TENOFOVIR DISOPROXIL ZENTIVA 245mg tablets medication leaflet

Tenofovir disoproxil Zentiva 245 mg film-coated tablets

Each film-coated tablet contains tenofovir disoproxil phosphate (equivalent to 245 mg of tenofovirdisoproxil).

Excipient with known effect: Each tablet contains 214.5 mg lactose monohydrate equivalent to203.7 mg lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet

Oblong-shaped, light blue colored film-coated tablets with dimensions approx. 17.2 x 8.2 mm.

HIV-1 infection

Tenofovir disoproxil Zentiva is indicated in combination with other antiretroviral medicinal products forthe treatment of HIV-1 infected adults.

In adults, the demonstration of the benefit of tenofovir disoproxil in HIV-1 infection is based on resultsof 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) inantiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with themajority of patients having < 5,000 copies/ml).

Tenofovir disoproxil Zentiva is also indicated for the treatment of HIV-1 infected adolescents, with

NRTI resistance or toxicities precluding the use of first line agents, aged 12 to < 18 years.

The choice of Tenofovir disoproxil Zentiva to treat antiretroviral-experienced patients with HIV-1infection should be based on individual viral resistance testing and/or treatment history of patients.

Hepatitis B infection

Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adults with:

- compensated liver disease, with evidence of active viral replication, persistently elevated serumalanine aminotransferase (ALT) levels and histological evidence of active inflammation and/orfibrosis (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, pct. 4.8 and 5.1).

Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adolescents 12 to< 18 years of age with:

- compensated liver disease and evidence of immune active disease, i.e. active viral replication andpersistently elevated serum ALT levels, or histological evidence of moderate to severeinflammation and/or fibrosis. With respect to the decision to initiate treatment in paediatricpatients, see sections 4.2, pct. 4.4, pct. 4.8 and 5.1.

Therapy should be initiated by a physician experienced in the management of HIV infection and/ortreatment of chronic hepatitis B.

HIV-1 and chronic hepatitis B

Adults and adolescents aged 12 to < 18 years and weighing ≥ 35 kg

The recommended dose of Tenofovir disoproxil Zentiva for the treatment of HIV or for the treatment ofchronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.

The decision to treat paediatric patients (adolescents) should be based on careful consideration ofindividual patient needs and with reference to current paediatric treatment guidelines including the valueof baseline histological information. The benefits of long-term virologic suppression with continuedtherapy must be weighed against the risk of prolonged treatment, including the emergence of resistanthepatitis B virus and the uncertainties as regards the long term impact of bone and renal toxicity (seesection 4.4).

Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric patientswith compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 months inpatients with HBeAg negative disease.

Duration of therapy in adult and adolescent patients with chronic hepatitis B

The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:

- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 12months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection ontwo consecutive serum samples at least 3-6 months apart) is confirmed or until HBsseroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levelsshould 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 HBsseroconversion or there is evidence of loss of efficacy. Treatment discontinuation may also beconsidered after stable virological suppression is achieved (i.e. for at least 3 years) providedserum ALT and HBV DNA levels are followed regularly after treatment discontinuation to detectany late virological relapse. With prolonged treatment for more than 2 years, regular reassessmentis recommended to confirm that continuing the selected therapy remains appropriate for thepatient.

In adult patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.

Reduced doses of tenofovir (the active ingredient of Tenofovir disoproxil Zentiva) are also used forthe treatment of HIV-1 infection and chronic hepatitis B in paediatric patients aged 2 to < 12 years.

Tenofovir disoproxil Zentiva is available only as 245 mg film-coated tablets, it is not suitable for the usein paediatric patients aged 2 < 12 years. Other suitable formulations should be checked for theiravailability.

The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with chronichepatitis B under 2 years of age have not been established. No data are available.

If a patient misses a dose of Tenofovir disoproxil Zentiva within 12 hours of the time it is usually taken,the patient should take Tenofovir disoproxil Zentiva with food as soon as possible and resume theirnormal dosing schedule. If a patient misses a dose of Tenofovir disoproxil Zentiva by more than12 hours and it is almost time for their next dose, the patient should not take the missed dose and simplyresume the usual dosing schedule.

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

If the patient vomits more than 1 hour after taking Tenofovir disoproxil Zentiva they do not need to takeanother dose.

No data are available on which to make a dose recommendation for patients over the age of 65 years(see section 4.4).

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

There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients with moderateand severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data has not beenevaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in adult patientswith renal impairment tenofovir disoproxil should only be used if the potential benefits of treatment areconsidered to outweigh the potential risks.

Mild renal impairment (creatinine clearance 50-80 ml/min)

Limited data from clinical studies support once daily dosing of 245 mg tenofovir disoproxil in patientswith mild renal impairment.

Moderate renal impairment (creatinine clearance 30-49 ml/min)

If administration of a lower dose is not possible, prolonged dose intervals using the 245 mg film-coatedtablets may be used.

Administration of 245 mg tenofovir disoproxil every 48 hours can be used based on modelling ofsingle-dose pharmacokinetic data in HIV-negative and non-HBV infected subjects with varying degreesof renal impairment, including end-stage renal disease requiring haemodialysis, but has not beenconfirmed in clinical studies. Therefore, clinical response to treatment and renal function should beclosely monitored in these patients (see sections 4.4 and 5.2).

Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients

Adequate dose adjustments cannot be applied with this product due to lack of alternative tabletstrengths, therefore use in this group of patients is not recommended. If no alternative treatment isavailable, prolonged dose intervals using the 245 mg film-coated tablets may be used as follows:

Severe renal impairment: 245 mg tenofovir disoproxil may be administered every 72-96 hours (dosingtwice a week).

Haemodialysis patients: 245 mg tenofovir disoproxil may be administered every 7 days followingcompletion of a haemodialysis session*.

These dose interval adjustments have not been confirmed in clinical studies. Simulations suggest thatthe prolonged dose interval using Tenofovir disoproxil Zentiva 245 mg film-coated tablets is notoptimal and could result in increased toxicity and possibly inadequate response. Therefore clinicalresponse 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 ofapproximately 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.

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (seesection 4.4).

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

If Tenofovir disoproxil Zentiva is discontinued in patients with chronic hepatitis B with or without HIVco-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis (seesection 4.4).

Tenofovir disoproxil Zentiva tablets should be taken once daily, orally with food.

In exceptional circumstances in patients having particular difficulty in swallowing, Tenofovir disoproxil

Zentiva can be administered following disintegration of the tablet in at least 100 ml of water, orangejuice or grape juice.

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

HIV antibody testing should be offered to all HBV infected patients before initiating tenofovirdisoproxil therapy (see below Co-infection with HIV-1 and hepatitis B).

Hepatitis B

Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk oftransmission of HBV to others through sexual contact or contamination with blood. Appropriateprecautions must continue to be used.

- Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinalproducts containing tenofovir disoproxil or tenofovir alafenamide.

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

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

Triple therapy with nucleosides/nucleotides

There have been reports of a high rate of virological failure and of emergence of resistance at an earlystage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well aswith 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 withthe 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 withtenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitoredafter two to four weeks of treatment, after three months of treatment and every three to six monthsthereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequentmonitoring 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 inany 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 (seesection 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment withtenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or decreases inserum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with tenofovir disoproxil shouldalso be considered in case of progressive decline of renal function when no other cause has beenidentified.

Co-administration and risk of renal toxicity

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinalproduct (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin,cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil and nephrotoxic agents isunavoidable, renal function should be monitored weekly.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatorydrugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors forrenal dysfunction. If tenofovir disoproxil is co-administered with an NSAID, renal function should bemonitored adequately.

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil incombination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renalfunction is required in these patients (see section 4.5). In patients with renal risk factors, theco-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefullyevaluated.

Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products whichare secreted by the same renal pathway, including the transport proteins human organic aniontransporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). Theserenal transport proteins may be responsible for tubular secretion and in part, renal elimination oftenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which aresecreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might bemodified if they are co-administered. Unless clearly necessary, concomitant use of these medicinalproducts which are secreted by the same renal pathway is not recommended, but if such use isunavoidable, renal function should be monitored weekly (see section 4.5).

Renal safety with tenofovir disoproxil has only been studied to a very limited degree in adult patientswith 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 renalfunction. Therefore, tenofovir disoproxil should only be used if the potential benefits of treatment areconsidered 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 beclosely 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-inducedproximal renal tubulopathy (see section 4.8).

Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil in randomizedcontrolled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients (see section 4.8and 5.1). These BMD decreases generally improved after treatment discontinuation.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen inpatients 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 oflong-term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternativetreatment regimens should be considered for patients with osteoporosis or with a history of bonefractures.

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, thereversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach isrecommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decidethe appropriate monitoring during treatment (including decision for treatment withdrawal) and considerthe need for supplementation.

Renal effects

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV-1infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see sections 4.8 and5.1).

Renal monitoring

Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, andmonitored 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 receivingtenofovir disoproxil renal function should be re-evaluated within one week, including measurements ofblood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximaltubulopathy). If renal abnormalities are suspected or detected then consultation with a nephrologistshould be obtained to consider interruption of tenofovir disoproxil treatment.

Interrupting treatment with tenofovir disoproxil should also be considered in case of progressive declineof 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).

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (seesection 4.2). Tenofovir disoproxil should not be initiated in paediatric patients with renal impairmentand should be discontinued in paediatric patients who develop renal impairment during tenofovirdisoproxil therapy.

Bone effects

Tenofovir disoproxil Zentiva may cause a reduction in BMD. The effects of tenofovirdisoproxil-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 anendocrinologist and/or nephrologist should be obtained.

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 withdecompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. These patients maybe at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary andrenal 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 arecharacterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT mayincrease in some patients (see section 4.8). In patients with compensated liver disease, these increases inserum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepaticdecompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation followinghepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patientswho have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated withrising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, includingfatalities, have been reported. Hepatic function should be monitored at repeated intervals with bothclinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. Ifappropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver diseaseor cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation ofhepatitis may lead to hepatic decompensation.

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

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

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovirdisoproxil 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 activehepatitis have an increased frequency of liver function abnormalities during combination antiretroviraltherapy (CART) and should be monitored according to standard practice. If there is evidence ofworsening 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 withtenofovir, see above Exacerbations of hepatitis.

Use with certain hepatitis C virus antiviral agents

Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir,especially when used together with an HIV regimen containing tenofovir disoproxil and apharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil in the setting ofledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and apharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevirwith tenofovir disoproxil given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir ordarunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patientsreceiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevirconcomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored foradverse reactions related to tenofovir disoproxil.

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 casesevidence for a treatment effect, while for weight gain there is no strong evidence relating this to anyparticular treatment. For monitoring of blood lipids and glucose reference is made to established HIVtreatment guidelines. Lipid disorders should be managed as clinically appropriate.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown etiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause seriousclinical conditions, or aggravation of symptoms. Typically, such reactions have been observed withinthe first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis,generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Anyinflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported, 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 stiffnessor difficulty in movement.

Tenofovir disoproxil has not been studied in patients over the age of 65. Elderly patients are more likelyto have decreased renal function; therefore caution should be exercised when treating elderly patientswith tenofovir disoproxil.

Tenofovir disoproxil Zentiva contains lactose monohydrate. Patients with rare hereditary problems ofgalactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take thismedicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Interaction studies have only been performed in adults.

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, thepotential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.

Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal productscontaining tenofovir disoproxil or tenofovir alafenamide.

Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil.

Didanosine

Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and Table1).

Renally eliminated medicinal products

Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil withmedicinal products that reduce renal function or compete for active tubular secretion via transportproteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovirand/or the co-administered medicinal products.

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinalproduct. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet,ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

Given that tacrolimus can affect renal function, close monitoring is recommended when it isco-administered with tenofovir disoproxil.

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 dailyas “q.d.”).

Table 1: Interactions between tenofovir disoproxil and other medicinal products

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

ANTI-INFECTIVES

Antiretrovirals

Protease inhibitors

Atazanavir/Ritonavir Atazanavir: No dose adjustment is(300 mg q.d./100 mg q.d.) AUC: ↓ 25% recommended. The

Cmax: ↓ 28% increased exposure of

C : ↓ 26% tenofovir could potentiatemin

Tenofovir: tenofovir-associated

AUC: 37% adverse events, including↑ renal disorders. Renal

Cmax: ↑ 34% function should be

Cmin: ↑ 29% closely monitored (seesection 4.4).

Lopinavir/Ritonavir Lopinavir/ritonavir: No dose adjustment is(400 mg b.i.d./100 mg b.i.d.) No significant effect on recommended. Thelopinavir/ritonavir PK parameters. increased exposure of

Tenofovir: tenofovir could potentiate

AUC: ↑ 32% tenofovir-associated

Cmax: ↔ adverse events, including

Cmin: ↑ 51% renal disorders. Renalfunction should beclosely monitored (seesection 4.4).

Darunavir/Ritonavir Darunavir: No dose adjustment is(300 mg/100 mg b.i.d.) No significant effect on recommended. Thedarunavir/ritonavir increased exposure of

PK parameters. tenofovir could potentiate

Tenofovir: tenofovir-associated

AUC: ↑ 22% adverse events, including

Cmin: ↑ 37% renal disorders. Renalfunction should beclosely monitored (seesection 4.4).

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

NRTIs

Didanosine Co-administration of tenofovir Co-administration ofdisoproxil and didanosine results in tenofovir disoproxil anda 40-60% increase in systemic didanosine is notexposure to didanosine. recommended (seesection 4.4).

Increased systemicexposure to didanosinemay increase didanosinerelated adverse reactions.

Rarely, pancreatitis andlactic acidosis,sometimes fatal, havebeen reported. Co-administration oftenofovir disoproxil anddidanosine at a dose of400 mg daily has beenassociated with asignificant decrease in

CD4 cell count, possiblydue to an intracellularinteraction increasingphosphorylated (i.e.active) didanosine. Adecreased dosage of 250mg didanosine co-administered withtenofovir disoproxiltherapy has beenassociated with reports ofhigh rates of virologicalfailure within severaltested combinations forthe treatment of HIV-1infection.

Adefovir dipivoxil AUC: ↔ Tenofovir disoproxil

Cmax: ↔ should not beadministeredconcurrently withadefovir dipivoxil (seesection 4.4).

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Entecavir AUC: ↔ No clinically significant

Cmax: ↔ pharmacokineticinteractions whentenofovir disoproxil wasco-administered withentecavir.

Hepatitis C virus antiviral agents

Ledipasvir/Sofosbuvir Ledipasvir: Increased plasma(90 mg/400 mg q.d.) + AUC: ↑ 96% concentrations of

Atazanavir/Ritonavir Cmax: ↑ 68% tenofovir resulting from(300 mg q.d./100 mg q.d.) + C : ↑ 118% co-administration ofmin

Emtricitabine/Tenofovir tenofovir disoproxil,disoproxil1 Sofosbuvir: ledipasvir/sofosbuvir and(200 mg/245 mg q.d.) AUC: ↔ atazanavir/ritonavir may

C increase adversemax: ↔reactions related to

GS-3310072: tenofovir disoproxil,

AUC: ↔ including renal disorders.

C : ↔ The safety of tenofovirmax disoproxil when used

Cmin: ↑ 42% withledipasvir/sofosbuvir and

Atazanavir: a pharmacokinetic

AUC: ↔ enhancer (e.g. ritonavir

Cmax: ↔ or cobicistat) has not

Cmin: ↑ 63% been established.

Ritonavir: The combination should

AUC: ↔ be used with caution with

Cmax: ↔ frequent renal

Cmin: ↑ 45% monitoring, if otheralternatives are not

Emtricitabine: available (see section

AUC: ↔ 4.4).

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 47%

Cmin: ↑ 47%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Ledipasvir/Sofosbuvir Ledipasvir: Increased pla sma(90 mg/400 mg q.d.) + AUC: ↔ concentrations of

Darunavir/Ritonavir Cmax: ↔ tenofovir resulting from(800 mg q.d./100 mg q.d.) + Cmin: ↔ co-administration of

Emtricitabine/Tenofovir tenofovir disoproxil,disoproxil Sofosbuvir: ledipasvir/sofosbuvir and(200 mg/245 mg q.d.)1 AUC: ↓ 27% darunavir/ritonavir may

Cmax: ↓ 37% increase adversereactions related to

GS-3310072: tenofovir disoproxil,

AUC: ↔ including renal disorders.

Cmax: ↔ The safety of tenofovir

C : ↔ disoproxil when usedminwith

Darunavir: ledipasvir/sofosbuvir and

AUC: ↔ a pharmacokinetic

C : ↔ enhancer (e.g. ritonavirmax

C : ↔ or cobicistat) has notminbeen established.

AUC: ↔ The combination should

Cmax: ↔ be used with caution withfrequent renal

Cmin: ↑ 48% monitoring, if otheralternatives are not

Emtricitabine: available (see section

AUC: ↔ 4.4).

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 50%

Cmax: ↑ 64%

Cmin: ↑ 59%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Ledipasvir/Sofosbuvir Ledipasvir: No dose adju stment is(90 mg/400 mg q.d.) + AUC: ↓ 34% recommended. The

Efavirenz/Emtricitabine/Teno Cmax: ↓ 34% increased exposure offovir disoproxil C : ↓ 34% tenofovir could potentiate(600 mg/200 mg/245 mg minadverse reactionsq.d.) Sofosbuvir: associated with tenofovir

AUC: ↔ disoproxil, including

C : ↔ renal disorders. Renalmaxfunction should be

GS-3310072: closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98%

Cmax: ↑ 79%

Cmin: ↑ 163%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Ledipasvir/Sofosbuvir Ledipasvir: No dose adju stment is(90 mg/400 mg q.d.) + AUC: ↔ recommended. The

Emtricitabine/Rilpivirine/Ten Cmax: ↔ increased exposure ofofovir disoproxil Cmin: ↔ tenofovir could potentiate(200 mg/25 mg/245 mg q.d.) adverse reactions

Sofosbuvir: associated with tenofovir

AUC: ↔ disoproxil, including

Cmax: ↔ renal disorders. Renalfunction should be

GS-3310072 closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↔

Cmin: ↑ 91%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Ledipasvir/Sofosbuvir Sofosbuvir: No dose adju stment is(90 mg/400 mg q.d.) + AUC: ↔ recommended. The

Dolutegravir (50 mg q.d.) + Cmax: ↔ increased exposure of

Emtricitabine/Tenofovir tenofovir could potentiatedisoproxil (200 mg/245 mg GS-3310072: adverse reactionsq.d.) AUC: ↔ associated with tenofovir

Cmax: ↔ disoproxil, including

Cmin: ↔ renal disorders. Renalfunction should be

Ledipasvir: closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

Dolutegravir

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 65%

Cmax: ↑ 61%

Cmin: ↑ 115%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir Sofosbuvir: Increased pla sma(400 mg/100 mg q.d.) + AUC: ↔ concentrations of

Atazanavir/Ritonavir Cmax: ↔ tenofovir resulting from(300 mg q.d./100 mg q.d.) + co-administration of

Emtricitabine/Tenofovir GS-3310072: tenofovir disoproxil,disoproxil AUC: ↔ sofosbuvir/velpatasvir(200 mg/245 mg q.d.) Cmax: ↔ and atazanavir/ritonavir

Cmin: ↑ 42% may increase adversereactions related to

Velpatasvir: tenofovir disoproxil,

AUC: ↑ 142% including renal disorders.

C : 55% The safety of tenofovirmax ↑ disoproxil when used

Cmin: ↑ 301% withsofosbuvir/velpatasvir

Atazanavir: and a pharmacokinetic

AUC: ↔ enhancer (e.g. ritonavir

Cmax: ↔ or cobicistat) has not

Cmin: ↑ 39% been established.

Ritonavir: The combination should

AUC: ↔ be used with caution with

Cmax: ↔ frequent renal monitoring

Cmin: ↑ 29% (see section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 55%

Cmin: ↑ 39%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir Sofosbuvir: Increased pla sma(400 mg/100 mg q.d.) + AUC: ↓28% concentrations of

Darunavir/Ritonavir Cmax: ↓ 38% tenofovir resulting from(800 mg q.d./100 mg q.d.) + co-administration of

Emtricitabine/Tenofovir GS-3310072: tenofovir disoproxil,disoproxil AUC: ↔ sofosbuvir/velpatasvir(200 mg/245 mg q.d.) C : ↔ and darunavir/ritonavirmax

C : ↔ may increase adverseminreactions related to

Velpatasvir: tenofovir disoproxil,

AUC: ↔ including renal disorders.

C : 24% The safety of tenofovirmax ↓ disoproxil when used

Cmin: ↔ withsofosbuvir/velpatasvir

Darunavir: and a pharmacokinetic

AUC: ↔ enhancer (e.g. ritonavir

Cmax: ↔ or cobicistat) has not

Cmin: ↔ been established.

Ritonavir: The combination should

AUC: ↔ be used with caution with

Cmax: ↔ frequent renal monitoring

Cmin: ↔ (see section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 55%

Cmin: ↑ 52%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir Sofosbuvir: Increased pla sma(400 mg/100 mg q.d.) + AUC: ↓ 29% concentrations of

Lopinavir/Ritonavir Cmax: ↓ 41% tenofovir resulting from(800 mg/200 mg q.d.) + co-administration of

Emtricitabine/Tenofovir GS-3310072: tenofovir disoproxil,disoproxil AUC: ↔ sofosbuvir/velpatasvir(200 mg/245 mg q.d.) C and lopinavir/ritonavirmax: ↔

C : ↔ may increase adverseminreactions related to

Velpatasvir: tenofovir disoproxil,

AUC: ↔ including renal disorders.

C : 30% The safety of tenofovirmax ↓ disoproxil when used

Cmin: ↑ 63% withsofosbuvir/velpatasvir

Lopinavir: and a pharmacokinetic

AUC: ↔ enhancer (e.g. ritonavir

Cmax: ↔ or cobicistat) has not

Cmin: ↔ been established.

Ritonavir: The combination should

AUC: ↔ be used with caution with

Cmax: ↔ frequent renal monitoring

Cmin: ↔ (see section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 42%

Cmin: ↔

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir Sofosbuvir: No dose adju stment is(400 mg/100 mg q.d.) + AUC: ↔ recommended. The

Raltegravir Cmax: ↔ increased exposure of(400 mg b.i.d) + tenofovir could potentiate

Emtricitabine/Tenofovir GS-3310072: adverse reactionsdisoproxil AUC: ↔ associated with tenofovir(200 mg/245 mg q.d.) Cmax: ↔ disoproxil, including

Cmin: ↔ renal disorders. Renalfunction should be

Velpatasvir: closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

Raltegravir:

AUC: ↔

Cmax: ↔

Cmin: ↓ 21%

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↑ 46%

Cmin: ↑ 70%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir Sofosbuvir: Concomitant(400 mg/100 mg q.d.) + AUC: ↔ administration of

Efavirenz/Emtricitabine/ Cmax: ↑ 38% sofosbuvir/velpatasvir

Tenofovir disoproxil and efavirenz is expected(600 mg/200 mg/245 mg GS-3310072: to decrease plasmaq.d.) AUC: ↔ concentrations of

Cmax: ↔ velpatasvir.

Cmin: ↔ Co-administration ofsofosbuvir/velpatasvir

Velpatasvir: with efavirenz-containing

AUC: ↓ 53% regimens is not

C : 47% recommended.max ↓

Cmin: ↓ 57%

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81%

Cmax: ↑ 77%

Cmin: ↑ 121%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir Sofosbuvir: No dose adju stment is(400 mg/100 mg q.d.) + AUC: ↔ recommended. The

Emtricitabine/Rilpivirine/ Cmax: ↔ increased exposure of

Tenofovir disoproxil tenofovir could potentiate(200 mg/25 mg/245 mg q.d.) GS-3310072: adverse reactions

AUC: ↔ associated with tenofovir

Cmax: ↔ disoproxil, including

Cmin: ↔ renal disorders. Renalfunction should be

Velpatasvir: closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↑ 44%

Cmin: ↑ 84%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir/Velpatasvir/ Sofosbuvir: Increased pla sma

Voxilaprevir AUC: ↔ concentrations of(400 mg/100 mg/ Cmax: ↓ 30% tenofovir resulting from100 mg+100 mg q.d.)3 + Cmin: N/A co-administration of

Darunavir (800 mg q.d.) + tenofovir disoproxil,

Ritonavir (100 mg q.d.) + GS-3310072: sofosbuvir/velpatasvir/vo

Emtricitabine/Tenofovir AUC: ↔ xilaprevir anddisoproxil (200 mg/245 mg Cmax: ↔ darunavir/ritonavir mayq.d.) Cmin: N/A increase adversereactions related to

Velpatasvir: tenofovir disoproxil,

AUC: ↔ including renal disorders.

C : ↔ The safety of tenofovirmax

Cmin: ↔ disoproxil when usedwith

Voxilaprevir: sofosbuvir/velpatasvir/vo

AUC: 143% xilaprevir and a↑ pharmacokinetic

Cmax: ↑ 72% enhancer (e.g. ritonavir

Cmin: ↑ 300% or cobicistat) has notbeen established.

AUC: ↔ The combination should

Cmax: ↔ be used with caution with

Cmin: ↓ 34% frequent renal monitoring(see section 4.4).

AUC: ↑ 45%

Cmax: ↑ 60%

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 48%

Cmin: ↑ 47%

Medicinal product by Effects on drug levels Recommendationtherapeutic areas Mean percent change in AUC, Cmax, concerning(dose in mg) Cmin co-administration with245 mg tenofovirdisoproxil

Sofosbuvir Sofosbuvir: No dose adju stment is(400 mg q.d.) + AUC: ↔ required.

Efavirenz/Emtricitabine/Teno Cmax: ↓ 19%fovir disoproxil(600 mg/200 mg/245 mg GS-3310072:q.d.) AUC: ↔

Cmax: ↓ 23%

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 25%

Cmin: ↔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.

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavirboosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptivenorgestimate/ethinyl oestradiol.

Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir (seesection 5.2).

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate nomalformations or foetal/neonatal toxicity associated with tenofovir disoproxil. Animal studies do notindicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil may be consideredduring pregnancy, if necessary.

In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown toreduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, inaddition to hepatitis B immune globulin and hepatitis B vaccine in infants.

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection wereadministered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to2 months postpartum; women and their infants were followed for up to 12 months after delivery. Nosafety signal has emerged from these data.

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

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk isconsidered negligible. Although long-term data is limited, no adverse reactions have been reported inbreast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animalstudies do not indicate harmful effects of tenofovir disoproxil on fertility.

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.

HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, renalfailure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimesleading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring ofrenal function is recommended for patients receiving Tenofovir disoproxil Zentiva (see section 4.4).

HIV-1: Approximately one third of patients can be expected to experience adverse reactions followingtreatment with tenofovir disoproxil in combination with other antiretroviral agents. These reactions areusually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil -treatedadult patients discontinued treatment due to the gastrointestinal events.

Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactionsfollowing treatment with tenofovir disoproxil, most of which are mild. In clinical trials of HBV infectedpatients, 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 whohave discontinued hepatitis B therapy (see section 4.4).

Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studiesand post-marketing experience. All adverse reactions are presented in Table 2.

HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based onexperience in two studies in 653 treatment-experienced patients receiving treatment with tenofovirdisoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patientsreceived treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) in combinationwith lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarilybased on experience in two double-blind comparative controlled studies in which 641 adult patients withchronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mgdaily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactionsobserved with continued treatment for 384 weeks were consistent with the safety profile of tenofovirdisoproxil. 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 first4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovirdisoproxil 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 withdecompensated 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 plustenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverseevent; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or confirmedserum phosphate of < 2 mg/dl through week 48; there were no statistically significant differencesbetween the combined tenofovir-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) ofthe 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 tenofovirdisoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 9% (2/22) of theentecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphateof < 2 mg/dl.

At week 168, in this population of patients with decompensated liver disease, the rate of death was of13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxilgroup and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) inthe 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 (seesection 4.4).

Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxilwere identified from a randomised, double-blind study (GS-US-174-0121) in which280 lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) oremtricitabine/tenofovir disoproxil (n = 139) for 240 weeks.

The adverse reactions with suspected (at least possible) relationship to treatment are listed below bybody system organ class and frequency. Within each frequency grouping, undesirable effects arepresented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10),common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based onclinical study and post-marketing experience

Frequency Tenofovir disoproxil

Very common: hypophosphataemia1

Uncommon: hypokalaemia1

Rare: lactic acidosis

Very common: dizziness

Common: headache

Very common: diarrhoea, vomiting, nausea

Common: abdominal pain, abdominal distension, flatulence

Uncommon: pancreatitis

Common: increased transaminases

Rare: hepatic steatosis, hepatitis

Very common: rash

Rare: angioedema

Common: bone mineral density decreased3

Uncommon: rhabdomyolysis1, muscular weakness1osteomalacia (manifested as bone pain and infrequently contributing to

Rare: fractures)1, 2, myopathy1

Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconisyndrome)acute renal failure, renal failure, acute tubular necrosis, nephritis (including

Rare: acute interstitial nephritis)2, nephrogenic diabetes insipidus

Very common: asthenia

Common: fatigue1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not consideredto 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 inrandomised controlled clinical trials or the tenofovir disoproxil expanded access program. Thefrequency category was estimated from a statistical calculation based on the total number of patientsexposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded accessprogram (n = 7,319).

3 The frequency of this adverse reaction was estimated based on safety data derived from differentclinical studies with TDF in HBV infected patients. See also sections 4.4 and 5.1.

HIV-1 and hepatitis B:

As Tenofovir disoproxil Zentiva may cause renal damage monitoring of renal function is recommended(see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolvedor improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinineclearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk ofrenal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patientsreceiving concomitant nephrotoxic medications) are at increased risk of experiencing incompleterecovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with otherantiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, orpatients receiving concomitant medications known to induce lactic acidosis are at increased risk ofexperiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

HIV-1:

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4).

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (seesection 4.4).

Hepatitis B:

Exacerbations of hepatitis during treatment

In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit ofnormal) and > 2-times baseline occurred in 2.6% of tenofovir disoproxil-treated patients. ALTelevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majorityof cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or coincidedwith the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (seesection 4.4).

Exacerbations of hepatitis after discontinuation of treatment

In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurredafter discontinuation of HBV therapy (see section 4.4).

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 receivedtreatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination withother antiretroviral agents for 48 weeks (see section 5.1). The adverse reactions observed in paediatricpatients who received treatment with tenofovir disoproxil were consistent with those observed inclinical studies of tenofovir disoproxil in adults (see sections 4.8 Tabulated summary of adversereactions 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 insubjects who received placebo. In HIV-1 infected children, the BMD Z-scores observed in subjects whoswitched to tenofovir disoproxil were lower than those observed in subjects who remained on theirstavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1).

In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse events.

Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 ofwhom 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 clinicallymeaningful decline in estimated GFR which improved after discontinuation of tenofovir disoproxil.

Chronic hepatitis B

Assessment of adverse reactions is based on a randomised study (study GS-US-174-0115) in 106adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with tenofovirdisoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks and a randomised study (Study GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to < 12 years of age) receiving treatment withtenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks. The adverse reactions observed inpaediatric patients who received treatment with tenofovir disoproxil were consistent with thoseobserved in clinical studies of tenofovir disoproxil in adults (see sections 4.8 Tabulated summary ofadverse reactions and 5.1).

Reductions in BMD have been observed in HBV infected paediatric patients 2 to < 18 years of age. The

BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observedin subjects who received placebo (see sections 4.4 and 5.1).

Other special population(s)

Tenofovir disoproxil has not been studied in patients over the age of 65. Elderly patients are more likelyto have decreased renal function, therefore caution should be exercised when treating elderly patientswith tenofovir disoproxil (see section 4.4).

Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommendedin adult patients with renal impairment treated with Tenofovir disoproxil Zentiva (see sections 4.2, pct. 4.4and 5.2). The use of tenofovir disoproxil is not recommended in paediatric patients with renalimpairment (see sections 4.2 and 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system listedin Appendix V.

If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), andstandard supportive treatment applied as necessary.

Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is134 ml/min. It is not known whether tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse transcriptaseinhibitors, ATC code: J05AF07

Mechanism of action and pharmacodynamic effects

Tenofovir disoproxil phosphate is the phosphate salt of the prodrug tenofovir disoproxil. Tenofovirdisoproxil is absorbed and converted to the active substance tenofovir, which is a nucleosidemonophosphate (nucleotide) analogue. Tenofovir is then converted to the active metabolite, tenofovirdiphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes. Tenofovirdiphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheralblood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the

HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, afterincorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor ofcellular polymerases α, β, and γ. At concentrations of up to 300 µmol/l, tenofovir has also shown noeffect 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 thewild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l againstprimary 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 activityin 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 reversetranscriptase 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 hasbeen 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 tenofovirdisoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors. The results indicatethat patients whose HIV expressed 3 or more thymidine-analogue associated mutations (TAMs) thatincluded either the M41L or L210W reverse transcriptase mutation showed reduced response totenofovir disoproxil 245 mg therapy.

The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adultshave 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 tenofovirdisoproxil 245 mg for 24 weeks. The mean baseline CD4 cell count was 427 cells/mm3, the meanbaseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of < 5,000copies/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 associatedwith nucleoside reverse transcriptase inhibitors, 58% had mutations associated with protease inhibitorsand 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 disoproxil245 mg recipients (p < 0.0001). A statistically significant difference in favour of tenofovir disoproxil245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4count (+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 or50 copies/ml was 41% and 18% respectively). Eight (2%) tenofovir disoproxil 245 mg treated patientsdeveloped the K65R mutation within the first 48 weeks.

The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy andsafety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine andefavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy. The mean baseline CD4 cellcount was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% ofpatients 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 > 100,000copies/ml and 39% had CD4 cell counts < 200 cells/ml.

By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered asfailure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 48 weeksof 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 below400 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 similarin both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the tenofovirdisoproxil 245 mg and stavudine groups, respectively). At 144 weeks of treatment, the average changefrom 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 consistentresponse 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 groupthan the active control group (2.7% versus 0.7%). Efavirenz or lamivudine resistance either preceded orwas coincident with the development of K65R in all cases. Eight patients had HIV that expressed K65Rin the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks of treatment andthe last one at week 96. No further K65R development was observed up to week 144. One patient in thetenofovir disoproxil arm developed the K70E substitution in the virus. From both the genotypic andphenotypic 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 inthe 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 asusceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus. HBV strains expressingthe rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with resistance toentecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-type virus. HBVstrains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed asusceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus. Viruses containing thertA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild-type virus.

The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease isbased on virological, biochemical and serological responses in adults with HBeAg positive and HBeAgnegative chronic hepatitis B. Treated patients included those who were treatment-naïve,lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovirdipivoxil resistance mutations at baseline. Benefit has also been demonstrated based on histologicalresponses 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 tenofovirdisoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in Table 3below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg positive patientswhile 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 theprimary 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 Knodellfibrosis). Treatment with tenofovir disoproxil 245 mg was also associated with significantly greaterproportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mgtreatment. Both treatments produced similar results with regard to histological response (defined as

Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodellfibrosis) at week 48 (see Table 3 below).

In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil groupthan 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 atweek 48

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

Parameter Tenofovir Adefovir Tenofovir Adefovirdisoproxil dipivoxil disoproxil dipivoxil245 mg 10 mg 245 mg 10 mgn = 250 n = 125 n = 90n = 176

Completeresponse (%)a 71* 49 67* 12

Histology

Histological 72 69 74 68response (%)b

Median HBV

DNA reductionfrom baselinec -4.7* -4.0 -6.4* -3.7(log10 copies/ml)

HBV DNA (%)< 400 copies/ml 93* 63 76* 13(< 69 IU/ml)

ALT (%)

Normalised ALTd 76 77 68* 54

Serology (%)

HBeAg loss/n/a n/a 22/21 18/18seroconversion

HBsAg loss/0/0 0/0 3*/1 0/0seroconversion

* p-value versus adefovir dipivoxil < 0.05,a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatoryscore improvement of at least 2 points without worsening in Knodell fibrosis,b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodellfibrosis,c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNAand the limit of detection (LOD) of the assay,d The population used for analysis of ALT normalisation included only patients with ALT above ULNat 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 HBVassay), 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) andnucleoside-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-nineof the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-threepercent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response totreatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV DNAsuppression < 400 copies/ml. All patients with normal ALT at baseline and 88% of patients withabnormal 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 nointerruption 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 weremaintained 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 Adefovir dipivoxil 10 mg roll over ton = 250 tenofovir disoproxil 245 mgn = 125

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

HBV DNA (%) 90 87 84 83 80 74 89 88 87 84 84 76< 400 copies/ml(< 69 IU/ml)

ALT (%) 72 73 67 70 68 64 68 70 77 76 74 69

Normalised

ALTd

Serology (%)

HBeAg loss/n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/aseroconversion

HBsAg loss/0/0 0/0 0/0 0/0 0/0 1/1n 0/0 0/0 0/0 0/0k 1/1n 1/1nseroconversiona Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study atany 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 ULNat 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 wasongoing in the study at the time of the data cut-off. However, the subject’s HBsAg loss was ultimatelyconfirmed 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 datacollected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovirdisoproxil).

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 Adefovir dipivoxil 10 mg roll over ton = 176 tenofovir disoproxil 245 mgn = 90

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

HBV DNA (%) 76 72 68 64 61 56 74 71 72 66 65 61< 400 copies/ml(< 69 IU/ml)

ALT (%) 60 55 56 46 47 47 65 61 59 56 57 56

Normalised

ALTd

Serology (%)

HBeAg loss/26/ 29/ 34/ 38/ 37/ 30/ 24/ 33/ 36/ 38/ 40/ 35/seroconversion 23 23 25 30 25 20 20 26 30 31 31 24

HBsAg loss/5/4 8/ 11/ 11/ 12/ 15/ 6/ 8/ 8/ 10/ 11/ 13/seroconversion 6g 8g 8l 8l 12l 5 7g 7g 10l 10l 11la Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study atany 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 ULNat 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 datacollected 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 datacollected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovirdisoproxil).

m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.

n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.

Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained instudies 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 atbaseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patientswith cirrhosis at baseline (Ishak fibrosis score 5-6), 26% (24) experienced no change in Ishak fibrosisscore and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak fibrosisscore of at least 2 points.

Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positivesubjects at week 240 compared to baseline

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

Tenofovir Adefovir dipivoxil Tenofovir Adefovir dipivoxildisoproxil 10 mg roll over to disoproxil 10 mg roll over to245 mg tenofovir 245 mg tenofovircn = 250 disoproxil cn = 176 disoproxil 245 mg245 mg dn = 90dn = 125

Histological 88 85 90 92a,bresponse (%) [130/148] [63/74] [63/70] [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 17subjects across both studies).

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

c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label.d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovirdisoproxil.

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 adultpatients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study ACTG5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir arm were9.45 log10 copies/ml (n = 27). Treatment with tenofovir disoproxil 245 mg was associated with a meanchange in serum HBV DNA from baseline, in the patients for whom there was 48-week data, of -5.74log10 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 mgemtricitabine 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 plustenofovir 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 HBVassay) 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 hadthe option to intensify treatment to open-label emtricitabine plus tenofovir disoproxil. Long-term studiesto evaluate the benefit/risk of bitherapy with emtricitabine plus tenofovir disoproxil in HBVmonoinfected patients are ongoing.

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

Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety andefficacy 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 of61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 months of prior lamivudineexperience, 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 safetyendpoints 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 emtricitabineplus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 48 weeks oftreatment.

Overall, the data derived from this study are too limited to draw any definitive conclusions on thecomparison 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 Emtricitabine 200 mg/ Entecavir245 mg (n = 45) tenofovir disoproxil (0.5 mg or 1 mg)245 mg n = 22(n = 45)

Tolerability failure 3 (7%) 2 (4%) 2 (9%)(permanentdiscontinuation ofstudy drug due to atreatment emergent

AE)n (%)a

Study 174-0108

Confirmed increase in 4 (9%) 3 (7%) 1 (5%)serum creatinine≥ 0.5 mg/dl frombaseline or confirmedserum phosphate of< 2 mg/dln (%)b

HBV DNA n (%) 31/44 (70%) 36/41 (88%) 16/22 (73%)< 400 copies/mln (%)

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

Normal ALT≥ 2 point decrease in 7/27 (26%) 12/25 (48%) 5/12 (42%)

CPT from baselinen (%)

Mean change from -0.8 -0.9 -1.3baseline in CPT score

Mean change from -1.8 -2.3 -2.6baseline in MELDscorea p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622,b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000.

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

Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir disoproxil,76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) of subjectsreceiving 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-blindstudy (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with compensatedliver 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. Onehundred forty-one and 139 adult subjects were randomised to a tenofovir disoproxil and emtricitabineplus tenofovir disoproxil treatment arm, respectively. Baseline demographics were similar between thetwo 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 oftreatment 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 positivesubjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced HBeAg loss, and 8 of65 subjects (12%) experienced anti-HBe seroconversion through week 240. In the HBeAg positivesubjects 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 notseroconversion to anti-HBs. Five subjects randomised to emtricitabine plus tenofovir disoproxilexperienced 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 treatmentand 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) and384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with tenofovirdisoproxil 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 thenswitched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes in HBVpolymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400copies/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 tenofovirdisoproxil resistance have developed.

In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxilresistance 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 totenofovir disoproxil were identified in these isolates. Genotypic analysis was conducted for 5 subjects inthe tenofovir disoproxil arm post week 48. No amino acid substitutions associated with tenofovirdisoproxil resistance were detected in any subject.

In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline receivedtenofovir disoproxil for up to 240 weeks. Cumulatively, there were 4 patients who experienced aviremic episode (HBV DNA > 400 copies/ml) at their last timepoint on tenofovir disoproxil. Amongthem, sequence data from paired baseline and on treatment HBV isolates were available for 2 of 4patients. No amino acid substitutions associated with resistance to tenofovir disoproxil were identifiedin these isolates.

In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistancemutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 51/52patients 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 tenofovirdisoproxil (PLB-tenofovir disoproxil group). Genotypic evaluations were performed on all patientswithin 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 inthese isolates.

In a paediatric study (GS-US-174-0144), genotypic data from paired baseline and on treatment HBVisolates from patients who received blinded tenofovir disoproxil were available for 9 of 10 patients atweek 48 who had plasma HBV DNA > 400 copies/ml. Genotypic data from paired baseline and ontreatment HBV isolates from patients who switched to open-label tenofovir disoproxil from blindedtenofovir disoproxil (TDF-TDF group) or from placebo (PLB-TDF group) after at least 48 weeks ofblinded treatment were available for 12 of 16 patients at week 96, 4 of 6 patients at week 144 and 4 of 4patients at week 192 who had plasma HBV DNA > 400 copies/ml. No amino acid substitutionsassociated with resistance to tenofovir disoproxil were identified in these isolates by weeks 48, 96, 144or 192.

HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years ofage were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an optimisedbackground regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovirdisoproxil 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 andcomparative 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 lumbarspine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxil andplacebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil groupcompared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil group and oneadolescent in the placebo group had significant lumbar spine BMD loss (defined as > 4% loss). Among28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z-scores declined by -0.341for 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 eitherreplace 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 week48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil treatmentgroup. When missing data were excluded, 91% of patients in the tenofovir disoproxil treatment groupand 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 withtenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034and -0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline. Meanchanges 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 zidovudinegroups, respectively. The mean rate of lumbar spine bone gain at week 48 was similar between thetenofovir disoproxil treatment group and the stavudine or zidovudine treatment group. Total body bonegain was less in the tenofovir disoproxil treatment group compared to the stavudine or zidovudinetreatment group. One tenofovir disoproxil treated subject and no stavudine or zidovudine treatedsubjects 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 tenofovirdisoproxil 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 disoproxildiscontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findingsclinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxiltherapy (median tenofovir disoproxil exposure 331 weeks).

Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients aged12 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 withtenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks. Subjects must have been naïve totenofovir 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 disoproxiltreatment 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 week72 compared to 31% (13/42) in the placebo group. Response to treatment with tenofovir disoproxil wascomparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-experienced (n = 32) patients, includinglamivudine-resistant patients (n = 6). Ninety-five percent of nucleos(t)ide-naïve patients, 84% ofnucleos(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 priorlamivudine 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) ofpatients in the placebo group had HBV DNA < 400 copies/ml. Seventy-five percent (21/28) ofimmune-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 tenofovirdisoproxil treatment up to week 192. After week 72, virologic suppression was maintained for thosereceiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (tenofovirdisoproxil-tenofovir disoproxil group): 86.5% (45/52) of subjects in the tenofovir disoproxil-tenofovirdisoproxil group had HBV DNA < 400 copies/ml at week 192. Among the subjects who receivedplacebo during the double-blind period, the proportion of subjects with HBV DNA < 400 copies/ml rosesharply after they began treatment with open-label tenofovir disoproxil (PLB-tenofovir disoproxilgroup): 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 thetenofovir disoproxil-tenofovir disoproxil group was 75.8% (25/33) among those who were HBeAgpositive 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-tenofovirdisoproxil groups (37.5% and 41.7%, respectively) experienced seroconversion to anti-HBe throughweek 192.

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

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

Baseline Week 72 Week 192

Tenofovir Tenofovir Tenofovirdisoproxil- PLB-tenofovir disoproxil- PLB- disoproxil- PLB-tenofovir tenofovir tenofovir tenofovir tenofovirdisoproxil disoproxil disoproxil disoproxil disoproxil disoproxil

Lumbar spinemean (SD) −0.42 -0.26 -0.49 -0.23 -0.37 -0.44

BMD Z-scorea (0.762) (0.806) (0.852) (0.893) (0.946) (0.920)

Lumbar spinemean (SD) change NA NA -0.06 0.10 0.02 -0.10from baseline (0.320) (0.378) (0.548) (0.543)

BMD Z-scorea

Whole body mean(SD) −0.19 −0.23 −0.36 −0.12 −0.38 −0.42

BMD Z-scorea (1.110) (0.859) (1.077) (0.916) (0.934) (0.942)

Whole body mean(SD) change from NA NA −0.16 0.09 -0.16 -0.19baseline (0.355) (0.349) (0.521) (0.504)

BMD Z-scorea

Lumbar spine

BMD at least 6% NA NA 1.9% 0% 3.8% 3.7%decreaseb (1 subject) (2 subjects) (2 subjects)

Whole body BMDat least 6% NA NA 0% 0% 0% 1.9%decreaseb (1 subject)

Lumbar spine

BMD mean % NA NA 5.14% 8.08% 10.05% 11.21%increase

Whole body BMDmean % increase NA NA 3.07% 5.39% 6.09% 7.22%

NA = Not Applicablea BMD Z-scores not adjusted for height and weightb Primary safety endpoint through week 72

In study GS-US-174-0144, 89 HBeAg negative and positive patients aged 2 to < 12 years with chronichepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of 245 mg (n = 60)or placebo (n = 29) once daily for 48 weeks. Subjects must have been naïve to tenofovir disoproxil, with

HBV DNA > 105 copies/ml (~ 4.2 log10 IU/ml) and ALT > 1.5 × the upper limit of normal (ULN) atscreening. At Week 48, 77% (46 of 60) of patients in the tenofovir disoproxil treatment group and 7%(2 of 29) of patients in the placebo group had HBV DNA < 400 copies/ml (69 IU/ml). Sixty-six percent(38 of 58) of patients in the tenofovir disoproxil group had normalized ALT at week 48 compared with15% (4 of 27) in the placebo group. Twenty-five percent (14 of 56) of patients in the tenofovirdisoproxil group and 24% (7 of 29) of patients in the placebo group achieved HBeAg seroconversion at

Week 48.

Response to treatment with tenofovir disoproxil was comparable in treatment-naïve andtreatment-experienced subjects with 76% (38/50) of treatment-naïve and 80% (8/10) oftreatment-experienced subjects achieving HBV DNA < 400 copies/ml (69 IU/ml) at Week 48. Responseto treatment with tenofovir disoproxil was also similar in subjects who were HBeAg-negative comparedwith those who were HBeAg positive at baseline with 77% (43/56) HBeAg positive and 75.0% (3/4)

HBeAg-negative subjects achieving HBV DNA < 400 copies/ml (69 IU/ml) at Week 48. Thedistribution of HBV genotypes at baseline was similar between the TDF and Placebo groups. Themajority of subjects were either genotypes C (43.8%) or D (41.6%) with a lower and similar frequencyof genotypes A and B (6.7% each). Only 1 subject randomized to the TDF group was genotype E atbaseline. In general, treatment responses to tenofovir disoproxil were similar for genotypes A, B, C and

E [75-100% of subjects achieved HBV DNA < 400 copies/ml (69 IU/ml) at Week 48] with a lowerresponse rate in subjects with genotype D infection (55%).

After at least 48 weeks of blinded randomized treatment, each subject could switch to open-labeltenofovir disoproxil treatment up to week 192. After week 48, virologic suppression was maintained forthose receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil(TDF-TDF group): 83.3% (50/60) of subjects in the TDF-TDF group had HBV DNA < 400 copies/ml(69 IU/ml) at week 192. Among the subjects who received placebo during the double-blind period, theproportion of subjects with HBV DNA < 400 copies/ml rose sharply after receiving treatment withopen-label TDF (PLB-TDF group): 62.1% (18/29) of subjects in the PLB-TDF group had HBV DNA< 400 copies/ml at week 192. The proportion of subjects with ALT normalization at week 192 in the

TDF-TDF and PLB-TDF groups 79.3% and 59.3%, respectively (based on central laboratory criteria).

Similar percentages of subjects in the TDF-TDF and PLB-TDF groups (33.9% and 34.5%, respectively)had experienced HBeAg seroconversion through week 192. No subjects in either treatment group hadexperienced HBsAg seroconversion at week 192. Treatment response rates to tenofovir disoproxil atweek 192 were maintained for all genotypes A, B and C (80-100%) in the TDF-TDF group. At week192 a lower response rate is still observed in subjects with genotype D infection (77%) but with animprovement compared to 48 week results (55%).

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

Table 9: Bone Mineral Density Evaluation at Baseline, Week 48 and Week 192

Baseline Week 48 Week 192

TDF PLB TDF-TDF PLB-TDF TDF-TDF PLB-TDF

Lumbar spinemean (SD) BMD -0.08 -0.31 -0.09 -0.16 -0.20 -0.38

Z-score (1.044) (1.200) (1.056) (1.213) (1.032) (1.344)

Lumbar spinemean (SD) change NA NA -0.03 0.23 -0.15 0.21from baseline (0.464) (0.409) (0.661) (0.812)

BMD Z-score

Whole bodymean (SD) -0.46 −0.34 -0.57 -0.05 -0.56 -0.31

BMD Z-score (1.113) (1.468) (0.978) (1.360) (1.082) (1.418)

Whole body mean(SD) change from NA NA −0.18 0.26 -0.18 0.38baseline BMD (0.514) (0.516) (1.020) (0.934)

Z-score

Cumulativeincidence ≥ 4% NA NA 18.3% 6.9% 18.3% 6.9%decrease frombaseline in lumbarspine BMDa

Cumulativeincidence ≥ 4% NA NA 6.7% 0% 6.7% 0%decrease frombaseline in wholebody BMDa

Lumbar spine

BMD mean % NA NA 3.9% 7.6% 19.2% 26.1%increase

Whole body BMDmean % increase NA NA 4.6% 8.7% 23.7% 27.7%

NA = Not Applicablea No additional subjects had ≥ 4% BMD decreases beyond week 48

The European Medicines Agency has deferred the obligation to submit the results of studies withtenofovir 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).

Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir andformaldehyde.

Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component,tenofovir diphosphate.

Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil israpidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxilwith a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of326 (36.6%) ng/ml, 3,324 (41.2%) ng*h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum tenofovirconcentrations are observed in serum within one hour of dosing in the fasted state and within two hourswhen taken with food. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted patientswas approximately 25%. Administration of tenofovir disoproxil with a high fat meal enhanced the oralbioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately14%. Following the first dose of tenofovir disoproxil in fed patients, the median Cmax in serum rangedfrom 213 to 375 ng/ml. However, administration of tenofovir disoproxil with a light meal did not have asignificant effect on the pharmacokinetics of tenofovir.

Following intravenous administration the steady-state volume of distribution of tenofovir was estimatedto be approximately 800 ml/kg. After oral administration of tenofovir disoproxil, tenofovir is distributedto 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 0.7and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/ml.

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 thoseobserved 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 CYP450isoforms, 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 significantinteractions involving tenofovir disoproxil and medicinal products metabolised by CYP450 wouldoccur.

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport systemwith approximately 70-80% of the dose excreted unchanged in urine following intravenousadministration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately210 ml/min), which is in excess of the glomerular filtration rate. This indicates that active tubularsecretion is an important part of the elimination of tenofovir. Following oral administration the terminalhalf-life of tenofovir is approximately 12 to 18 hours.

Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximaltubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by themultidrug resistant protein 4 (MRP 4).

The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 75to 600 mg and were not affected by repeated dosing at any dose level.

Pharmacokinetic studies have not been performed in the elderly (over 65 years of age).

Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect.

Pharmacokinetics have not been specifically studied in different ethnic groups.

HIV-1: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescentpatients (aged 12 to < 18 years) with body weight ≥ 35 kg. Mean (± SD) Cmax and AUCtau are0.38 ± 0.13 μg/ml and 3.39 ± 1.22 μg h/ml, respectively. Tenofovir exposure achieved in adolescentpatients receiving oral daily doses of tenofovir disoproxil 245 mg was similar to exposures achieved inadults 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 exposuresachieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg.

Tenofovir exposure in HBV infected paediatric patients 2 to < 12 years of age receiving an oral dailydose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of245 mg was similar to exposures achieved in HIV-1 infected paediatric patients 2 to < 12 years of agereceiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovirdisoproxil 245 mg.

Pharmacokinetic studies have not been performed with tenofovir disoproxil 245 mg tablets in childrenunder 12 years or with renal impairment.

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose oftenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees ofrenal 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) tenofovirexposure 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 andsevere renal impairment. The dosing recommendations in patients with renal impairment, with increaseddosing interval, are expected to result in higher peak plasma concentrations and lower Cmin levels inpatients with renal impairment compared with patients with normal renal function. The clinicalimplications of this are unknown.

In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, betweendialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of1,032 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 patientswith creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis (seesection 4.2).

The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/minand 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).

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adultpatients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT)classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepaticimpairment 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 normalsubjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with moderatehepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with severe hepaticimpairment.

In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovirdiphosphate was found to be approximately 50 hours, whereas the half-life inphytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours.

Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in repeateddose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinicalexposure levels and with possible relevance to clinical use include renal and bone toxicity and adecrease 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 anddogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurredin juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold theexposure in patients). Findings in the rat and monkey studies indicated that there was asubstance-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 inone of the strains used in the Ames test, and weakly positive results in an UDS test in primary rathepatocytes. 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 anextremely 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 foetalparameters. However, tenofovir disoproxil reduced the viability index and weight of pups inperi-postnatal toxicity studies at maternally toxic doses.

Environmental Risk Assessment (ERA)

The active substance tenofovir disoproxil phosphate and its main transformation products are persistentin the environment.

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Povidone

Magnesium stearate

Lactose monohydrate

Hypromellose

Titanium dioxide

Triacetin

Indigo Carmine Aluminum lake

Not applicable.

2 years

Shelf-life after first opening is 60 days.

Do not store above 30 °C. Store in the original package in order to protect from moisture.

High density polyethylene (HDPE) bottle with a polypropylene child-resistant cap and induction heatsealing (with aluminium foil).

The bottle contains 30 film-coated tablets and a silica gel desiccant (in a container).

The following pack sizes are available:

Outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of30) film-coated tablets.

Not all pack sizes may be marketed.

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

Open bottles by pressing the child proof cap down and turning it counter-clock wise.

Zentiva, k.s.

U Kabelovny 130102 37 Prague 10

Czech Republic

EU/1/16/1127/001

EU/1/16/1127/002

Date of first authorisation: 15 September 2016

Date of latest renewal: 16 July 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.