TENOFOVIR DISOPROXIL MYLAN 245mg tablets medication leaflet

Tenofovir disoproxil Viatris 245 mg film-coated tablets

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

Each tablet contains 155 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Light blue, round, biconvex, film-coated tablets, 12.20 ± 0.20 mm in diameter, debossed with‘TN245’ on one side and ‘M’ on other side.

HIV-1 infection

Tenofovir disoproxil 245 mg film-coated tablets are indicated in combination with otherantiretroviral medicinal products for the treatment of HIV-1 infected adults.

In adults, the demonstration of the benefit of tenofovir disoproxil in HIV-1 infection is based onresults of one study in treatment-naïve patients, including patients with a high viral load(> 100,000 copies/ml) and studies in which tenofovir disoproxil was added to stable backgroundtherapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virologicalfailure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).

Tenofovir disoproxil 245 mg film-coated tablets are also indicated for the treatment of HIV-1infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged12 to < 18 years.

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

Hepatitis B infection

Tenofovir disoproxil 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis Bin adults with:

* compensated liver disease, with evidence of active viral replication, persistently elevatedserum alanine aminotransferase (ALT) levels and histological evidence of active inflammationand/or fibrosis (see section 5.1).

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

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

Tenofovir disoproxil 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis Bin adolescents 12 to < 18 years of age with:

* compensated liver disease and evidence of immune active disease, i.e. active viral replicationand persistently 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.

The recommended dose of tenofovir disoproxil 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 thevalue of baseline histological information. The benefits of long-term virologic suppression withcontinued therapy must be weighed against the risk of prolonged treatment, including the emergenceof resistant hepatitis B virus and the uncertainties as regards the long term impact of bone and renaltoxicity (see section 4.4).

Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatricpatients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least12 months in patients with HBeAg negative disease.

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

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

- In HBeAg positive patients without cirrhosis, treatment should be administered for at least12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detectionon two 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 virologicalrelapse.

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

HBs seroconversion or there is evidence of loss of efficacy. Treatment discontinuation mayalso be considered after stable virological suppression is achieved (i.e. for at least 3 years)provided serum ALT and HBV DNA levels are followed regularly after treatmentdiscontinuation to detect any late virological relapse. With prolonged treatment for more than2 years, regular reassessment is recommended to confirm that continuing the selected therapyremains appropriate for the patient.

In adult patients with decompensated liver disease or cirrhosis, treatment cessation is notrecommended.

For treatment of HIV-1 infection and chronic hepatitis B in adults for whom a solid dosage form is notappropriate, other suitable formulations may be checked for their availability.

Tenofovir disoproxil Viatris is available only as 245 mg film-coated tablets. Other suitableformulations may be checked for their availability.

HIV-1: In adolescents aged 12 to < 18 years and weighing ≥ 35 kg, the recommended dose oftenofovir disoproxil is 245 mg (one tablet) once daily taken orally with food (see sections 4.8 and5.1).

Reduced doses of tenofovir disoproxil are used for treatment of HIV-1 infected paediatric patientsaged 2 to < 12 years. As Tenofovir disoproxil Viatris is available only as 245 mg film-coated tablets, itis not suitable for the use in paediatric patients aged 2 to < 12 years. Other suitable formulations maybe checked for their availability.

The safety and efficacy of tenofovir disoproxil in HIV-1 infected children under 2 years of age havenot been established. No data are available.

Chronic hepatitis B: In adolescents aged 12 to < 18 years and weighing ≥ 35 kg, therecommended dose of tenofovir disoproxil is 245 mg (one tablet) once daily, taken orally withfood (see sections 4.8 and 5.1). The optimal duration of treatment is currently unknown.

The safety and efficacy of tenofovir disoproxil in children with chronic hepatitis B aged 2 to <12 years or weighing < 35 kg have not been established. No data are available.

For treatment of HIV-1 infection and chronic hepatitis B in adolescents aged 12 to <18 years forwhom a solid dosage form is not appropriate, other suitable formulations may be checked for theiravailability.

If a patient misses a dose of tenofovir disoproxil within 12 hours of the time it is usually taken, thepatient should take tenofovir disoproxil with food as soon as possible and resume their normaldosing schedule. If a patient misses a dose of tenofovir disoproxil by more than 12 hours and it isalmost time for their next dose, the patient should not take the missed dose and simply resume theusual dosing schedule.

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

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

There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients withmoderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety datahas not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, inadult patients with renal impairment tenofovir disoproxil should only be used if the potentialbenefits of treatment are considered to outweigh the potential risks. Administration of tenofovirdisoproxil 33 mg/g granules to provide a reduced daily dose of tenofovir disoproxil is recommendedfor adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients.

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

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

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

Since administration of a lower dose with the 245 mg tablet is not possible, prolonged dose intervalsusing the 245 mg film-coated tablets may be used. Administration of 245 mg tenofovir disoproxilevery 48 hours can be used based on modelling of single-dose pharmacokinetic data in HIV negativeand non-HBV infected subjects with varying degrees of renal impairment, including end-stage renaldisease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinicalresponse to treatment and renal function should be closely monitored in these patients (see sections4.4 and 5.2).

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

Adequate dose adjustments cannot be applied due to lack of alternative tablet strengths, therefore usein this group of patients is not recommended. If no alternative treatment is available, prolonged doseintervals 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 245 mg film-coated tablets is not optimal andcould result in increased toxicity and possibly inadequate response. Therefore, clinical response totreatment 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.

Paediatrics

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 is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis (seesection 4.4).

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

However, in exceptional circumstances Tenofovir disoproxil Viatris 245 mg film-coated tablets canbe administered following disintegration of the tablet in at least 100 ml of water, orange juice orgrape 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).

Chronic 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 Viatris should not be administered concomitantly with othermedicinal products containing tenofovir disoproxil or tenofovir alafenamide.

- Tenofovir disoproxil Viatris 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 wellas with lamivudine and didanosine as a once-daily regimen.

Renal and bone effects in adult population

Renal effects

Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevatedcreatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have beenreported with the use of tenofovir disoproxil in clinical practice (see section 4.8).

Renal monitoring

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy 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 morefrequent monitoring of renal function is required.

Renal management

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min 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 nephrotoxicmedicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine,vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil and nephrotoxicagents is unavoidable, 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 factorsfor renal dysfunction. If tenofovir disoproxil is co-administered with an NSAID, renal function shouldbe monitored 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, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefullyevaluated.

Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal productswhich are secreted by the same renal pathway, including the transport proteins human organicanion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinalproduct). These renal transport proteins may be responsible for tubular secretion and in part, renalelimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinalproducts, which are secreted by the same renal pathway including transport proteins hOAT 1 and 3or MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitantuse of these medicinal products which are secreted by the same renal pathway is not recommended,but if such use is unavoidable, renal function should be monitored weekly (see section 4.5).

Renal 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 impairedrenal function. Therefore, tenofovir disoproxil should only be used if the potential benefits oftreatment are considered to outweigh the potential risks. In patients with severe renal impairment(creatinine clearance < 30 ml/min) and in patients who require haemodialysis use of tenofovirdisoproxil is not recommended. If no alternative treatment is available, the dosing interval must beadjusted and renal function should be closely monitored (see sections 4.2 and 5.2).

Bone effects

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and,which can infrequently contribute to fractures may be associated with tenofovir disoproxil-inducedproximal renal tubulopathy (see section 4.8).

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

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD wereseen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted proteaseinhibitor.

Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitationsof long-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) andconsider the 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 4.8and 5.1).

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, includingmeasurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8,proximal tubulopathy). If renal abnormalities are suspected or detected then consultation with anephrologist should be obtained to consider interruption of tenofovir disoproxil treatment.

Interrupting treatment with tenofovir disoproxil should also be considered in case of progressivedecline of renal function when no other cause has been identified.

Co-administration and risk of renal toxicity

The same recommendations apply as in adults (see above).

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment(see section 4.2). Tenofovir disoproxil should not be initiated in paediatric patients with renalimpairment and should be discontinued in paediatric patients who develop renal impairmentduring tenofovir disoproxil therapy.

Bone effects

Tenofovir disoproxil may cause a reduction in BMD. The effects of tenofovir disoproxil -associated changes in BMD on long-term bone health and future fracture risk are uncertain (seesection 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 patientswith decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. Thesepatients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore,hepatobiliary and renal parameters should be closely monitored in this patient population.

Exacerbations of hepatitis

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and 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 increasesin serum ALT are generally not accompanied by an increase in serum bilirubin concentrations orhepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensationfollowing hepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported inpatients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usuallyassociated with rising HBV DNA, and the majority appears to be self-limited. However, severeexacerbations, including fatalities, have been reported. Hepatic function should be monitored atrepeated intervals with both clinical and laboratory follow-up for at least 6 months afterdiscontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may bewarranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is notrecommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

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

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

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, 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 combinationantiretroviral therapy (CART) and should be monitored according to standard practice. If there isevidence of worsening liver disease in such patients, interruption or discontinuation of treatment mustbe considered. However, it should be noted that increases of ALT can be part of HBV clearanceduring therapy with tenofovir, see above Exacerbations of hepatitis.

Use with certain hepatitis C virus antiviral agents

Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir 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 withco-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIVprotease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients atincreased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIVprotease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment 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;these have predominantly concerned treatment with regimens containing zidovudine. The mainadverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolicdisorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onsetneurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. Thesefindings should be considered for any child exposed in utero to nucleos(t)ide analogues, who presentwith severe clinical findings of unknown etiology, particularly neurologic findings. These findingsdo not affect current national recommendations to use antiretroviral therapy in pregnant women toprevent vertical transmission 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 causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirusretinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.

Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reportedto occur in the setting of immune reactivation; however, the reported time to onset is more variableand these 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, jointstiffness or difficulty in movement.

Tenofovir disoproxil has not been studied in patients over the age of 65. Elderly patients are morelikely to have decreased renal function; therefore caution should be exercised when treating elderlypatients with tenofovir disoproxil.

Tenofovir disoproxil Viatris 245 mg film-coated tablets contain lactose monohydrate. Patients withrare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactosemalabsorption should not take this medicinal product.

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 islow.

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

Tenofovir disoproxil should not be administered concomitantly with adefovir dipivoxil.

Didanosine

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

Table 1).

Renally eliminated medicinal products

Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil 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 nephrotoxicmedicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B,foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

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

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 oncedaily as “q.d.”).

Table 1: Interactions between tenofovir disoproxil and other medicinal products

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

ANTI-INFECTIVES

Antiretrovirals

Protease inhibitors

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

Cmax: ↓ 28% increased exposure of

Cmin: ↓ 26% tenofovir could

Tenofovir: potentiate tenofovir-

AUC: ↑ 37% associated adverse

C : ↑ 34% events, including renalmax

C : ↑ 29% disorders. Renalminfunction should beclosely monitored (seesection 4.4).

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

PK parameters. tenofovir couldpotentiate tenofovir-

Tenofovir:associated adverse

AUC: ↑ 32% events, including renal

Cmax: ↔ disorders. Renal

Cmin: ↑ 51% function should beclosely monitored (see

Medicinal product by Effects on drug levels Recommendationtherapeutic areas (dose in Mean percent change in AUC, Cmax, concerningmg) Cmin co-administration with245 mg tenofovirdisoproxilsection 4.4).

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

PK parameters. tenofovir couldpotentiate tenofovir-

Tenofovir:associated adverse

AUC: ↑ 22% events, including renal

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

NRTIs

Didanosine Co-administration of tenofovir disoproxil Co-administration ofand didanosine results in a 40-60% tenofovir disoproxil andincrease in systemic exposure to didanosine is notdidanosine. 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 of250 mg didanosineco-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).

Entecavir AUC: ↔ No clinically significant

Cmax: ↔ pharmacokinetic

Medicinal product by Effects on drug levels Recommendationtherapeutic areas (dose in Mean percent change in AUC, Cmax, concerningmg) Cmin co-administration with245 mg tenofovirdisoproxilinteractions 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.) + Cmin: ↑ 118% co-administration of

Emtricitabine/Tenofovir tenofovir disoproxil,disoproxil Sofosbuvir: ledipasvir/sofosbuvir and(200 mg/245 mg q.d.)1 AUC: ↔ atazanavir/ritonavir may

Cmax: ↔ increase adversereactions related to

GS-3310072: tenofovir disoproxil,

AUC: ↔ including renal disorders.

Cmax: ↔ The safety of tenofovir

Cmin: ↑ 42% disoproxil when usedwith

Atazanavir: ledipasvir/sofosbuvir and

AUC: ↔ a pharmacokinetic

Cmax: ↔ enhancer (e.g. ritonavir

Cmin: ↑ 63% or cobicistat) has notbeen established.

AUC: ↔ The combination should

C : ↔ be used with cautionmax

C : ↑ 45% with frequent renalminmonitoring, if otheralternatives are not

Emtricitabine: available (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 47%

Cmin: ↑ 47%

Ledipasvir/Sofosbuvir Ledipasvir: Increased plasma(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

Cmin: ↔ disoproxil when used

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

Darunavir: ledipasvir/sofosbuvir and

AUC: ↔ a pharmacokinetic

Cmax: ↔ enhancer (e.g. ritonavir

Cmin: ↔ or cobicistat) has notbeen established.

AUC: ↔ The combination should

C : ↔ be used with cautionmax

C : ↑ 48% with frequent renalminmonitoring, if otheralternatives are not

Emtricitabine: available (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 50%

Cmax: ↑ 64%

Cmin: ↑ 59%

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

Efavirenz/Emtricitabine/Tenofovi C : ↓ 34% increased exposure ofmaxtenofovir couldr disoproxil Cmin: ↓ 34%potentiate adverse(600 mg/200 mg/245 mg q.d.) reactions associated with

Sofosbuvir: tenofovir disoproxil,

AUC: ↔ including renal disorders.

Cmax: ↔ Renal function should beclosely monitored (see

GS-3310072: section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98%

Cmax: ↑ 79%

Cmin: ↑ 163%

Ledipasvir/Sofosbuvir Ledipasvir: No dose adjustment is(90 mg/400 mg q.d.) + AUC: ↔ recommended. Theincreased exposure of

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

Emtricitabine/Rilpivirine/ Cmax: ↔ tenofovir could

Tenofovir disoproxil C : ↔ potentiate adversemin(200 mg/25 mg/245 mg q.d.) reactions associated withtenofovir disoproxil,

Sofosbuvir:including renal disorders.

AUC: ↔ Renal function should be

Cmax: ↔ closely monitored (seesection 4.4).

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↔

Cmin: ↑ 91%

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

Dolutegravir (50 mg q.d.) + C increased exposure ofmax: ↔tenofovir could

Emtricitabine/Tenofovirpotentiate adversedisoproxil (200 mg/245 mg GS 3310072 reactions associated withq.d.) AUC: ↔ tenofovir disoproxil,

Cmax: ↔ including renal disorders.

Cmin: ↔ Renal function should beclosely monitored (see

Ledipasvir: section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

Dolutegravir

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

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

Tenofovir:

AUC: ↑ 65%

Cmax: ↑ 61%

Cmin: ↑ 115%

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

Atazanavir/Ritonavir C : ↔ tenofovir resulting frommaxco-administration of(300 mg q.d./100 mg q.d.) +tenofovir disoproxil,

Emtricitabine/Tenofovir GS 3310072: sofosbuvir/velpatasvirdisoproxil AUC: ↔ and atazanavir/ritonavir(200 mg/245 mg q.d.) Cmax: ↔ may increase adverse

Cmin: ↑ 42% reactions related totenofovir disoproxil,

Velpatasvir: including renal disorders.

The safety of tenofovir

AUC: ↑ 142%disoproxil when used

Cmax: ↑ 55% with

Cmin: ↑ 301% sofosbuvir/velpatasvirand a pharmacokinetic

Atazanavir: enhancer (e.g. ritonavir

AUC: ↔ or cobicistat) has not

C : ↔ been established.max

Cmin: ↑ 39%

The combination shouldbe used with caution

Ritonavir: with frequent renal

AUC: ↔ monitoring (see section

Cmax: ↔ 4.4).

Cmin: ↑ 29%

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 55%

Cmin: ↑ 39%

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

Darunavir/Ritonavir C : ↓ 38% tenofovir resulting frommaxco-administration of(800 mg q.d./100 mg q.d.) +2 tenofovir disoproxil,

Emtricitabine/Tenofovir GS 331007 : sofosbuvir/velpatasvirdisoproxil AUC: ↔ and darunavir/ritonavir(200 mg/245 mg q.d.) Cmax: ↔ may increase adverse

Cmin: ↔ reactions related totenofovir disoproxil,

Velpatasvir: including renal disorders.

The safety of tenofovir

AUC: ↔disoproxil when used

Cmax: ↓ 24% with

Cmin: ↔ sofosbuvir/velpatasvir

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

Darunavir: enhancer (e.g. ritonavir

AUC: ↔ or cobicistat) has notbeen established.

Cmax: ↔

Cmin: ↔ The combination shouldbe used with caution

Ritonavir: with frequent renal

AUC: ↔ monitoring (see section

Cmax: ↔ 4.4).

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 55%

Cmin: ↑ 52%

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

Lopinavir/Ritonavir Cmax: ↓ 41% tenofovir resulting fromco-administration of(800 mg/200 mg q.d.) +2 tenofovir disoproxil,

Emtricitabine/Tenofovir GS 331007 : sofosbuvir/velpatasvirdisoproxil AUC: ↔ and lopinavir/ritonavir(200 mg/245 mg q.d.) Cmax: ↔ may increase adverse

Cmin: ↔ reactions related totenofovir disoproxil,

Velpatasvir: including renal disorders.

The safety of tenofovir

AUC: ↔disoproxil when used

Cmax: ↓ 30% with

Cmin: ↑ 63% sofosbuvir/velpatasvirand a pharmacokinetic

Lopinavir: enhancer (e.g. ritonavir

AUC: ↔ or cobicistat) has not

C : ↔ been established.max

Cmin: ↔

The combination shouldbe used with caution

Ritonavir: with frequent renal

AUC: ↔ monitoring (see section

Cmax: ↔ 4.4).

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

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

AUC: ↔

Cmax: ↑ 42%

Cmin: ↔

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

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

Emtricitabine/Tenofovir GS 3310072: reactions associated withdisoproxil AUC: ↔ tenofovir disoproxil,(200 mg/245 mg q.d.) Cmax: ↔ including renal disorders.

Cmin: ↔ Renal function should beclosely monitored (see

Velpatasvir: section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

Raltegravir:

AUC: ↔

Cmax: ↔

Cmin: ↓ 21%

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↑ 46%

Cmin: ↑ 70%

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

Efavirenz/Emtricitabine/Tenofo C : ↑ 38% sofosbuvir/velpatasvirmaxand efavirenz is expectedvir disoproxilto decrease plasma(600 mg/200 mg/245 mg q.d.) GS 3310072: concentrations of

AUC: ↔ velpatasvir. Co-

Cmax: ↔ administration of

Cmin: ↔ sofosbuvir/velpatasvirwith efavirenz-

Velpatasvir: containing regimens isnot recommended.

AUC: ↓ 53%

Cmax: ↓ 47%

Cmin: ↓ 57%

AUC: ↔

Cmax: ↔

Cmin: ↔

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

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81%

Cmax: ↑ 77%

Cmin: ↑ 121%

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

Emtricitabine/Rilpivirine/Tenof C : ↔ increased exposure ofmaxtenofovir couldovir disoproxil2 potentiate adverse(200 mg/25 mg/245 mg q.d.) GS 331007 : reactions associated with

AUC: ↔ tenofovir disoproxil,

Cmax: ↔ including renal disorders.

Cmin: ↔ Renal function should beclosely monitored (see

Velpatasvir: section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↑ 44%

Cmin: ↑ 84%

Sofosbuvir/Velpatasvir/ Sofosbuvir: Increased plasma

Voxilaprevir (400 mg/100 mg/ AUC: ↔ concentrations of tenofovir100 mg+100 mg q.d.)3 + Cmax: ↓ 30% resulting from co-

Darunavir (800 mg q.d.) + Cmin: N/A administration of tenofovir

Ritonavir (100 mg q.d.) + disoproxil,

Emtricitabine/Tenofovir GS-3310072: sofosbuvir/velpatasvir/voxdisoproxil (200 mg/245 mg q.d.) AUC: ↔ ilaprevir and

Cmax:↔ darunavir/ritonavir may

Cmin: N/A increase adverse reactionsrelated to tenofovir

Velpatasvir: disoproxil, including renal

AUC: ↔ disorders.

Cmax: ↔ The safety of tenofovir

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

Cmin: ↔ disoproxil when used withsofosbuvir/velpatasvir/vox

Voxilaprevir: ilaprevir and a

AUC: ↑ 143% pharmacokinetic enhancer

Cmax:↑ 72% (e.g. ritonavir or

Cmin: ↑ 300% cobicistat) has not beenestablished.

AUC: ↔

Cmax: ↔ The combination should

C : ↓ 34% be used with cautionminwith frequent renalmonitoring (see section

Ritonavir:4.4).

AUC: ↑ 45%

Cmax: ↑ 60%

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 48%

Cmin: ↑ 47%

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

Efavirenz/Emtricitabine/ Cmax: ↓ 19%

Tenofovir disoproxil(600 mg/200 mg/245 mg q.d.) GS-3310072:

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 wasco-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir(ritonavir boosted), 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 donot indicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil may beconsidered during pregnancy, if necessary.

In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has beenshown to reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is givento mothers, in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection wereadministered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2months 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 milkis considered negligible. Although long-term data is limited, no adverse reactions have beenreported in breast-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 do not 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 tenofovirdisoproxil.

HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment,renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome)sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.

Monitoring of renal function is recommended for patients receiving tenofovir disoproxil (see section4.4).

HIV-1: Approximately one third of patients can be expected to experience adverse reactionsfollowing treatment with tenofovir disoproxil in combination with other antiretroviral agents. Thesereactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovirdisoproxil -treated adult 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 HBVinfected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was nausea(5.4%).

Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients whohave discontinued hepatitis B therapy (see section 4.4).

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

HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based 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 productsfor 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïvepatients received treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) incombination with lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data isprimarily based on experience in two double-blind comparative controlled studies in which 641 adultpatients with chronic hepatitis B and compensated liver disease received treatment with tenofovirdisoproxil 245 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. Theadverse reactions observed with continued treatment for 384 weeks were consistent with the safetyprofile of tenofovir disoproxil. After an initial decline of approximately -4.9 ml/min (using

Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease[MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline ofrenal function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using

Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation).

Patients with decompensated liver disease: The safety profile of tenofovir disoproxil inpatients with decompensated liver disease was assessed in a double-blind active controlledstudy (GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil(n = 45) or emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverseevent; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl orconfirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significantdifferences between the combined tenofovir-containing arms and the entecavir arm. After168 weeks, 16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plustenofovir disoproxil group, and 14% (3/22) of the entecavir group experienced tolerability failure.

Thirteen percent (6/45) of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plustenofovir disoproxil group, and 9% (2/22) of the entecavir group had a confirmed increase in serumcreatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl.

At week 168, in this population of patients with decompensated liver disease, the rate of death was 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(see section 4.4).

Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovirdisoproxil were 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 belowby body system organ class and frequency. Within each frequency grouping, undesirable effectsare presented in order of decreasing seriousness. Frequencies are defined as very common(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to< 1/1,000).

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

Frequency Tenofovir disoproxil

Very common: hypophosphataemia1

Uncommon: hypokalaemia

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 weakness1

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,2, myopathy1

Uncommon: increased creatinine, proximal renal tubulopathy (including Fanconi syndrome)

Rare: acute renal failure, renal failure, acute tubular necrosis, nephritis (including acuteinterstitial 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 considered to becausally associated with tenofovir disoproxil in the absence of this condition.2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlledclinical trials or the tenofovir disoproxil expanded access program. The frequency category was estimated from astatistical calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlledclinical trials and the expanded access program (n = 7,319).3 The frequency of this adverse reaction was estimated based on safety data derived from different clinical studies with

TDF in HBV infected patients. See also sections 4.4 and 5.1.

HIV-1 and hepatitis B:

As tenofovir disoproxil may cause renal damage monitoring of renal function is recommended (seesections 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 increatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation.

Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIVdisease, or patients receiving concomitant nephrotoxic medications) are at increased risk ofexperiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (seesection 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 acknowledgedrisk factors, advanced HIV disease or long-term exposure to CART. The frequency of this isunknown (see section 4.4).

Hepatitis B:

Exacerbations of hepatitis during treatment

In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limitof normal) 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 amajority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded orcoincided with the ALT elevation. Periodic monitoring of hepatic function is recommended duringtreatment (see section 4.4).

Exacerbations of hepatitis after discontinuation of treatment

In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis haveoccurred after 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 combinationwith other antiretroviral agents for 48 weeks (see section 5.1). 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 section 4.8 Tabulated summaryof adverse reactions and 5.1).

Reductions in BMD have been reported in paediatric patients. In HIV-1 infected adolescents, the

BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than thoseobserved in subjects who received placebo. In HIV-1 infected children, the BMD Z-scores observedin subjects who switched to tenofovir disoproxil were lower than those observed in subjects whoremained on their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1).

In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil(median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverseevents. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renaltubulopathy, 4 of whom discontinued tenofovir disoproxil therapy. Seven patients had estimatedglomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2. Among them, 3 patientsexperienced a clinically meaningful decline in estimated GFR which improved after discontinuationof tenofovir disoproxil.

Chronic hepatitis B

Assessment of adverse reactions is based on a randomised study (study GS-US-174-0115) in106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment withtenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks and a randomised study (Study

GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to < 12 years of age) receiving treatmentwith tenofovir 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 section 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 thoseobserved in 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 morelikely to have decreased renal function, therefore caution should be exercised when treating elderlypatients with tenofovir disoproxil (see section 4.4).

Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function isrecommended in adult patients with renal impairment treated with Tenofovir disoproxil Viatris(see sections 4.2, pct. 4.4 and 5.2). The use of tenofovir disoproxil is not recommended in paediatricpatients with renal impairment (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 systemlisted in Appendix V.

If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and5.3), and standard 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 nucleotidereverse transcriptase inhibitors, ATC code: J05AF07.

Mechanism of action and pharmacodynamic effects

Tenofovir disoproxil maleate is the maleate 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 andthe HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrateand, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weakinhibitor of cellular polymerases α, β, and γ. At concentrations of up to 300 µmol/l, tenofovir has alsoshown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitroassays.

Data pertaining to HIV

HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) ofthe wild-type laboratory strain HIV-1 is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against

IIIBprimary 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 showsactivity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells.

Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation inreverse transcriptase have been selected in vitro and in some patients (see Clinical efficacy andsafety). Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strainsharbouring the K65R mutation (see section 4.4). In addition, a K70E substitution in HIV-1 reversetranscriptase has been selected by tenofovir and results in low-level reduced susceptibility totenofovir.

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 resultsindicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations(TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reducedresponse to tenofovir disoproxil 245 mg therapy.

The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1infected adults have been demonstrated in trials of 48 weeks and 144 weeks duration,respectively.

In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or 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 analysisof HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance mutationsassociated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated withprotease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptaseinhibitors.

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 tenofovirdisoproxil 245 mg recipients (p < 0.0001). A statistically significant difference in favour oftenofovir disoproxil 245 mg was seen in the time-weighted average change from baseline at week24 (DAVG24) for CD4 count (+13 cells/mm3 for tenofovir disoproxil 245 mg versus -11 cells/mm3for placebo, p-value = 0.0008). The antiviral response to tenofovir disoproxil was durable through48 weeks (DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400or 50 copies/ml was 41% and 18% respectively). Eight (2%) tenofovir disoproxil 245 mg treatedpatients developed the K65R mutation within the first 48 weeks.

The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy andsafety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudineand efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy. The mean baseline

CD4 cell count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml,19% of patients had symptomatic HIV-1 infection and 18% had AIDS. Patients were stratified bybaseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml.

By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered asfailure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm,compared to 84% and 80% in the stavudine arm. At 144 weeks, the proportion of patients with

HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in thetenofovir 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 wassimilar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in thetenofovir disoproxil 245 mg and stavudine groups, respectively). At 144 weeks of treatment, theaverage change from baseline remained similar in both treatment groups (-3.07 and -3.03 log10copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg and stavudine groups,respectively). A consistent response to treatment with tenofovir disoproxil 245 mg was seenregardless of baseline HIV-1 RNA and CD4 count.

The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxilgroup than the active control group (2.7% versus 0.7%). Efavirenz or lamivudine resistance eitherpreceded or was coincident with the development of K65R in all cases. Eight patients had HIV thatexpressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeksof treatment and the last one at week 96. No further K65R development was observed up to week144. One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus. Fromboth the genotypic and phenotypic analyses there was no evidence for other pathways of resistance totenofovir.

Data pertaining to HBV

HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessedin the HepG2 2.2.15 cell line. The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l,with CC50 (50% cytotoxicity concentration) values > 100 µmol/l.

Resistance: No HBV mutations associated with tenofovir disoproxil resistance have been identified(see Clinical efficacy and safety). In cell based assays, HBV strains expressing the rtV173L,rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudineshowed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus. HBVstrains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associatedwith resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that ofwild-type virus. HBV strains expressing the adefovir-associated resistance mutations rtA181V andrtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus.

Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild-type virus.

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

HBeAg negative 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 3 below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAgpositive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated)patients negative for HBeAg and positive for HBeAb.

In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for 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 disoproxilgroup than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week48 (see Table 3 below).

Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patientsat week 48

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

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

Complete response 71* 49 67* 12(%)a

Histology

Histological response 72 69 74 68(%)b

Median HBV DNA -4.7* -4.0 -6.4* -3.7reduction frombaselinec(log10 copies/ml)

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

ALT (%)

Normalised ALTd 76 77 68* 54

Serology (%)

HBeAg n/a n/a 22/21 18/18loss/seroconversion0/0 0/0 3*/1 0/0

HBsAgloss/seroconversion

* p-value versus adefovir dipivoxil < 0.05.a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvementof at least 2 points without worsening in Knodell fibrosis.b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and thelimit of detection (LOD) of the assay.d The population used for analysis of ALT normalisation included only patients with ALT above ULN atbaseline.

n/a = not applicable.

Tenofovir disoproxil was associated with significantly greater proportions of patients withundetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche

Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%,56% and study GS-US-174-0103; 69%, 9%), respectively.

Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51)and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT(n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined. Forty-nineof the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-threepercent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete responseto treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV

DNA suppression < 400 copies/ml. All patients with normal ALT at baseline and 88% of patients 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. Atweeks 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 at any time prior to week 384due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label.c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil.d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label.f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil.g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label.h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil.i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label.j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil.k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at the time ofthe data cut-off. However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit.l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition ofemtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil).o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.

n/a = not applicable.

Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192,240, 288 and 384 open-label treatment

Study 174-0103 (HBeAg positive)

Parametera

Tenofovir disoproxil 245 mg Adefovir dipivoxil 10 mg roll over ton = 176 tenofovir disoproxil 245 mgn = 90b o p

Week 96 144e192h j m c f i k n240 288 384 96 144 192 240 288 384

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/ 8/ 11/ 11/ 12/ 15/ 6/ 8/ 8/ 10/ 11/seroconversion 13/g g l l4 6 8 8 8 121 g g5 7 7 10l l10 111a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time priorto week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in thedenominator.b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label.c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil.d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label.f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil.g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected afterthe addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT).h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label.i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil.j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label.k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil.l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected afterthe addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil).m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.

Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained 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 (HBeAg negative) Study 174-0103 (HBeAg positive)

Tenofovir disoproxil Adefovir dipivoxil Tenofovir disoproxil Adefovir dipivoxil245 mg 10 mg roll over to 245 mg 10 mg roll over ton = 250ctenofovir disoproxil n = 176ctenofovir disoproxil245 mg 245 mgn = 125d n = 90d

Histological 88 85 90 92responsea,b (%)[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 17 subjects across both studies).b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score.c 48 weeks of double-blind tenofovir disoproxil followed by up to 192 weeks open-label.d 48 weeks of double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil.

Experience in patients with HIV co-infection and prior lamivudine experience

In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg in adultpatients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study

ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovirarm were 9.45 log10 copies/ml (n = 27). Treatment with tenofovir disoproxil 245 mg was associatedwith a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-weekdata, of -5.74 log10 copies/ml (n = 18). In addition, 61% of patients had normal ALT at week 48.

Experience in patients with persistent viral replication (study GS-US-174-0106)

The efficacy and safety of tenofovir disoproxil 245 mg or tenofovir disoproxil 245 mg plus 200 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 toemtricitabine plus tenofovir disoproxil treatment group had previously been treated withlamivudine. Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) ofpatients with HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated withemtricitabine plus tenofovir disoproxil (p = 0.672). In addition 55% (29/53) of patients treatedwith tenofovir disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit ofquantification of the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treatedwith emtricitabine plus tenofovir disoproxil (p = 0.504). Comparisons between treatment groupsbeyond week 24 are difficult to interpret since investigators had the option to intensify treatment toopen-label emtricitabine plus tenofovir disoproxil. Long-term studies to evaluate the benefit/risk ofbitherapy with emtricitabine plus tenofovir disoproxil in HBV monoinfected patients are ongoing.

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

Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safetyand efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), andentecavir (n = 22), in patients with decompensated liver disease. In the tenofovir disoproxiltreatment arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml andmean serum ALT of 61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 monthsof prior lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and9 of 45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline.

The co-primary safety endpoints were discontinuation due to an adverse event and confirmedincrease 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) ofemtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after48 weeks of treatment.

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 7below).

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

Study 174-0108

Parameter Tenofovir disoproxil Emtricitabine 200 mg/ Entecavir245 mg tenofovir disoproxil (0.5 mg or 1 mg)(n = 45) 245 mg (n = 45)n = 22

Tolerability failure 3 (7%) 2 (4%) 2 (9%)(permanentdiscontinuation of studydrug due to a treatmentemergent AE)n (%)a

Confirmed increase in 4 (9%) 3 (7%) 1 (5%)serum creatinine ≥0.5 mg/dl from baselineor confirmed serumphosphate 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 MELD scorea 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 tenofovirdisoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52%(11/21) of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168.

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

The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blindstudy (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) withcompensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence oflamivudine resistance (rtM204I/V +/- rtL180M). Only five had adefovir-associated resistancemutations at baseline. One hundred forty-one and 139 adult subjects were randomised to a tenofovirdisoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively. Baselinedemographics were similar between the two treatment arms: At baseline, 52.5% of subjects were

HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, andmean 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 weeksof treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had HBV DNA< 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation. Among the HBeAg positivesubjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced HBeAg loss, and8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240. In the HBeAgpositive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects (19%)experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion throughweek 240. Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by Week 240,but not seroconversion to anti-HBs. Five subjects randomised to emtricitabine plus tenofovirdisoproxil experienced HBsAg loss with 2 of these 5 subjects experiencing seroconversion to anti-

HBs.

Clinical resistance

Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive(GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxiltreatment and then switched to open-label tenofovir disoproxil treatment were evaluated forgenotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on allpatients with HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n =5), 240 (n = 4), 288 (n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that nomutations associated with tenofovir disoproxil resistance have developed.

Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive (GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment and 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 >400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 (n = 1) and384 (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 adefovirdipivoxil resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks.

Genotypic data from paired baseline and on treatment HBV isolates were available for 6/8 patientswith HBV DNA > 400 copies/ml at week 48. No amino acid substitutions associated with resistanceto tenofovir disoproxil were identified in these isolates. Genotypic analysis was conducted for 5subjects in the tenofovir disoproxil arm post week 48. No amino acid substitutions associated withtenofovir disoproxil resistance were detected in any subject.

In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baselinereceived tenofovir disoproxil for up to 240 weeks. Cumulatively, there were 4 patients whoexperienced a viremic episode (HBV DNA>400 copies/ml) at their last timepoint on tenofovirdisoproxil. Among them, sequence data from paired baseline and on treatment HBV isolates wereavailable for 2 of 4 patients. No amino acid substitutions associated with resistance to tenofovirdisoproxil were identified in these isolates.

In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudineresistance mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeksand then 51/52 patients switched to open-label tenofovir disoproxil (tenofovir disoproxil-tenofovirdisoproxil 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 resistancemutations at baseline) initially received blinded placebo treatment for 72 weeks, and 52/54 patientsfollowed with tenofovir disoproxil (PLB-tenofovir disoproxil group). Genotypic evaluations wereperformed on all patients within this group with HBV DNA > 400 copies/ml at week 96 (n = 17),week 144 (n = 7), and week 192(n = 8). No amino acid substitutions associated with resistance totenofovir disoproxil were identified in these 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 of4 patients 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 yearsof age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with anoptimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit oftenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at week24. However, a benefit is expected for the adolescent population based on extrapolation of adult dataand comparative pharmacokinetic data (see section 5.2).

In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, respectively,at baseline. Mean changes at week 48 (end of double-blind phase) were -0.215 and -0.165 in lumbarspine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxiland placebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxilgroup compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil groupand one adolescent in the placebo group had significant lumbar spine BMD loss (defined as > 4%loss). Among 28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z-scoresdeclined by -0.341 for lumbar spine and -0.458 for total body.

In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable,virologic suppression on stavudine- or zidovudine-containing regimens were randomised toeither replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on theiroriginal regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxiltreatment 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 whomaintained < 400 copies/ml at week 48 was mainly influenced by the higher number ofdiscontinuations in the tenofovir disoproxil treatment group. When missing data were excluded,91% of patients in the tenofovir disoproxil treatment group and 94% of patients in the stavudineor 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 treatmentwith tenofovir 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 orzidovudine groups, respectively. The mean rate of lumbar spine bone gain at week 48 was similarbetween the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group.

Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudineor zidovudine treatment group. One tenofovir disoproxil treated subject and no stavudine orzidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48. BMD

Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects whowere treated with tenofovir disoproxil for 96 weeks. BMD Z-scores were not adjusted for height andweight.

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 patientsaged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT(≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated withtenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks. Subjects must have beennaïve to tenofovir disoproxil, but could have received interferon based regimens (> 6 months priorto screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotidetherapy (> 16 weeks prior to screening). At week 72, overall 88% (46/52) of patients in the tenofovirdisoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA <400 copies/ml. Seventy-four percent (26/35) of patients in the tenofovir disoproxil group hadnormalised ALT at week 72 compared to 31% (13/42) in the placebo group. Response to treatmentwith tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-experienced (n = 32) patients, including lamivudine- resistant patients (n = 6). Ninety-five percentof nucleos(t)ide-naïve patients, 84% of nucleos(t)ide- experienced patients, and 83% of lamivudine-resistant patients achieved HBV DNA < 400 copies/ml at week 72. Thirty-one of the 32nucleos(t)ide-experienced patients had prior lamivudine experience. At week 72, 96% (27/28) ofimmune-active patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovirdisoproxil treatment group and 0% (0/32) of patients in the placebo group had HBV DNA <400 copies/ml. Seventy-five percent (21/28) of immune-active patients in the tenofovir disoproxilgroup 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-tenofovir disoproxil group had HBV DNA < 400 copies/ml at week 192. Among the subjects whoreceived placebo during the double-blind period, the proportion of subjects with HBV DNA< 400 copies/mL rose sharply after they began treatment with open-label tenofovir disoproxil(PLB-tenofovir disoproxil group): 74.1% (40/54) of subjects in the PLB-tenofovir disoproxil grouphad HBV DNA < 400 copies/ml at week 192. The proportion of subjects with ALT normalization atweek 192 in the tenofovir disoproxil-tenofovir disoproxil group was 75.8% (25/33) among those whowere HBeAg positive at baseline and 100.0% (2 of 2 subjects) among those who were HBeAgnegative at baseline. Similar percentages of subjects in the tenofovir disoproxil-tenofovir disoproxiland PLB-tenofovir disoproxil groups (37.5% and 41.7%, respectively) experienced seroconversion toanti-HBe through week 192.

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

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

Baseline Week 72 Week 192

Tenofovir Tenofovir Tenofovir

PLB- PLB- PLB-disoproxil- disoproxil- disoproxil-tenofovir tenofovir tenofovirtenofovir tenofovir tenofovirdisoproxil disoproxil disoproxildisoproxil disoproxil disoproxil

Lumbar spine mean −0.42 -0.26 -0.49 -0.44a -0.23(0.893) -0.37(0.946)(SD) BMD Z-score (0.762) (0.806) (0.852) (0.920)

Lumbar spine mean(SD) change from -0.06 0.10 0.02 -0.10

NA NAbaseline (0.320) (0.378) (0.548) (0.543)

BMD Z-scorea

Whole body mean −0.19 −0.23 −0.36 −0.12 −0.38 −0.42(SD) BMD Z-scorea (1.110) (0.859) (1.077) (0.916) (0.934) (0.942)

Whole body mean(SD) change from −0.16 0.09 -0.16 -0.19

NA NAbaseline (0.355) (0.349) (0.521) (0.504)

BMD Z-scorea

Lumbar spine BMD 1.9% 3.8% 3.7%

NA NA 0%at least 6% decreaseb (1 subject) (2 subjects) (2 subjects)

Whole body BMD at 1.9%b NA NA 0% 0% 0%least 6% decrease (1 subject)

Lumbar spine BMD

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

Whole body BMD

NA NA 3.07% 5.39% 6.09% 7.22%mean % increase

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 withchronic hepatitis B were treated with tenofovir disoproxil 6.5 mg/kg up to a maximum dose of245 mg (n = 60) or placebo (n = 29) once daily for 48 weeks. Subjects must have been naïve totenofovir disoproxil, with HBV DNA > 105 copies/mL (~ 4.2 log10 IU/mL) and ALT > 1.5 × theupper limit of normal (ULN) at screening. At Week 48, 77% (46 of 60) of patients in the tenofovirdisoproxil 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 disoproxilgroup had normalized ALT at week 48 compared with 15% (4 of 27) in the placebo group. Twenty-five percent (14 of 56) of patients in the tenofovir disoproxil group and 24% (7 of 29) of patients inthe placebo group achieved HBeAg seroconversion at Week 48.

Response to treatment with tenofovir disoproxil was comparable in treatment-naïve and treatment-experienced subjects with 76% (38/50) of treatment-naïve and 80% (8/10) of treatment-experiencedsubjects achieving HBV DNA < 400 copies/mL (69 IU/mL) at Week 48. Response to treatment withtenofovir disoproxil was also similar in subjects who were HBeAg-negative compared with thosewho were HBeAg-positive at baseline with 77% (43/56) HBeAg-positive and 75.0% (3/4) HBeAg-negative subjects achieving HBV DNA < 400 copies/mL (69 IU/mL) at Week 48. The distributionof HBV genotypes at baseline was similar between the TDF and Placebo groups. The majority ofsubjects were either genotypes C (43.8%) or D (41.6%) with a lower and similar frequency ofgenotypes 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, Cand E [75-100% of subjects achieved HBV DNA < 400 copies/mL (69 IU/mL) at Week 48] with alower response rate in subjects with genotype D infection (55%).

After at least 48 weeks of blinded randomised treatment, each subject could switch to open-labeltenofovir disoproxil treatment up to week 192. After week 48, virologic suppression was maintainedfor those 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 duringthe double-blind period, the proportion of subjects with HBV DNA < 400 copies/mL rose sharplyafter receiving treatment with open-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 was 79.3% and 59.3%,respectively (based on central laboratory criteria). Similar percentages of subjects in the TDF-TDFand PLB-TDF groups (33.9% and 34.5%, respectively) had experienced HBeAg seroconversionthrough week 192. No subjects in either treatment group had experienced HBsAg seroconversion atweek 192. Treatment response rates to tenofovir disoproxil at week 192 were maintained for allgenotypes A, B and C (80-100%) in the TDF TDF group. At week 192 a lower response rate is stillobserved in subjects with genotype D infection (77%) but with an improvement compared to48 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- PLB- TDF- PLB-

TDF TDF TDF TDF

Lumbar spine mean -0.08 -0.31 -0.09 -0.16 -0.20 -0.38(SD) BMD Z-score (1.044) (1.200) (1.056) (1.213) (1.032) (1.344)

Lumbar spine mean NA NA -0.03 0.23 -0.15 0.21(SD) change from (0.464) (0.409) (0.661) (0.812)baseline BMD Z-score

Whole body mean -0.46 −0.34 -0.57 -0.05 -0.56 -0.31(SD) BMD Z-score (1.113) (1.468) (0.978) (1.360) (1.082) (1.418)

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

Cumulative NA NA 18.3% 6.9% 18.3% 6.9%incidence ≥ 4%decrease frombaseline inlumbar spine

BMDa

Cumulative incidence NA NA 6.7% 0% 6.7% 0%≥ 4% decrease frombaseline in wholebody BMDa

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

Whole body BMD NA NA 4.6% 8.7% 23.7% 27.7%mean % increase

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 chronichepatitis 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 tenofovirand formaldehyde.

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 valuesof 326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively. Maximumtenofovir concentrations are observed in serum within one hour of dosing in the fasted state andwithin two hours when taken with food. The oral bioavailability of tenofovir from tenofovirdisoproxil in fasted patients was approximately 25%. Administration of tenofovir disoproxil with ahigh fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately40% and Cmax by approximately 14%. Following the first dose of tenofovir disoproxil in fed patients,the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of tenofovirdisoproxil with a light meal did not have a significant effect on the pharmacokinetics of tenofovir.

Following intravenous administration the steady-state volume of distribution of tenofovir wasestimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil, tenofoviris distributed to most tissues with the highest concentrations occurring in the kidney, liver and theintestinal contents (preclinical studies). In vitro protein binding of tenofovir to plasma or serumprotein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to25 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) thanthose observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of themajor 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 anyof the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reductionin metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinicallysignificant interactions involving tenofovir disoproxil and medicinal products metabolised by

CYP450 would occur.

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transportsystem with 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 theterminal half-life of tenofovir is approximately 12 to 18 hours.

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

The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the doserange 75 to 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 inadolescent patients receiving oral daily doses of tenofovir disoproxil 245 mg was similar toexposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg.

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

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

Pharmacokinetic parameters of tenofovir were determined following administration of a single doseof tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degreesof renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal functionwhen CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min andsevere with CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean(%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min torespectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients withmild, moderate and severe renal impairment. The dosing recommendations in patients with renalimpairment, with increased dosing interval, are expected to result in higher peak plasmaconcentrations and lower Cmin levels in patients with renal impairment compared with patients withnormal renal function. The clinical implications 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 adultpatients with creatinine clearance < 50 ml/min or in patients who already have ESRD and requiredialysis (see section 4.2).

The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance< 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have notbeen 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 normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects withmoderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects withsevere hepatic impairment.

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 in phytohaemagglutinin-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 toxicityoccurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was asubstance-related decrease in intestinal absorption of phosphate with potential secondary reductionin BMD.

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal resultsin one 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 in peri-postnatal toxicity studies at maternally toxic doses.

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

Microcrystalline cellulose

Lactose monohydrate

Hydroxypropylcellulose, low substituted

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose

Lactose monohydrate

Titanium dioxide (E171)

Triacetin

Indigo carmine aluminium lake (E132)

Not applicable.

2 years.

For bottles only:

After first opening: use within 90 days

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

High density polyethylene (HDPE) bottle with polypropylene (PP) child resistant closure with wadcontaining aluminium induction sealing liner and desiccant (silica gel), available in the following packsizes: 30 film-coated tablets and multipacks containing 90 (3 packs of 30) film-coated tablets.

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

OPA/Aluminium/PE/Desiccant/PE- Aluminium perforated unit dose blister pack containing 30 x 1film-coated tablets.

Not all pack sizes may be marketed.

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

Viatris Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/16/1129/001

EU/1/16/1129/002

EU/1/16/1129/003

EU/1/16/1129/004

EU/1/16/1129/005

Date of first authorisation: 08 December 2016

Date of latest renewal: 26 August 2021

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

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