Tenofovir disoproxil Zentiva

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Tenofovir disoproxil Zentiva 245 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains tenofovir disoproxil phosphate (equivalent to 245 mg of tenofovir 
disoproxil). 
 
Excipient with known effect: Each tablet contains 214.5 mg lactose monohydrate.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
Oblong-shaped, light blue colored film-coated tablets with dimensions approx. 17.2 x 8.2 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
HIV-1 infection 
Tenofovir disoproxil Zentiva is indicated in combination with other antiretroviral medicinal products for 
the treatment of HIV-1 infected adults. 
 
In adults, the demonstration of the benefit of tenofovir disoproxil 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 tenofovir disoproxil 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). 
 
Tenofovir disoproxil Zentiva is 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 Tenofovir disoproxil Zentiva 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 
Tenofovir disoproxil Zentiva is 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). 
 
Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adolescents 12 to < 18 
years of age 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 



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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 Tenofovir disoproxil Zentiva for the treatment of HIV or for the treatment of 
chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food. 
 
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 
Reduced doses of tenofovir (the active ingredient of Tenofovir disoproxil Zentiva) are also used for 
the treatment of HIV-1 infection and chronic hepatitis B in paediatric patients aged 2 to < 12 years. 
Tenofovir disoproxil Zentiva is available only as 245 mg film-coated tablets, it is not suitable for the use in 
paediatric patients aged 2 < 12 years. Other suitable formulations should be checked for their availability. 
 
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 Tenofovir disoproxil Zentiva within 12 hours of the time it is usually taken, the 
patient should take Tenofovir disoproxil Zentiva with food as soon as possible and resume their normal 
dosing schedule. If a patient misses a dose of Tenofovir disoproxil Zentiva 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. 



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If the patient vomits within 1 hour of taking Tenofovir disoproxil Zentiva another tablet should be taken. If 
the patient vomits more than 1 hour after taking Tenofovir disoproxil Zentiva 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. 
 
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) 
If administration of a lower dose is not possible, 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: 
Adequate dose adjustments cannot be applied with this product due to lack of alternative tablet strengths, 
therefore use in this group of patients is not recommended. If no alternative treatment is 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). 
 
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 Tenofovir disoproxil Zentiva 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. 
 



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Paediatric population 
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 Tenofovir disoproxil Zentiva 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 
Tenofovir disoproxil Zentiva tablets should be taken once daily, orally with food. 
 
In exceptional circumstances in patients having particular difficulty in swallowing, Tenofovir disoproxil 
Zentiva 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 
- Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal 

products containing tenofovir disoproxil or tenofovir alafenamide. 
- Tenofovir disoproxil Zentiva 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 



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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). 
 
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, 



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in a 144-week controlled clinical study (GS-99-903) 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 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 
Tenofovir disoproxil Zentiva 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. 
 



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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. 
 
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 



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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 (hyperlactataemia, 
hyperlipasaemia). 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. 
 
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. 
 
Lactose 
Tenofovir disoproxil Zentiva contains lactose monohydrate. Patients with rare hereditary problems of 
galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
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 
Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products 
containing tenofovir disoproxil or tenofovir alafenamide. 
 
Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil. 
 
Didanosine 



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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.”). 
 
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 mg q.d./100 mg 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 mg b.i.d./100 mg 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 mg/100 mg 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). 



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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  
 

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. 



12 
 

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). 



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.) + 
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). 



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  
 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofo
vir 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). 



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  
 

Ledipasvir/Sofosbuvir 
(90 mg/400 mg q.d.) + 
Emtricitabine/Rilpivirine/Tenof
ovir 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). 



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  
 

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). 



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.) + 
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). 
 



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.) + 
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). 



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 
(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). 



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/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). 



21 
 

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.) + 
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. 



22 
 

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). 



23 
 

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/voxil
aprevir and 
darunavir/ritonavir may 
increase adverse reactions 
related to tenofovir 
disoproxil, including renal 
disorders. 
The safety of tenofovir 
disoproxil when used with 
sofosbuvir/velpatasvir/voxil
aprevir 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). 



24 
 

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/Tenofo
vir 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. 
 
Breast-feeding 
Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with hepatitis 



25 
 

B may breast-feed her infant. 
 
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 breast-feed 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 Tenofovir disoproxil Zentiva (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. 
 



26 
 

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 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 



27 
 

Frequency Tenofovir disoproxil  
Uncommon: pancreatitis 
Hepatobiliary disorders: 
Common: increased transaminases 
Rare: hepatic steatosis, hepatitis 
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 Tenofovir disoproxil Zentiva 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). 
 



28 
 

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 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). 
 



29 
 

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 Tenofovir disoproxil Zentiva (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 phosphate is the phosphate 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 (TAMs) that included 

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


30 
 

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. 
 
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 



31 
 

(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). 
 



32 
 

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/seroconversionHBsAg 
loss/seroconversion 

 
n/a 

 
0/0 

 
n/a 

 
0/0 

 
22/21 

 
3*/1 

 
18/18 

 
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 



33 
 

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 

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. 



34 
 

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). 
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. 
 



35 
 

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 = 250

c
 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg  

       n = 125
d
 

Tenofovir disoproxil 
245 mg  

     n = 176
c
 

Adefovir dipivoxil 
10 mg roll over to 

tenofovir disoproxil 
245 mg        
n = 90

d
 

Histological 
response

a,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. 
 
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. 
 



36 
 

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. 
 
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. 
 



37 
 

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 time point 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. 
 
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. 
 



38 
 

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 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 



39 
 

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. 
 



40 
 

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)  

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%). 
 



41 
 

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 baselin  
BMD Z-scorea 

NA NA −0.18 
(0.334) 

0.22 
(0.446) 

Lumbar spine BMD at 
least 4% decrease 

 
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 
tenofovir disoproxil 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 



42  

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. 
 
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 



43  

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. 
 
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. 
 



44  

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 phosphate and its main transformation products are persistent 
in the environment. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Povidone 
Magnesium stearate 
 
Film-coating 
Lactose monohydrate 
Hypromellose  
Titanium dioxide  
Triacetin  
Indigo Carmine Aluminum lake  
 
6.2 Incompatibilities 
 
Not applicable. 
 



45  

6.3 Shelf life 
 
2 years 
Shelf-life after first opening is 60 days. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant cap and induction heat 
sealing (with aluminium foil). 
The bottle contains 30 film-coated tablets and a silica gel desiccant (in a container). 
 
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 and other handling 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
Open bottles by pressing the child proof cap down and turning it counter-clock wise. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1127/001 
EU/1/16/1127/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 September 2016 
 
 
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/


46  

 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 



47  

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
S.C. Zentiva S.A. 
50 Theodor Pallady Blvd. 
Bucharest 032266 
Romania 
 
Winthrop Arzneimittel GmbH 
Brüningstraße 50 
65926 Frankfurt am Main 
Germany 
 
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  
 
The requirements for submission of periodic safety update reports 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 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.  

 



48  

• Additional risk minimisation measures  
 
The Marketing Authorisation Holder (MAH) shall ensure that all physicians who are expected to 
prescribe/use Tenofovir disoproxil Zentiva in adolescent patients are provided with a physician 
educational pack containing the Summary of Product Characteristics and an appropriate educational 
brochure, as detailed below: 
 

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

tenofovir disoproxil-containing products such as Tenofovir disoproxil Zentiva 
• That Tenofovir disoproxil Zentiva is not recommended for use in paediatric patients with renal 

impairment 
• That use of Tenofovir disoproxil Zentiva should be avoided with concomitant or recent use of 

nephrotoxic medicinal products. If Tenofovir disoproxil Zentiva 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 Tenofovir 
disoproxil Zentiva therapy 

• The importance of regular monitoring of renal function during Tenofovir disoproxil Zentiva 
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 adolescent patient 
receiving tenofovir disoproxil, 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 Tenofovir disoproxil Zentiva treatment. Interrupting 
treatment with Tenofovir disoproxil Zentiva should also be considered in case of progressive 
decline of renal function when no other cause has been identified. 

• That Tenofovir disoproxil Zentiva may cause a reduction in BMD and the effects of Tenofovir 
disoproxil Zentiva 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 

 



49  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



50  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



51  

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Bottle label and outer carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tenofovir disoproxil Zentiva 245 mg film-coated tablets 
Tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 245 mg of tenofovir disoproxil (as phosphate).  
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
 
90 (3 bottles of 30) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before 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 
 



52  

 
9. SPECIAL STORAGE CONDITIONS 
 
Use within 60 days after first opening. Do not store above 30 °C. Store in the original package in order 
to protect from moisture. 
Open date: [outer packaging only] 
 
 
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 
 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1127/001 30 film-coated tablets 
EU/1/16/1127/002 90 (3x30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tenofovir disoproxil Zentiva [outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [outer packaging only] 
 
 



53  

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: [outer packaging only] 
SN: [outer packaging only] 
NN: [outer packaging only] 



54  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



55  

Package leaflet: Information for the user 
 

Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva is and what it is used for 
2. What you need to know before you take Tenofovir disoproxil Zentiva 
3. How to take Tenofovir disoproxil Zentiva 
4. Possible side effects 
5. How to store Tenofovir disoproxil Zentiva 
6. Contents of the pack and other information 
 
If Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva is and what it is used for 
 
Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva should always be 
used combined with other medicines to treat HIV infection. 
 
Tenofovir disoproxil Zentiva is 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. 

 
Tenofovir disoproxil Zentiva is 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 Tenofovir disoproxil Zentiva for HBV. 
 



56  

This medicine is not a cure for HIV infection. While taking Tenofovir disoproxil Zentiva 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. 
 
 
2. What you need to know before you take Tenofovir disoproxil Zentiva  
 
Do not take Tenofovir disoproxil Zentiva  
• If you are allergic to tenofovir, tenofovir disoproxil phosphate or any of the other ingredients of 

this medicine (listed in section 6). 
 

If this applies to you, tell your doctor immediately and do not take Tenofovir disoproxil Zentiva. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Tenofovir disoproxil Zentiva  
 
• 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. Tenofovir disoproxil Zentiva 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. Tenofovir disoproxil Zentiva should not be given to adolescents 
with existing kidney problems. Before starting treatment, your doctor may order blood tests to 
assess your kidney function. Tenofovir disoproxil Zentiva 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.  
 
Tenofovir disoproxil Zentiva is not usually taken with other medicines that can damage your 
kidneys (see Other medicines and Tenofovir disoproxil Zentiva). 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. 

 
For adult patients: 
 
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 



57  

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. 
 
For adolescents/paediatric patients: 
 
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. 

 
• 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 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 Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva. 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. Tenofovir disoproxil Zentiva has not 

been studied in patients over 65 years of age. If you are older than this and are prescribed 
Tenofovir disoproxil Zentiva, your doctor will monitor you carefully. 

 



58  

Children and adolescents 
Tenofovir disoproxil Zentiva is 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. 
 
Tenofovir disoproxil Zentiva is 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 Tenofovir disoproxil Zentiva. 
 
Other medicines and Tenofovir disoproxil Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
 
• Do not stop any anti-HIV medicines prescribed by your doctor when you start Tenofovir 

disoproxil Zentiva if you have both HBV and HIV. 
 
• Do not take Tenofovir disoproxil Zentiva if you are already taking other medicines containing 

tenofovir disoproxil or tenofovir alafenamide. Do not take Tenofovir disoproxil Zentiva 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) 
- 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 Tenofovir disoproxil 

Zentiva 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. 

 
Tenofovir disoproxil Zentiva with food and drink  
Take Tenofovir disoproxil Zentiva with food (for example, a meal or a snack). 
 
Pregnancy, breast-feeding and fertility 



59  

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
• You must not take Tenofovir disoproxil Zentiva during pregnancy unless specifically 

discussed with your doctor. Although there are limited clinical data on the use of Tenofovir 
disoproxil Zentiva in pregnant women, it is not usually used unless absolutely necessary. 

 
• If you become pregnant, or plan to become pregnant, ask your doctor about the potential 

benefits and risks of your antiretroviral therapy to you and your child. 
 
• If you have taken Tenofovir disoproxil Zentiva 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. 

 
For adult patients: 
• 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 breast-feed your infant, but first talk to your doctor to 
get more information. 

 
• If you are a mother with HIV do not breast-feed, to avoid passing the virus to the baby in breast 

milk. 
 

For adolescents/paediatric patients: 
• 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 breast-feed, to avoid passing the virus to the baby in breast 
milk. 

 
Driving and using machines 
Tenofovir disoproxil Zentiva can cause dizziness. If you feel dizzy while taking Tenofovir disoproxil 
Zentiva, do not drive or ride a bicycle and do not use any tools or machines. 
 
Tenofovir disoproxil Zentiva contains lactose monohydrate 
Tenofovir disoproxil Zentiva contains lactose monohydrate. If you have been told by your doctor that 
you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. How to take Tenofovir disoproxil Zentiva 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. 
 
The recommended dose is: 
 
• Adults: One 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: one tablet each day with 

food (for example, a meal or a snack). 
 



60  

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 

Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva than you should 
If you accidentally take too many Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva  
It is important not to miss a dose of Tenofovir disoproxil Zentiva. 
If you miss a dose of Tenofovir disoproxil Zentiva, 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 Tenofovir disoproxil Zentiva, take another tablet. You 
do not need to take another tablet if you were sick more than 1 hour after taking Tenofovir disoproxil 
Zentiva. 
 
If you stop taking Tenofovir disoproxil Zentiva  
 
Do not stop taking Tenofovir disoproxil Zentiva without your doctor’s advice. Stopping treatment with 
Tenofovir disoproxil Zentiva 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 Tenofovir disoproxil Zentiva treatment without talking to your doctor first. Some patients 
have had blood tests or symptoms indicating that their hepatitis has got worse after stopping Tenofovir 
disoproxil Zentiva. 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 Tenofovir disoproxil Zentiva for any reason, 

particularly if you are experiencing any side effects or you have another illness. 
 



61  

• 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 Tenofovir disoproxil Zentiva 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 (may affect up to 1 in 1,000 people) 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 (may affect up to 1 in 100 people): 
• pain in the tummy (abdomen) caused by inflammation of the pancreas, 
• damage to kidney tubule cells. 
 
The following side effects are rare (may affect up to 1 in 1,000 people): 
• 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 (may affect more than 1 in 10 people): 
• diarrhoea, 
• being sick (vomiting),  
• feeling sick (nausea),  
• dizziness,  
• rash,  



62  

• feeling weak. 
 
Tests may also show: 
• decreases in phosphate in the blood. 
 
Other possible side effects 
 
The following side effects are common (may affect up to 1 in 10 people): 
• headache,  
• stomach pain,  
• feeling tired,  
• feeling bloated,  
• flatulence. 
 
Tests may also show: 
• liver problems. 
 
The following side effects are uncommon (may affect up to 1 in 100 people): 
• 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 (may affect up to 1 in 1,000 people): 
• 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 Tenofovir disoproxil Zentiva  
 
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. 
 
Use within 60 days after first opening. Do not store above 30 °C. Store in the original package in order 
to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

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


63  

throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tenofovir disoproxil Zentiva contains 
‐ The active substance is tenofovir. Each tablet contains tenofovir disoproxil phosphate (equivalent 

to 245 mg of tenofovir disoproxil). 
‐ The other ingredients are:  
‐ Tablet core: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, 

magnesium stearate. 
Film-coating: lactose monohydrate, hypromellose, titanium dioxide, triacetin, indigo carmine 
aluminum lake. 

 
What Tenofovir disoproxil Zentiva looks like and contents of the pack 
Tenofovir disoproxil Zentiva 245 mg film-coated tablets are oblong-shaped, light blue colored film-
coated tablets with dimensions approx. 17.2 x 8.2 mm. 
 
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. 
 
Open bottles by pressing the child proof cap down and turning it counter-clock wise. 
 
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 container and should not be swallowed. 
 
Marketing Authorisation Holder  
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
Manufacturer 
S.C. Zentiva S.A. 
50 Theodor Pallady Blvd. 
Bucharest 032266 
Romania 
 
or 
 
Winthrop Arzneimittel GmbH 
Brüningstraße 50 
65926 Frankfurt am Main 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



64  

België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 

România 
ZENTIVA S.A. 
Tel: +40 021.304.7597 
zentivaRO@zentiva.com 

Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 

Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 



65  

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
Tel: +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 845 372 7101 
PV-United-Kingdom@zentiva.com 

 
 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	1. NAME OF THE MEDICINAL PRODUCT
	2. QUALITATIVE AND QUANTITATIVE COMPOSITION
	3. PHARMACEUTICAL FORM
	4. CLINICAL PARTICULARS

	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