
for the viruses to reproduce themselves.  In HIV Viread should always be used combined with other 
medicines to treat HIV infection. 
 
Viread 33 mg/g granules are a treatment for HIV (Human Immunodeficiency Virus) infection.  
They are suitable for: 
• adults 
• children and adolescents aged 2 to less than 18 years who have already been treated with 

other HIV medicines which are no longer fully effective due to development of resistance, or 
have caused side effects. 

 
Viread 33 mg/g granules are also a treatment for chronic hepatitis B, an infection with HBV 
(hepatitis B virus).  They are suitable for: 
• adults 
• children and adolescents aged 2 to less than 18 years. 
 
You do not have to have HIV to be treated with Viread for HBV. 
 
This medicine is not a cure for HIV infection.  While taking Viread you may still develop infections or 
other illnesses associated with HIV infection.  You can also pass on HIV or HBV to others, so it is 
important to take precautions to avoid infecting other people. 
 
 



257 

2. What you need to know before you take Viread 
 
Do not take Viread 
 
• If you are allergic to tenofovir, tenofovir disoproxil or any of the other ingredients of this 

medicine listed in section 6. 
 

 If this applies to you, tell your doctor immediately and don’t take Viread. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Viread. 
 
• Take care not to infect other people.  You can still pass on HIV when taking this medicine, 

although the risk is lowered by effective antiretroviral therapy.  Discuss with your doctor the 
precautions needed to avoid infecting other people.  Viread does not reduce the risk of passing 
on HBV to others through sexual contact or blood contamination.  You must continue to take 
precautions to avoid this. 

 
• Talk to your doctor or pharmacist if you have had kidney disease or if tests have shown 

problems with your kidneys.  Viread should not be given to children with existing kidney 
problems.  Before starting treatment, your doctor may order blood tests to assess your kidney 
function.  Viread may affect your kidneys during treatment.  Your doctor may order blood tests 
during treatment to monitor how your kidneys work.  If you are an adult, your doctor may 
advise you to reduce your daily dose of the granules.  Do not reduce the prescribed dose, unless 
your doctor has told you to do so. 

 
Viread is not usually taken with other medicines that can damage your kidneys (see Other 
medicines and Viread).  If this is unavoidable, your doctor will monitor your kidney function 
once a week. 

 
• Bone problems.  Some adult patients with HIV taking combination antiretroviral therapy may 

develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply 
to the bone).  The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be some 
of the many risk factors for developing this disease.  Signs of osteonecrosis are joint stiffness, 
aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If you 
notice any of these symptoms tell your doctor. 

 
Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in 
fractures) may also occur due to damage to kidney tubule cells (see section 4, Possible side 
effects). Tell your doctor if you have bone pain or fractures. 
 
Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss was 
seen in clinical studies when patients were treated with tenofovir disoproxil in combination with 
a boosted protease inhibitor. 
 
Overall, the effects of tenofovir disoproxil on long term bone health and future fracture risk in 
adult and paediatric patients are uncertain. 
 
Tell your doctor if you know you suffer from osteoporosis. Patients with osteoporosis are at a 
higher risk for fractures. 

 
• Talk to your doctor if you have a history of liver disease, including hepatitis.  Patients with 

liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a 
higher risk of severe and potentially fatal liver complications.  If you have hepatitis B infection, 
your doctor will carefully consider the best treatment for you.  If you have a history of liver 



258 

disease or chronic hepatitis B infection your doctor may conduct blood tests to monitor your 
liver function. 

 
• Look out for infections.  If you have advanced HIV infection (AIDS) and have an infection, 

you may develop symptoms of infection and inflammation or worsening of the symptoms of an 
existing infection once treatment with Viread is started.  These symptoms may indicate that 
your body’s improved immune system is fighting infection.  Look out for signs of inflammation 
or infection soon after you start taking Viread.  If you notice signs of inflammation or infection, 
tell your doctor at once. 

 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection.  Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

 
• Talk to your doctor or pharmacist if you are over 65.  Viread has not been studied in patients 

over 65 years of age.  If you are older than this and are prescribed Viread, your doctor will 
monitor you carefully. 

 
Children and adolescents 
 
Viread 33 mg/g granules are only suitable for: 
• HIV-1 infected children and adolescents aged 2 to less than 18 years who have already 

been treated with other HIV medicines which are no longer fully effective due to development 
of resistance, or have caused side effects 

• HBV infected children and adolescents aged 2 to less than 18 years. 
 
Viread 33 mg/g granules are not suitable for the following groups: 
• Not for HIV-1 infected children under 2 years 
• Not for HBV (Hepatitis B virus) infected children under 2 years. 
 
For dosage see section 3, How to take Viread. 
 
Other medicines and Viread 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
• Don’t stop any anti-HIV medicines prescribed by your doctor when you start Viread if you 

have both HBV and HIV. 
 
• Do not take Viread if you are already taking other medicines containing tenofovir disoproxil or 

tenofovir alafenamide.  Do not take Viread together with medicines containing adefovir 
dipivoxil (a medicine used to treat chronic hepatitis B). 

 
• It is very important to tell your doctor if you are taking other medicines that may damage 

your kidneys. 
 

These include: 
 

• aminoglycosides, pentamidine or vancomycin (for bacterial infection), 
• amphotericin B (for fungal infection), 
• foscarnet, ganciclovir, or cidofovir (for viral infection), 



259 

• interleukin-2 (to treat cancer), 
• adefovir dipivoxil (for HBV), 
• tacrolimus (for suppression of the immune system), 
• non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains). 

 
• Other medicines containing didanosine (for HIV infection): Taking Viread with other 

antiviral medicines that contain didanosine can raise the levels of didanosine in your blood and 
may reduce CD4 cell counts.  Rarely, inflammation of the pancreas and lactic acidosis (excess 
lactic acid in the blood), which sometimes caused death, have been reported when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your doctor will carefully 
consider whether to treat you with combinations of tenofovir and didanosine. 
 

• It is also important to tell your doctor if you are taking ledipasvir/sofosbuvir, 
sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir to treat hepatitis C infection. 

 
Viread with food and drink 
 
Viread granules should be mixed with soft food which does not require chewing (for example, 
yoghurt, applesauce or baby food).  If the granules mixture is chewed, it will taste very bitter. 
 
Pregnancy and breastfeeding 
 
If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
 
• If you have taken Viread during your pregnancy, your doctor may request regular blood tests 

and other diagnostic tests to monitor the development of your child.  In children whose mothers 
took NRTIs during pregnancy, the benefit from the protection against HIVoutweighed the risk 
of side effects. 

 
• If you are a mother with HBV, and your baby has been given treatment to prevent hepatitis B 

transmission at birth, you may be able to breastfeed your infant, but first talk to your doctor to 
get more information. 

 
• If you are a mother with HIV do not breastfeed, to avoid passing the virus to the baby in breast 

milk. 
 
Driving and using machines 
 
Viread can cause dizziness.  If you feel dizzy while taking Viread, do not drive or ride a bicycle and 
do not use any tools or machines. 
 
Viread granules contain mannitol 
 
Mannitol may have a mild laxative effect. 
 
 
3. How to take Viread 
 
Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your 
doctor or pharmacist if you are not sure. 
 



260 

The recommended dose is: 
• Adults and adolescents aged 12 to less than 18 years and weighing at least 35 kg: 245 mg, 

equivalent to 7.5 scoops of granules, once a day. 
• Children aged 2 to less than 12 years: The daily dose in children depends on their weight.  

Your child’s doctor will determine the right dose of Viread granules based on your child’s 
weight. 

 
Viread granules should be measured with the supplied dosing scoop (see Figure A): 
 
Each level dosing scoop provides 1 g of the granules which contains 33 mg tenofovir disoproxil (as 
fumarate). 
 

 
 

 
 
• Measure out the correct number of level scoops of granules into a container. 
• You must mix the granules with soft food which does not require chewing, for example yoghurt, 

applesauce or baby food.  One tablespoon (15 ml) of soft food per one level scoop of granules is 
required.  Do not mix the granules with liquids. 

• You must take the granules mixed with food immediately. 
• Take all of the mixture you make each time. 
 
• Always take the dose recommended by your doctor.  This is to make sure that your medicine 

is fully effective, and to reduce the risk of developing resistance to the treatment.  Do not 
change the dose unless your doctor tells you to. 

 
• If you are an adult and have problems with your kidneys, your doctor may advise you to 

reduce your daily dose of the granules. 
 
• If you have HBV your doctor may offer you an HIV test to see if you have both HBV and HIV. 
 
Refer to the patient information leaflets of the other antiretrovirals for guidance on how to take those 
medicines. 

Figure A 

Figure B 
 

Figure C 
 

• For ½ scoop: 
• Fill the dosing scoop up to the “½ line” on the side (see Figure C). 

• Fill the dosing scoop to the top. 
• Use the flat edge of clean knife to make the granules even with the top of 

the scoop (see Figure B). 

½ line 
 



261 

 
If you take more Viread than you should 
 
If you accidentally take too much Viread, you may be at increased risk of experiencing possible side 
effects with this medicine (see section 4, Possible side effects).  Contact your doctor or nearest 
emergency department for advice.  Keep the granules bottle with you so that you can easily describe 
what you have taken. 
 
If you forget to take Viread 
 
It is important not to miss a dose of Viread.  If you miss a dose, work out how long since you should 
have taken it. 
 
• If it is less than 12 hours after it is usually taken, take it as soon as you can, and then take your 

next dose at its regular time. 
 
• If it is more than 12 hours since you should have taken it, forget about the missed dose.  Wait 

and take the next dose at the regular time.  Do not take a double dose to make up for a forgotten 
dose. 

 
If you throw up less than 1 hour after taking Viread, take another dose.  You do not need to take 
another dose if you were sick more than 1 hour after taking Viread. 
 
If you stop taking Viread 
 
Don’t stop taking Viread without your doctor’s advice.  Stopping treatment with Viread may reduce 
the effectiveness of the treatment recommended by your doctor. 
 
If you have hepatitis B or HIV and hepatitis B together (co-infection), it is very important not to 
stop your Viread treatment without talking to your doctor first.  Some patients have had blood tests or 
symptoms indicating that their hepatitis has got worse after stopping Viread.  You may require blood 
tests for several months after stopping treatment.  In some patients with advanced liver disease or 
cirrhosis, stopping treatment is not recommended as this may lead to worsening of your hepatitis. 
 
• Talk to your doctor before you stop taking Viread for any reason, particularly if you are 

experiencing any side effects or you have another illness. 
 
• Tell your doctor immediately about new or unusual symptoms after you stop treatment, 

particularly symptoms you associate with hepatitis B infection. 
 
• Contact your doctor before you restart taking Viread granules. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 



262 

Possible serious side effects: tell your doctor immediately 
 
• Lactic acidosis (excess lactic acid in the blood) is a rare (can affect up to 1 in every 

1,000 patients) but serious side effect that can be fatal.  The following side effects may be signs 
of lactic acidosis: 

 
• deep, rapid breathing 
• drowsiness 
• feeling sick (nausea), being sick (vomiting) and stomach pain 

 
 If you think that you may have lactic acidosis, contact your doctor immediately. 
 
Other possible serious side effects 
 
The following side effects are uncommon (this can affect up to 1 in every 100 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the pancreas 
 
• damage to kidney tubule cells 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• inflammation of the kidney, passing a lot of urine and feeling thirsty 
 
• changes to your urine and back pain caused by kidney problems, including kidney failure 
 
• softening of the bones (with bone pain and sometimes resulting in fractures), which may occur 

due to damage to kidney tubule cells 
 
• fatty liver 
 
 If you think that you may have any of these serious side effects, talk to your doctor. 
 
Most frequent side effects 
 
The following side effects are very common (these can affect at least 10 in every 100 patients): 
 
• diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, rash, feeling weak 
 
Tests may also show: 
 
• decreases in phosphate in the blood 
 
Other possible side effects 
 
The following side effects are common (these can affect up to 10 in every 100 patients): 
 
• headache, stomach pain, feeling tired, feeling bloated, flatulence 
 
Tests may also show: 
 
• liver problems 
 
The following side effects are uncommon (these can affect up to 1 in every 100 patients): 
 
• breakdown of muscle, muscle pain or weakness 



263 

 
Tests may also show: 
 
• decreases in potassium in the blood 
 
• increased creatinine in your blood 
 
• pancreas problems 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 
 
• pain in the tummy (abdomen) caused by inflammation of the liver 
 
• swelling of the face, lips, tongue or throat 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 
effects not listed in this leaflet.  You can also report side effects directly via the national reporting 
system listed in Appendix V.  By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Viread 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
Do not store above 25°C. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Viread contains 
 
- The active substance is tenofovir.  One gram of Viread granules contains 33 mg of tenofovir 

disoproxil (as fumarate). 
 
- The other ingredients are ethylcellulose (E462), hydroxypropyl cellulose (E463), mannitol 

(E421) and silicon dioxide (E551).  Refer to section 2 “Viread granules contain mannitol”. 
 
What Viread looks like and contents of the pack 
 
This medicine consists of white coated granules.  The granules are supplied in a bottle containing 60 g 
of granules and are packaged with a dosing scoop. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


264 

Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer: 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SRL-BV 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 



265 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



266 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 



267 

 
Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSURs for tenofovir disoproxil, the 
scientific conclusions of the CHMP are as follows: 
 
Having reviewed the cumulative safety review on osteopenia/osteoporosis, the PRAC considers that 
the section 4.4 of the SmPC needs to be amended to amend the information on bone effects. The 
Annex II and the Package leaflet are updated accordingly. 
 
Having reviewed the results of the cumulative review on breast-feeding in HBV indication and the 
most recent therapeutic guidelines, the PRAC considers that section 4.6 of the SmPC needs to be 
amended to downgrade the current recommendation for breast-feeding for products indicated in the 
treatment of HBV. The Package leaflet is updated accordingly. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
 
Grounds for the variation to the terms of the marketing authorisations 
 
On the basis of the scientific conclusions for tenofovir disoproxil, the CHMP is of the opinion that the 
benefit-risk balance of the medicinal products containing tenofovir disoproxil is unchanged subject to 
the proposed changes to the product information. 
 
The CHMP recommends that the terms of the marketing authorisations should be varied. 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)