Tenofovir disoproxil Mylan

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 245 mg of tenofovir disoproxil (corresponding to 

300 mg of tenofovir disoproxil maleate). 

 

Excipient with known effect 

Each tablet contains 155 mg lactose monohydrate.  

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

Light blue, round, biconvex, film-coated tablets, 12.20 ± 0.20 mm in diameter, debossed with 

‘TN245’ on one side and ‘M’ on other side. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

HIV-1 infection 

Tenofovir disoproxil 245 mg film-coated tablets are indicated in combination with other 

antiretroviral medicinal products for the treatment of HIV-1 infected adults. 

 
In adults, the demonstration of the benefit of 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 245 mg film-coated tablets are also indicated for the treatment of HIV-1 

infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged 

12 to < 18 years. 

 
The choice of tenofovir disoproxil 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 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis B 

in adults with: 

 
• compensated liver disease, with evidence of active viral replication, persistently elevated serum 

alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or 

fibrosis (see section 5.1). 

 
• evidence of lamivudine-resistant hepatitis B virus (see sections 4.8 and 5.1). 

 
• decompensated liver disease (see sections 4.4, 4.8 and 5.1). 

 



 

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Tenofovir disoproxil 245 mg film-coated tablets are 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, 

persistently elevated serum ALT levels and histological evidence of active inflammation 

and/or fibrosis (see sections 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 

 

Adults 

The recommended dose of tenofovir disoproxil for the treatment of HIV or for the treatment of 

chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food. 

 
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 6-

12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe 

detection) 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. With prolonged treatment for 

more than 2 years, regular reassessment is recommended to confirm that continuing the 

selected therapy remains appropriate for the patient. 

 
For treatment of HIV-1 infection and chronic hepatitis B in adults for whom a solid dosage form is not 

appropriate, other suitable formulations may be checked for their availability. 

 

Tenofovir disoproxil Mylan is available only as 245 mg film-coated tablets. Other suitable 

formulations may be checked for their availability. 

 
Paediatric population 

HIV-1: In adolescents aged 12 to < 18 years and weighing ≥ 35 kg, the recommended dose of 

tenofovir disoproxil is 245 mg (one tablet) once daily taken orally with food (see sections 4.8 and 

5.1). 

 

Reduced doses of tenofovir disoproxil are used for treatment of HIV-1 infected paediatric patients 

aged 2 to < 12 years. As Tenofovir disoproxil Mylan is available only as 245 mg film-coated tablets, it 

is not suitable for the use in paediatric patients aged 2 to < 12 years. Other suitable formulations may 

be checked for their availability. 

 
The safety and efficacy of tenofovir disoproxil in HIV-1 infected children under 2 years of age have 

not been established. No data are available. 

 
Chronic hepatitis B: In adolescents aged 12 to < 18 years and weighing ≥ 35 kg, the recommended 

dose of tenofovir disoproxil is 245 mg (one tablet) once daily, taken orally with food (see sections 

4.8 and 5.1). The optimal duration of treatment is currently unknown. 



 

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The safety and efficacy of tenofovir disoproxil in children with chronic hepatitis B aged 2 to < 

12 years or weighing < 35 kg have not been established. No data are available. 

 
For treatment of HIV-1 infection and chronic hepatitis B in adolescents aged 12 to <18 years for 

whom a solid dosage form is not appropriate, other suitable formulations may be checked for their 

availability. 

 
Missed dose 

If a patient misses a dose of tenofovir disoproxil within 12 hours of the time it is usually taken, the 

patient should take tenofovir disoproxil with food as soon as possible and resume their normal 

dosing schedule. If a patient misses a dose of tenofovir disoproxil by more than 12 hours and it is 

almost time for their next dose, the patient should not take the missed dose and simply resume the 

usual dosing schedule. 

 
If the patient vomits within 1 hour of taking tenofovir disoproxil, another tablet should be taken. 

If the patient vomits more than 1 hour after taking tenofovir disoproxil they do not need to take 

another dose. 

 
Special populations 

 

Elderly 

No data are available on which to make a dose recommendation for patients over the age of 65 years 

(see section 4.4). 

 
Renal impairment 

Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with 

renal dysfunction. 
 

Adults 

There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients with 

moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data 

has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in 

adult patients with renal impairment tenofovir disoproxil should only be used if the potential 

benefits of treatment are considered to outweigh the potential risks. Administration of tenofovir 

disoproxil 33 mg/g granules to provide a reduced daily dose of tenofovir disoproxil is recommended 

for adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients.  

 
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) 

Since administration of a lower dose with the 245 mg tablet 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 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 may be used as follows: 

 



 

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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 245 mg film-coated tablets is not optimal and 

could result in increased toxicity and possibly inadequate response. Therefore, clinical response to 

treatment and renal function should be closely monitored (see sections 4.4 and 5.2). 

 
*Generally, once weekly dosing assuming three haemodialysis sessions per week, each of 

approximately 4 hours duration or after 12 hours cumulative haemodialysis. 

 
No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance 

< 10 ml/min. 

 
Paediatrics 

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see 

section 4.4). 

 
Hepatic impairment 

No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). 

 
If tenofovir disoproxil 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 Mylan tablets should be taken once daily, orally with food. 

 

However, in exceptional circumstances Tenofovir disoproxil Mylan 245 mg film-coated tablets can 

be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape 

juice. 

 
4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

General 

 

HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir 

disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). 

 
HIV-1 

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 

the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent 

transmission should be taken in accordance with national guidelines. 

 
Chronic 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. 



 

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Co-administration of other medicinal products 

- Tenofovir disoproxil Mylan should not be administered concomitantly with other 

medicinal products containing tenofovir disoproxil or tenofovir alafenamide. 

- Tenofovir disoproxil Mylan should not be administered concomitantly with adefovir dipivoxil. 

- Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.5). 

 
Triple therapy with nucleosides/nucleotides 

 

There have been reports of a high rate of virological failure and of emergence of resistance at an early 

stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well as 

with lamivudine and didanosine as a once-daily regimen. 
 

Renal and bone effects in adult population 

 

Renal effects 

Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated 

creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been 

reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). 

 
Renal monitoring 

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with 

tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored 

after two to four weeks of treatment, after three months of treatment and every three to six months 

thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more 

frequent monitoring of renal function is required. 

 
Renal management 

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in 

any adult patient receiving tenofovir disoproxil, renal function should be re-evaluated within one week, 

including measurements of blood glucose, blood potassium and urine glucose concentrations (see 

section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with 

tenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or decreases in 

serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with tenofovir disoproxil should 

also be considered in case of progressive decline of renal function when no other cause has been 

identified. 

 
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 



 

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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, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 

combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in 

BMD of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and 

changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil 

treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 

96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone 

abnormalities over 144 weeks in this study. 

 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were 

seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 

inhibitor.  

 

Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations 

of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative 

treatment regimens should be considered for patients with osteoporosis that are at a high risk for 

fractures. 

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.  

 

Renal and bone effects in paediatric population 

 

There are uncertainties associated with the long term effects of bone and renal toxicity. Moreover, the 

reversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach is 

recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide 

the appropriate monitoring during treatment (including decision for treatment withdrawal) and 

consider the need for supplementation. 

 
Renal effects 

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV-1 

infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see sections 4.8 

and 5.1). 

 



 

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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 may cause a reduction in BMD. The effects of tenofovir disoproxil -

associated changes in BMD on long-term bone health and future fracture risk are uncertain (see 

section 5.1). 

 
If bone abnormalities are detected or suspected in paediatric patients, consultation with an 

endocrinologist and/or nephrologist should be obtained. 

 
Liver disease 

 

Safety and efficacy data are very limited in liver transplant patients. 

 
There are limited data on the safety and efficacy of tenofovir disoproxil in HBV infected patients 

with decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. These 

patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, 

hepatobiliary and renal parameters should be closely monitored in this patient population. 

 
Exacerbations of hepatitis 

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 

characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may 

increase in some patients (see section 4.8). In patients with compensated liver disease, these increases 

in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 

hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation 

following hepatitis exacerbation, and therefore should be monitored closely during therapy. 

 
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in 

patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually 

associated with rising HBV DNA, and the majority appears to be self-limited. However, severe 

exacerbations, including fatalities, have been reported. Hepatic function should be monitored at 

repeated intervals with both clinical and laboratory follow-up for at least 6 months after 

discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be 

warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 

recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 



 

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Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease. 

 
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-

infected with hepatitis C or D virus. 

 
Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir 

disoproxil should only be used as part of an appropriate antiretroviral combination regimen in 

HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction, including chronic active 

hepatitis, have an increased frequency of liver function abnormalities during combination 

antiretroviral therapy (CART) and should be monitored according to standard practice. If there is 

evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must 

be considered. However, it should be noted that increases of ALT can be part of HBV clearance 

during therapy with tenofovir, see above Exacerbations of hepatitis. 

 

Use with certain hepatitis C virus antiviral agents 

 

Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 

sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, 

especially when used together with an HIV regimen containing tenofovir disoproxil and a 

pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil in the setting of 

ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a 

pharmacokinetic enhancer has not been established. The potential risks and benefits associated with 

co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 

sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV 

protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at 

increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or 

sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV 

protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil. 

 

Weight and metabolic parameters 

 

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 

therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 

some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 

this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 

established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. 

 
Mitochondrial dysfunction following exposure in utero 

 

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 

pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial 

dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; 

these have predominantly concerned treatment with regimens containing zidovudine. The main 

adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic 

disorders (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 



 

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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. 

 
Tenofovir disoproxil Mylan 245 mg film-coated tablets contain lactose monohydrate. Consequently, 

patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-

galactose malabsorption should not take this medicinal product. 

 

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 should not be administered concomitantly with other medicinal products 

containing tenofovir disoproxil or tenofovir alafenamide. 

 
Tenofovir disoproxil should not be administered concomitantly with adefovir dipivoxil. 

 
Didanosine 

Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and 

Table 1). 

 
Renally eliminated medicinal products 

Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with 

medicinal products that reduce renal function or compete for active tubular secretion via transport 

proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir 

and/or the co-administered medicinal products. 

 
Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic 

medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, 

foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4). 

 



 

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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 q.d./100 q.d.) 

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

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

Lopinavir/Ritonavir 

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

Lopinavir/ritonavir: 

No significant effect on 

lopinavir/ritonavir 

PK parameters.  

Tenofovir:  

AUC: ↑ 32%  

Cmax: ↔ 
Cmin: ↑ 51% 

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

Darunavir/Ritonavir 

(300/100 b.i.d.) 

Darunavir: 

No significant effect on 

darunavir/ritonavir 

PK parameters.  

Tenofovir:  

AUC: ↑ 22%  

Cmin: ↑ 37% 

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

NRTIs 
Didanosine Co-administration of tenofovir disoproxil  

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

Co-administration of 
tenofovir disoproxil and 
didanosine is not 
recommended (see 
section 4.4). 
 
Increased systemic 
exposure to didanosine 



 

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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  
may increase didanosine 
related adverse reactions.  
Rarely, pancreatitis and 
lactic acidosis, 
sometimes fatal, have 
been reported.  
Co-administration of 
tenofovir disoproxil and 
didanosine at a dose of 
400 mg daily has been 
associated with a 
significant decrease in 
CD4 cell count, possibly 
due to an intracellular 
interaction increasing 
phosphorylated (i.e. 
active) didanosine.  A 
decreased dosage of 
250 mg didanosine 
co-administered with 
tenofovir disoproxil 
therapy has been 
associated with reports of 
high rates of virological 
failure within several 
tested combinations for 
the treatment of HIV-1 
infection. 

Adefovir dipivoxil AUC: ↔ 
Cmax: ↔ 

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

Entecavir AUC: ↔ 
Cmax: ↔ 

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

Hepatitis C virus antiviral agents 



 

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.) + 

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). 



 

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.) + 

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). 



 

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.) + 

Efavirenz/Emtricitabine/Tenofovi

r disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 

AUC: ↓ 34% 

Cmax: ↓ 34% 

Cmin: ↓ 34% 

 

Sofosbuvir: 

AUC: ↔ 

Cmax: ↔ 

 

GS-3310072: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Efavirenz: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Emtricitabine: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Tenofovir: 

AUC: ↑ 98% 

Cmax: ↑ 79% 
Cmin: ↑ 163% 

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



 

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.) + 

Emtricitabine/Rilpivirine/ 

Tenofovir disoproxil 
(200 mg/25 mg/245 mg q.d.) 

Ledipasvir: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Sofosbuvir: 

AUC: ↔ 

Cmax: ↔ 

 

GS-3310072: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Emtricitabine: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Rilpivirine: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Tenofovir: 

AUC: ↑ 40% 

Cmax: ↔ 
Cmin: ↑ 91% 

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



 

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  

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). 



 

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.) + 

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). 



 

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.) + 

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). 



 

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.) + 

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). 



 

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.) + 

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). 



 

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.) + 

Efavirenz/Emtricitabine/Tenofo

vir 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. 



 

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 

(400 mg/100 mg q.d.) + 

Emtricitabine/Rilpivirine/Tenof

ovir 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). 



 

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/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/vox

ilaprevir and 

darunavir/ritonavir may 

increase adverse reactions 

related to tenofovir 

disoproxil, including renal 

disorders.  

The safety of tenofovir 

disoproxil when used with 

sofosbuvir/velpatasvir/vox

ilaprevir 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). 



 

25 

 

Medicinal product by 

therapeutic areas (dose in 

mg) 

Effects on drug levels 

Mean percent change in AUC, Cmax, 

Cmin 

Recommendation 

concerning 

co-administration with 

245 mg tenofovir 

disoproxil  

Sofosbuvir 

(400 mg q.d.) + 

Efavirenz/Emtricitabine/ 

Tenofovir disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 

AUC: ↔ 

Cmax: ↓ 19% 

 

GS-3310072: 

AUC: ↔ 

Cmax: ↓ 23% 

 

Efavirenz: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Emtricitabine: 

AUC: ↔ 

Cmax: ↔ 

Cmin: ↔ 

 

Tenofovir: 

AUC: ↔ 

Cmax: ↑ 25% 
Cmin: ↔ 

No dose adjustment is 
required. 

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) 

provided similar results. 
2 The predominant circulating metabolite of sofosbuvir. 
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-

infected patients. 

 

Studies conducted with other medicinal products 

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was 

co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir 

(ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive 

norgestimate/ethinyl oestradiol. 

 
Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir (see 

section 5.2). 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

 

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no 

malformations or foetal/neonatal toxicity associated with tenofovir disoproxil. Animal studies do 

not indicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil may be 

considered during pregnancy, if necessary. 

 

In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been 

shown to reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given 

to mothers, in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.  



 

26 

 

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 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 breastfeed their infants 

in order to avoid transmission of HIV to the infant. 

 

Fertility 

 

There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animal 

studies do not indicate harmful effects of tenofovir disoproxil on fertility. 

 

4.7 Effects on ability to drive and use machines 

 

No studies on the effects on the ability to drive and use machines have been performed. However, 

patients should be informed that dizziness has been reported during treatment with tenofovir 

disoproxil. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, 

renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) 

sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. 

Monitoring of renal function is recommended for patients receiving tenofovir disoproxil (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. 



 

27 

 

 
HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on 

experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir 

disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products 

for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve 

patients received treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) in 

combination with lamivudine and efavirenz for 144 weeks. 

 
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is 

primarily based on experience in two double-blind comparative controlled studies in which 641 adult 

patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir 

disoproxil 245 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The 

adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 

profile of tenofovir disoproxil. After an initial decline of approximately -4.9 ml/min (using 

Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease 

[MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of 

renal 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). 

 



 

28 

 

Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based 

on clinical study and post-marketing experience 

Frequency Tenofovir disoproxil 

Metabolism and nutrition disorders: 

Very common: hypophosphataemia1
 

Uncommon: hypokalaemia1
 

Rare: lactic acidosis 

Nervous system disorders: 

Very common: dizziness 

Common: headache 

Gastrointestinal disorders: 

Very common: diarrhoea, vomiting, nausea 

Common: abdominal pain, abdominal distension, flatulence 

Uncommon: pancreatitis 

Hepatobiliary disorders: 

Common: increased transaminases 

Rare: hepatic steatosis, hepatitis 

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 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). 

 



 

29 

 

Lactic acidosis 

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other 

antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or 

patients receiving concomitant medications known to induce lactic acidosis are at increased risk of 

experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes. 

 

HIV-1: 

Metabolic parameters 

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 

4.4). 

 

Immune reactivation syndrome 

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an 

inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune 

disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 

reported time to onset is more variable and these events can occur many months after initiation of 

treatment (see section 4.4). 

 
Osteonecrosis 

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged 

risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is 

unknown (see section 4.4). 

 
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 



 

30 

 

tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy. Seven patients had estimated 

glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2. Among them, 3 patients 

experienced a clinically meaningful decline in estimated GFR which improved after discontinuation 

of tenofovir disoproxil. 

 
Chronic hepatitis B 

Assessment of adverse reactions is based on one randomised study (study GS-US-174-0115) in 

106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with 

tenofovir disoproxil 245 mg  (n = 52) or placebo (n = 54) for 72 weeks. The adverse reactions 

observed in adolescent 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 adolescents. 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). 

 
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 Mylan 

(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 

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


 

31 

 

Tenofovir disoproxil maleate is the maleate 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-1
IIIB 

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 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. 



 

32 

 

 
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 (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 



 

33 

 

dipivoxil resistance mutations at baseline. Benefit has also been demonstrated based on histological 

responses in compensated patients. 

 
Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and GS-

US-174-0103) 

Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir 

disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in 

Table 3 below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg 

positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) 

patients negative for HBeAg and positive for HBeAb. 

 
In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the 

primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and 

Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 

fibrosis). Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater 

proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg 

treatment. Both treatments produced similar results with regard to histological response (defined as 

Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell 

fibrosis) at week 48 (see Table 3 below). 

 
In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil 

group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 

48 (see Table 3 below). 

 
Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients 

at week 48 

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

Parameter Tenofovir 

disoproxil 245 mg  

 

n = 250 

Adefovir dipivoxil 

10 mg n = 125 

Tenofovir 

disoproxil 245 mg  

 

n = 176 

Adefovir dipivoxil 

10 mg  

 

n = 90 

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/seroconversio

n 

 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

22/21 

 

 

3*/1 

 

 

18/18 

 

 

0/0 



 

34 

 

HBsAg 

loss/seroconversio

n 
* p-value versus adefovir dipivoxil < 0.05. 
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement 

of at least 2 points without worsening in Knodell fibrosis. 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 
c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the 

limit of detection (LOD) of the assay. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at 

baseline. 

n/a = not applicable. 

 
Tenofovir disoproxil was associated with significantly greater proportions of patients with 

undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche 

Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 

56% and study GS-US-174-0103; 69%, 9%), respectively. 

 

Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) 

and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT 

(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined. Forty-nine 

of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three 

percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response 

to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV 

DNA suppression < 400 copies/ml. All patients with normal ALT at baseline and 88% of patients with 

abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. 

 
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 

In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 48 weeks 

(either tenofovir disoproxil 245 mg or adefovir dipivoxil 10 mg), patients rolled over with no 

interruption in treatment to open-label tenofovir disoproxil. In studies GS-US-174-0102 and GS-US-

174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively. At 

weeks 96, 144, 192, 240, 288 and 384 viral suppression, biochemical and serological responses were 

maintained with continued tenofovir disoproxil treatment (see Tables 4 and 5 below). 

 
Table 4: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 

240, 288 and 384 open-label treatment 

 

 Study 174-0102 (HBeAg negative) 

Parametera Tenofovir disoproxil 245 mg 

n = 250 

Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg 

n = 125 
Week 96b 144e 192g 240i 288l 384o 96c 144f 192h 240j 288m 384

p 

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  

 

HBsAg loss/ 

seroconversion 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

1/1n 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0 

 

 

n/a 

 

 

0/0k 

 

 

n/a 

 

 

1/1n 

 

 

n/a 

 

 

1/1n 

 



 

35 

 

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 

due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. 
b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label. 
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil. 
d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. 
e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label. 
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil. 
g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label. 
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil. 
i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label. 
j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil. 
k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at the time of 

the data cut-off. However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit. 
l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label. 
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil. 
n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of 

emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil). 
o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label. 
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 

n/a = not applicable. 

 

Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 

240, 288 and 384 open-label treatment 
 
 Study 174-0103 (HBeAg positive) 

Parametera
 Tenofovir disoproxil 245 mg  

n = 176 

Adefovir dipivoxil 10 mg roll over to 

tenofovir disoproxil 245 mg  
 

n = 90 

Week 96b
 144e

 192h
 240j

 288m
 384o 

96c
 144f

 192i
 240k

 288n
 384p 

HBV DNA (%) 
 

< 400 copies/ml 

(< 69 IU/ml) 

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

ALT (%) 
 

Normalised ALTd
 

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

Serology (%) 
 

HBeAg loss/ 

seroconversion 

HBsAg loss/ 

seroconversion 

 
 

26/ 

23 
 

5/ 

4 

 
 

29/ 

23 
 

8/ 

6
g
 

 
 

34/ 

25 
 

11/ 

8
g
 

 
 

38/ 

30 
 

11/ 

8
l
 

 
 

37/ 

25 
 

12/ 

8
l
 

 
 

30/ 
20 

 

15/ 

121 

 
 

24/ 

20 
 

6/ 

5 

 
 
33/ 

26 
 

8/ 

7
g
 

 
 

36/ 

30 
 

8/ 

7
g
 

 
 

38/ 

31 
 

10/ 

10l
 

 
 
40/ 

31 
 

11/ 

10l
 

 
 
35/ 

24 
 

13/ 

111 
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. 



 

36 

 

p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil. 

 
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in 

studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below). Ninety-five percent 

(225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at 

baseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patients 

with cirrhosis at baseline (Ishak fibrosis score 5-6), 26% (24) experienced no change in Ishak fibrosis 

score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak fibrosis 

score of at least 2 points. 

 

Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positive 

subjects at week 240 compared to baseline 
 
 Study 174-0102 (HBeAg negative) Study 174-0103 (HBeAg positive) 

Tenofovir disoproxil 

245 mg 

n = 250c
 

Adefovir dipivoxil 

10 mg roll over to 

tenofovir disoproxil 

245 mg 

n = 125d
 

Tenofovir disoproxil 

245 mg 

n = 176c
 

Adefovir dipivoxil 

10 mg roll over to 

tenofovir disoproxil 

245 mg 

n = 90d
 

Histological 

responsea,b (%) 

88 
 

[130/148] 

85 
 

[63/74] 

90 
 

[63/70] 

92 
 

[36/39] 
a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) 

by week 240. Response after addition of emtricitabine is excluded (total of 17 subjects across both studies). 
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. 
c 48 weeks of double-blind tenofovir disoproxil followed by up to 192 weeks open-label. 
d 48 weeks of 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. 

 



 

37 

 

Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) 

Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety 

and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and 

entecavir (n = 22), in patients with decompensated liver disease. In the tenofovir disoproxil 

treatment arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and 

mean serum ALT of 61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 months 

of prior lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 

9 of 45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline. 

The co-primary safety endpoints were discontinuation due to an adverse event and confirmed 

increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. 

 

In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of 

emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 

48 weeks of treatment. 

 
Overall, the data derived from this study are too limited to draw any definitive conclusions on the 

comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 7 

below). 

 
Table 7: Safety and efficacy parameters in decompensated patients at week 48 
 

 Study 174-0108 

Parameter Tenofovir disoproxil 

245 mg  

(n = 45) 

Emtricitabine 200 mg/ 

tenofovir disoproxil 

245 mg (n = 45) 

Entecavir 

(0.5 mg or 1 mg) 

n = 22 

Tolerability failure 

(permanent 

discontinuation of study 

drug due to a treatment 

emergent AE) 

n (%)a
 

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

Confirmed increase in 

serum creatinine ≥ 

0.5 mg/dl from baseline 

or confirmed serum 

phosphate of < 2 mg/dl 

n (%)b
 

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

HBV DNA n (%) 

< 400 copies/ml 
 

n (%) 

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

ALT n (%) 
 

Normal ALT 

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

≥ 2 point decrease in 

CPT from baseline 
 

n (%) 

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

Mean change from 

baseline in CPT score 

-0.8 -0.9 -1.3 

Mean change from 

baseline in MELD score 

-1.8 -2.3 -2.6 

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

 



 

38 

 

Experience beyond 48 weeks in study GS-US-174-0108 

Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir 

disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% 

(11/21) of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. 

 

Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121) 

The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind 

study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with 

compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of 

lamivudine resistance (rtM204I/V +/- rtL180M). Only five had adefovir-associated resistance 

mutations at baseline. One hundred forty-one and 139 adult subjects were randomised to a tenofovir 

disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively. Baseline 

demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were 

HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and 

mean ALT was 79 U/l, respectively. 

 
After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had 

HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation. After 240 weeks 

of treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had HBV DNA 

< 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation. Among the HBeAg positive 

subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced HBeAg loss, and 

8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240. In the HBeAg 

positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects (19%) 

experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion through 

week 240. Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by Week 240, 

but not seroconversion to anti-HBs. Five subjects randomised to emtricitabine plus tenofovir 

disoproxil experienced HBsAg loss with 2 of these 5 subjects experiencing seroconversion to anti-

HBs. 

 
Clinical resistance 

Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive 

(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil 

treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for 

genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all 

patients with HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 

5), 240 (n = 4), 288 (n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no 

mutations associated with tenofovir disoproxil resistance have developed. 

 
Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive (GS-US-

174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment and then 

switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes in HBV 

polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 

400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 (n = 1) and 

384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with tenofovir 

disoproxil resistance have developed. 

 
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir 

dipivoxil resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks. 

Genotypic data from paired baseline and on treatment HBV isolates were available for 6/8 patients 

with HBV DNA > 400 copies/ml at week 48. No amino acid substitutions associated with resistance 

to tenofovir disoproxil were identified in these isolates. Genotypic analysis was conducted for 5 

subjects in the tenofovir disoproxil arm post week 48. No amino acid substitutions associated with 

tenofovir disoproxil resistance were detected in any subject. 

 



 

39 

 

In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline 

received tenofovir disoproxil for up to 240 weeks. Cumulatively, there were 4 patients who 

experienced a viremic episode (HBV DNA>400 copies/ml) at their last timepoint on tenofovir 

disoproxil. Among them, sequence data from paired baseline and on treatment HBV isolates were 

available for 2 of 4 patients. No amino acid substitutions associated with resistance to tenofovir 

disoproxil were identified in these isolates. 

 
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. 

 
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. 



 

40 

 

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 lamivudine-
resistant patients achieved HBV DNA < 400 copies/ml at week 72. Thirty-one of the 32 
nucleos(t)ide-experienced patients had prior lamivudine experience. At week 72, 96% (27/28) of 

immune-active patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir 
disoproxil treatment group and 0% (0/32) of patients in the placebo group had HBV DNA < 
400 copies/ml. Seventy-five percent (21/28) of immune-active patients in the tenofovir disoproxil 
group had normal ALT at week 72 compared to 34% (11/32) in the placebo group. 
 
After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir 
disoproxil treatment up to week 192. After week 72, virologic suppression was maintained for those 
receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (tenofovir 
disoproxil-tenofovir disoproxil group): 86.5% (45/52) of subjects in the tenofovir disoproxil-
tenofovir disoproxil group had HBV DNA < 400 copies/ml at week 192. Among the subjects who 
received placebo during the double-blind period, the proportion of subjects with HBV DNA 
< 400 copies/mL rose sharply after they began treatment with open-label tenofovir disoproxil 
(PLB-tenofovir disoproxil group): 74.1% (40/54) of subjects in the PLB-tenofovir disoproxil group 
had HBV DNA < 400 copies/ml at week 192. The proportion of subjects with ALT normalization at 
week 192 in the tenofovir disoproxil-tenofovir disoproxil group was 75.8% (25/33) among those who 
were HBeAg positive at baseline and 100.0% (2 of 2 subjects) among those who were HBeAg 
negative at baseline. Similar percentages of subjects in the tenofovir disoproxil-tenofovir disoproxil 
and PLB-tenofovir disoproxil groups (37.5% and 41.7%, respectively) experienced seroconversion to 
anti-HBe through week 192. 
 

Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 8: 

 
Table 8: Bone Mineral Density Evaluation at Baseline, Week 72 and 192 

 



 

41 

 

 

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 

 
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. 

 



 

42 

 

Distribution 

Following intravenous administration the steady-state volume of distribution of tenofovir was 

estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil, tenofovir 

is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the 

intestinal contents (preclinical studies). In vitro protein binding of tenofovir to plasma or serum 

protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 

25 µg/ml. 

 

Biotransformation 

In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 

CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than 

those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the 

major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, 

CYP2E1, or CYP1A1/2). Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any 

of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction 

in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically 

significant interactions involving tenofovir disoproxil and medicinal products metabolised by 

CYP450 would occur. 

 
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. 



 

43 

 

 
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. 

 

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 



 

44 

 

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. 

 
The active substance tenofovir disoproxil and its main transformation products are persistent in the 

environment. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core  

 

Microcrystalline cellulose 

Lactose monohydrate 

Hydroxypropylcellulose, low substituted 

Silica, colloidal anhydrous 

Magnesium stearate 

 

Film-coating 

 

Hypromellose 

Lactose monohydrate 

Titanium dioxide (E171) 

Triacetin 

Indigo carmine aluminium lake (E132) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

2 years. 

 

For bottles only: 

After first opening: use within 90 days 

 

6.4 Special precautions for storage 

 

Do not store above 25 °C. Store in the original package in order to protect from light and moisture. 

 



 

45 

 

6.5 Nature and contents of container  

 

High density polyethylene (HDPE) bottle with polypropylene (PP) child resistant closure with wad 

containing aluminium induction sealing liner and desiccant (silica gel), available in the following pack 

sizes: 30 film-coated tablets and multipacks containing 90 (3 packs of 30) film-coated tablets. 

 

OPA/Aluminium/PE/Desiccant/PE- Aluminium blister packs containing 10 or 30 film coated tablets. 

OPA/Aluminium/PE/Desiccant/PE- Aluminium perforated unit dose blister pack containing 30 x 1 

film-coated tablets. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal  

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

MYLAN S.A.S 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1129/001 

EU/1/16/1129/002 

EU/1/16/1129/003 

EU/1/16/1129/004 

EU/1/16/1129/005 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 08 December 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/
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 

 

McDermott Laboratories Limited T/A Gerard Laboratories T/A Mylan Dublin 

Unit 35/36 Baldoyle Industrial Estate, 

Grange Road, Dublin 13, 

Ireland 

 

Mylan Hungary Kft 

Mylan utca 1, 

Komarom, 2900, 

Hungary 

 

Mylan Germany GmbH 

Zweigniederlassung Bad Homburg v. d. Hoehe,  

Benzstrasse 1,  

Bad Homburg v. d. Hoehe, 

Hessen, 61352,  

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 Mylan in patients aged 12 to < 18 years are provided with a 

physician educational pack containing the Summary of Product Characteristics and an appropriate 

educational brochure, as detailed below: 

- HIV patients aged 12 to < 18 years educational brochure 

- HBV patients aged 12 to < 18 years educational brochure 

 

The HIV and HBV patients aged 12 to < 18 years educational brochures should contain the following 

key messages: 

 

• That a multidisciplinary approach is recommended for the management of patients aged 12 to < 

18 years 

• 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 Mylan 

• That Tenofovir disoproxil Mylan is not recommended for use in patients aged 12 to < 18 years 

with renal impairment 

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

nephrotoxic medicinal products. If Tenofovir disoproxil Mylan 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 Mylan therapy 

• The importance of regular monitoring of renal function during Tenofovir disoproxil Mylan 

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 patient aged 12 to 

< 18 years 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 Mylan treatment. Interrupting treatment 

with Tenofovir disoproxil Mylan should also be considered in case of progressive decline of 

renal function when no other cause has been identified. 

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

disoproxil Mylan associated changes in BMD on long term bone health and future fracture risk 

are uncertain in patients aged 12 to < 18 years. 

• 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 CARTON AND BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets 

tenofovir disoproxil 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 245 mg of tenofovir disoproxil (as maleate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

30 film-coated tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

<for carton only> 

Open date: 

 

<for bottle label and carton > 



 

52 

 

After first opening use within 90 days 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25 °C. Store in original container in order to protect from light and moisture. 

 

 

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 

 

MYLAN S.A.S 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1129/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

[only for the carton] 

Tenofovir disoproxil Mylan 245 mg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 



 

53 

 

SN: 

NN: 

 

 

  



 

54 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets 

tenofovir disoproxil 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 245 mg of tenofovir disoproxil (as maleate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

Multipack: 90 (3 packs 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 

After first opening use within 90 days 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25 °C. Store in original container in order to protect from light and moisture. 

 



 

55 

 

 

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 

 

MYLAN S.A.S 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1129/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Tenofovir disoproxil Mylan 245 mg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 

  



 

56 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 

PACKAGING 

 

INNER CARTON OF MULTIPACK AND BOTTLE LABEL (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets 

tenofovir disoproxil 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 245 mg of tenofovir disoproxil (as maleate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

30 film-coated tablets 

 

<For inner carton of multipack:> 

Component of a multipack, can’t be sold separately. 

 

 

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 

 

<for carton only> 



 

57 

 

Open date: 

 

<for bottle label and carton> 

After first opening use within 90 days 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25 °C. Store in original container in order to protect from light and moisture. 

 

 

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 

 

MYLAN S.A.S 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1129/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

  



 

58 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON FOR BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets 

tenofovir disoproxil 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 245 mg of tenofovir disoproxil (as maleate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

10 film-coated tablets 

30 film-coated tablets 

30 x 1 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 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



 

59 

 

Do not store above 25 °C. Store in the original package in order to protect from light and moisture. 

 

 

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 

 

Mylan S.A.S 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1129/003 

EU/1/16/1129/004 

EU/1/16/1129/005 

 

 

13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

tenofovir disoproxil mylan 245 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<2D barcode carrying the unique identifier included.> 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

  



 

60 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets 

tenofovir disoproxil 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

5. OTHER 

 

 

  



 

61 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

62 

 

Package leaflet: Information for the patient 

 
Tenofovir disoproxil Mylan 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 Mylan is and what it is used for  

2. What you need to know before you take Tenofovir disoproxil Mylan  

3. How to take Tenofovir disoproxil Mylan  

4. Possible side effects  

5. How to store Tenofovir disoproxil Mylan  

6. Contents of the pack and other information 

 

 

If this medicine 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 Mylan is and what it is used for 

 

Tenofovir disoproxil Mylan 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 

Mylan should always be used combined with other medicines to treat HIV infection. 

 
Tenofovir disoproxil Mylan 245 mg tablets are a treatment for HIV (Human Immunodeficiency 

Virus) infection. The tablets are suitable for: 

• adults 

• adolescents aged 12 to less than 18 years who have already been treated with other HIV 

medicines which are no longer fully effective due to development of resistance, or have 

caused side effects. 

 
Tenofovir disoproxil Mylan 245 mg tablets are also a treatment for chronic hepatitis B, an 

infection with HBV (hepatitis B virus). The tablets are suitable for: 

• adults 

• adolescents aged 12 to less than 18 years. 

 
You do not have to have HIV to be treated with Tenofovir disoproxil Mylan for HBV. 

 
This medicine is not a cure for HIV infection. While taking Tenofovir disoproxil Mylan 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. 



 

63 

 

 

 

2. What you need to know before you take Tenofovir disoproxil Mylan  

 

Do not take Tenofovir disoproxil Mylan: 

- If you are allergic to tenofovir, tenofovir disoproxil or any of the other ingredients of this 

medicine listed in section 6. 

 

If this applies to you, tell your doctor immediately and do not take Tenofovir disoproxil Mylan. 

 

Warnings and precautions  

Talk to your doctor or pharmacist before taking Tenofovir disoproxil Mylan 

 

• 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 Mylan 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 Mylan 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 Mylan 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 Mylan is not usually taken with other medicines that can damage your 

kidneys (see Other medicines and Tenofovir disoproxil Mylan). If this is unavoidable, your 

doctor will monitor your kidney function once a week. 

 
• Bone problems. Some adult patients with HIV taking combination antiretroviral therapy may 

develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood 

supply to the bone). The length of combination antiretroviral therapy, corticosteroid use, 

alcohol consumption, severe immunosuppression, higher body mass index, among others, may 

be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint 

stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 

movement. If you notice any of these symptoms tell your doctor. 

 
Bone problems (manifesting as persistent or worsening bone pain and sometimes 

resulting in fractures) may also occur due to damage to kidney tubule cells (see section 4, 

Possible side effects). Tell your doctor if you have bone pain or fractures. 

 

Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss 

was seen in clinical studies when patients were treated with tenofovir disoproxil in 

combination with a boosted protease inhibitor. 

 

Overall, the effects of tenofovir disoproxil on long term bone health and future fracture 

risk in adult and paediatric patients are uncertain.  

 

Tell your doctor if you know you suffer from osteoporosis. Patients with osteoporosis are at a higher 

risk for fractures. 
• Talk to your doctor if you have a history of liver disease, including hepatitis. Patients with 

liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a 

higher risk of severe and potentially fatal liver complications. If you have hepatitis B infection, 

your doctor will carefully consider the best treatment for you. If you have a history of liver 



 

64 

 

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 Mylan 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 Mylan. 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 has not been 

studied in patients over 65 years of age. If you are older than this and are prescribed 

Tenofovir disoproxil Mylan, your doctor will monitor you carefully. 

 

Children and adolescents 

 

Tenofovir disoproxil Mylan 245 mg tablets are suitable for: 

• HIV-1 infected adolescents aged 12 to less than 18 years who weigh at least 35 kg and who 

have already been treated with other HIV medicines which are no longer fully effective due 

to development of resistance, or have caused side effects 

• HBV infected adolescents aged 12 to less than 18 years who weigh at least 35 kg. 

 
Tenofovir disoproxil Mylan 245 mg tablets are not suitable for the following groups: 

• Not for HIV-1 infected children under 12 years of age 

• Not for HBV infected children under 12 years of age.  

For dosage see section 3, How to take Tenofovir disoproxil Mylan. 

Other medicines and Tenofovir disoproxil Mylan 

Tell your doctor or pharmacist if you are taking have recently taken or might take any other medicines. 

 

Don’t stop any anti-HIV medicines prescribed by your doctor when you start Tenofovir disoproxil 

Mylan if you have both HBV and HIV. 

• Do not take Tenofovir disoproxil Mylan if you are already taking other medicines 

containing tenofovir disoproxil or tenofovir alafenamide. Do not take Tenofovir disoproxil 

Mylan 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), 



 

65 

 

• 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 

Mylan 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 Mylan with food and drink 

Take Tenofovir disoproxil Mylan with food (for example, a meal or a snack). 

 

Pregnancy and breast-feeding 

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 Mylan during pregnancy unless specifically discussed 

with your doctor. Although there are limited clinical data on the use of tenofovir disoproxil in 

pregnant women, it is not usually used unless absolutely necessary. 

 
• Try to avoid getting pregnant during treatment with Tenofovir disoproxil Mylan. You must 

use an effective method of contraception to avoid becoming pregnant. 

 
• 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 Mylan during your pregnancy, your doctor may 

request regular blood tests and other diagnostic tests to monitor the development of your child. 

In children whose mothers took NRTIs during pregnancy, the benefit from the protection 

against HIV outweighed the risk of side effects. 

 
• If you are a mother with HBV, and your baby has been given treatment to prevent hepatitis B 

transmission at birth, you may be able to 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. 

 

Driving and using machines 

 

Tenofovir disoproxil can cause dizziness. If you feel dizzy while taking Tenofovir disoproxil Mylan, 

do not drive or ride a bicycle and do not use any tools or machines. 

 

Tenofovir disoproxil Mylan contains lactose 

Tell your doctor before taking Tenofovir disoproxil Mylan if you cannot tolerate lactose or if you 

have an intolerance to any other sugars. 

 

 



 

66 

 

3. How to take Tenofovir disoproxil Mylan 

 

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: 1 tablet each day with food (for example, a meal or a snack). 

• Adolescents aged 12 to less than 18 years who weigh at least 35 kg: 1 tablet each day 

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

 

If you have particular difficulty swallowing, you can use the tip of a spoon to crush the tablet. Then 
mix the powder with about 100 ml (half a glass) of water, orange juice or grape juice and drink 
immediately 

 
• Always take the dose recommended by your doctor. This is to make sure that your medicine 

is fully effective, and to reduce the risk of developing resistance to the treatment. Do not change 

the dose unless your doctor tells you to. 

 

• If you are an adult and have problems with your kidneys, your doctor may advise you to 

take Tenofovir disoproxil Mylan 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. 

 

• Other forms of this medicine may be more suitable for patients who have difficulty 

swallowing; ask your doctor or pharmacist. 

 

If you take more Tenofovir disoproxil Mylan than you should 

If you accidentally take too many Tenofovir disoproxil Mylan 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 Mylan 

It is important not to miss a dose of Tenofovir disoproxil Mylan. If you miss a dose, work out how 

long since you should have taken it. 

• If it is less than 12 hours after it is usually taken, take it as soon as you can, and then take 

your next dose at its regular time. 

 
• If it is more than 12 hours since you should have taken it, forget about the missed dose. Wait 

and take the next dose at the regular time. Do not take a double dose to make up for a forgotten 

tablet. 

 

If you throw up less than 1 hour after taking Tenofovir disoproxil Mylan, take another tablet. You 

do not need to take another tablet if you were sick more than 1 hour after taking Tenofovir disoproxil 

Mylan 

 

If you stop taking Tenofovir disoproxil Mylan 

Don’t stop taking Tenofovir disoproxil Mylan without your doctor’s advice. Stopping treatment 

with Tenofovir disoproxil Mylan 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 Mylan 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 



 

67 

 

disoproxil. 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 Mylan for any reason, 

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

 
• Tell your doctor immediately about new or unusual symptoms after you stop treatment, 

particularly symptoms you associate with hepatitis B infection. 

 
• Contact your doctor before you restart taking Tenofovir disoproxil Mylan tablets. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 

is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 

medicines themselves. Your doctor will test for these changes.  

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Possible serious side effects: tell your doctor immediately 

 

• Lactic acidosis (excess lactic acid in the blood) is a rare (can affect up to 1 in every 1,000 

patients) but serious side effect that can be fatal. The following side effects may be signs of lactic 

acidosis: 

• deep, rapid breathing 

• drowsiness 

• feeling sick (nausea), being sick (vomiting) and stomach pain 

 
If you think that you may have lactic acidosis, contact your doctor immediately. 
 

Other possible serious side effects 

 

The following side effects are uncommon (this can affect up to 1 in every 100 patients): 

• pain in the tummy (abdomen) caused by inflammation of the pancreas 

• damage to kidney tubule cells 

 
The following side effects are rare (these can affect up to 1 in every 1,000 patients): 

• inflammation of the kidney, passing a lot of urine and feeling thirsty 

• changes to your urine and back pain caused by kidney problems, including kidney failure 

• softening of the bones (with bone pain and sometimes resulting in fractures), which may 

occur due to damage to kidney tubule cells 

• fatty liver 

 
If you think that you may have any of these serious side effects, talk to your doctor. 
 

Most frequent side effects 

 
The following side effects are very common (these can affect at least 10 in every 100 patients): 

• diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, rash, feeling weak 

 
Tests may also show: 

• decreases in phosphate in the blood 



 

68 

 

 

Other possible side effects 

 
The following side effects are common (these can affect up to 10 in every 100 patients): 

• headache, stomach pain, feeling tired, feeling bloated, flatulence 

 
Tests may also show: 

• liver problems 

 
The following side effects are uncommon (these can affect up to 1 in every 100 patients): 

• breakdown of muscle, muscle pain or weakness 

 
Tests may also show: 

• decreases in potassium in the blood 

• increased creatinine in your blood 

• pancreas problems 

 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 

fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 

occur due to damage to kidney tubule cells. 

 

The following side effects are rare (these can affect up to 1 in every 1,000 patients): 

• pain in the tummy (abdomen) caused by inflammation of the liver 

• swelling of the face, lips, tongue or throat 

 
Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Tenofovir disoproxil Mylan 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}. 

The expiry date refers to the last day of that month. 

 

Do not store above 25°C. Store in the original package in order to protect from light and moisture. 

For bottles: after first opening the bottle use within 90 days. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Tenofovir disoproxil Mylan contains  

- The active substance is tenofovir disoproxil. Each Tenofovir disoproxil Mylan tablet contains 

245 mg of tenofovir disoproxil (as maleate). 

- The other ingredients are microcrystalline cellulose, lactose monohydrate (see section 2, 

Tenofovir disoproxil Mylan contains lactose), hydroxypropylcellulose, colloidal anhydrous 

silica, magnesium stearate, hypromellose, titanium dioxide (E171), triacetin, indigo carmine 

aluminium lake (E132). 

 

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


 

69 

 

What Tenofovir disoproxil Mylan looks like and contents of the pack 

 

Tenofovir disoproxil Mylan 245 mg film-coated tablets are light blue, round, biconvex, debossed 

with ‘TN245’ on one side and ‘M’ on other side. 

This medicine is available in plastic bottles with a child resistant cap and wad containing 30 film-

coated tablets and in multipacks of 90 film-coated tablets comprising 3 bottles, each containing 

30 film-coated tablets. The bottles also contain desiccant. Do not eat the desiccant. 

 

The tablets are also available in blister packs containing 10, 30 or 30 x 1 (unit dose) tablets. 

 

Not all pack sizes may be marketed. 

 

 

Marketing Authorisation Holder and Manufacturer 

Marketing Authorisation Holder: 

Mylan S.A.S 

117 Allée des Parcs 

69800 Saint-Priest 

France  

 

Manufacturer: 

McDermott Laboratories Limited T/A Gerard Laboratories T/A Mylan Dublin 

Unit 35/36 Baldoyle Industrial Estate, 

Grange Road, Dublin 13, 

Ireland  

 

Mylan Hungary Kft 

Mylan utca 1, 

Komarom, H-2900, 

Hungary 

 

Mylan Germany GmbH 

Zweigniederlassung Bad Homburg v. d. Hoehe,  

Benzstrasse 1, Bad Homburg v. d. Hoehe 

Hessen, 61352 

Germany  

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Mylan bvba/sprl 

Tél/Tel: + 32 (0)2 658 61 00 

 

Lietuva 

Mylan Healthcare UAB  

Tel: + 370 5 205 1288 

 

България 

Майлан ЕООД 

Тел: + 359 2 44 55 400 

 

Luxembourg/Luxemburg 

Mylan bvba/sprl 

Tel: + 32 (0)2 658 61 00 

(Belgique/Belgien) 

 

Česká republika 

Mylan Healthcare CZ s.r.o. 

Tel: + 420 222 004 400 

 

Magyarország 

Mylan EPD Kft 

Tel: + 36 1 465 2100 



 

70 

 

Danmark 

Mylan Denmark ApS 

Tlf: + 45 28 11 69 32 

Malta 

V.J. Salomone Pharma Ltd 

Tel: + 356 21 22 01 74 

 

Deutschland 

Mylan Healthcare GmbH  

Tel: + 49 800 0700 800 

 

Nederland 

Mylan BV 

Tel: + 31 (0)20 426 3300 

Eesti 

BGP Products Switzerland GmbH  

Eesti filiaal  

Tel: + 372 6363 052 

 

Norge 

Mylan Healthcare Norge AS 

Tel: + 47 66 75 33 00 

Ελλάδα  

Generics Pharma Hellas ΕΠΕ  

Τηλ:  + 30 210 993 6410  

 

Österreich 

Arcana Arzneimittel GmbH 

Tel: + 43 1 416 2418 

 

España 

Mylan Pharmaceuticals, S.L 

Tel: + 34 900 102 712 

 

Polska 

Mylan Healthcare Sp. z o.o. 

Tel: + 48 22 546 64 00 

 

France 

Mylan S.A.S 

Tel: + 33 4 37 25 75 00 

 

Portugal 

Mylan, Lda. 

Tel: + 351 21 412 72 56 

 

Hrvatska 

Mylan Hrvatska d.o.o.  

Tel: + 385 1 23 50 599 

 

România 

BGP Products  SRL 

Tel: + 40 372 579 000 

 

Ireland 

Mylan Ireland Limited 

Tel: + 353 (0) 87 1684982 

Slovenija 

Mylan Healthcare d.o.o. 

Tel: + 386 1 23 63 180 

 

Ísland 

Icepharma hf  

Tel: + 354 540 8000 

 

Slovenská republika 

Mylan s.r.o. 

Tel: + 421 2 32 199 100 

Italia 

Mylan Italia S.r.l. 

Tel: + 39 02 612 46921 

 

Suomi/Finland 

Mylan Finland OY 

Puh/Tel: + 358 20 720 9555 

 

Κύπρος 

Varnavas Hadjipanayis Ltd. 

Τηλ: + 357 2220 7700 

 

Sverige 

Mylan AB  

Tel: + 46 855 522 750 

 

Latvija 

Mylan Healthcare SIA  

Tel: + 371 676 055 80 

United Kingdom 

Generics [UK] Ltd 

Tel: + 44 1707 853000 

 

This leaflet was last revised in {MM/YYYY}. 

 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

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


 

71 

 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

 

  



 

72 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Annex IV 

Scientific conclusions and grounds for the variation to the terms of the marketing 

authorisation(s) 

  



 

73 

 

Scientific conclusions  

Taking into account the PRAC Assessment Report on the PSURs for tenofovir disoproxil, the 

scientific conclusions of the CHMP are as follows:  

Having reviewed the cumulative safety review on osteopenia/osteoporosis, the PRAC considers that 

the section 4.4 of the SmPC needs to be amended to amend the information on bone effects. The 

Annex II and the Package leaflet are updated accordingly. 

Having reviewed the results of the cumulative review on breast-feeding in HBV indication and the 

most recent therapeutic guidelines, the PRAC considers that section 4.6 of the SmPC needs to be 

amended to downgrade the current recommendation for breast-feeding for products indicated in the 

treatment of HBV. The Package leaflet is updated accordingly. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisations 

On the basis of the scientific conclusions for tenofovir disoproxil, the CHMP is of the opinion that 

the benefit-risk balance of the medicinal products containing tenofovir disoproxil is unchanged 

subject to the proposed changes to the product information. 

The CHMP recommends that the terms of the marketing authorisations should be varied. 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)