SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tenofovir Zentiva 245 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 245 mg of tenofovir disoproxil (as 300 mg of tenofovir disoproxil fumarate).

Excipient(s) with known effect: lactose monohydrate. Each tablet contains 214 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Light blue, oblong biconvex-shaped, film-coated tablets

4.1 Therapeutic indications

HIV-1 infection

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

In adults, the demonstration of the benefit of Tenofovir 245 mg film-coated tablets in HIV-1 infection is based on results of one study in treatment-naive patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which Tenofovir 245 mg film-coated tablets was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).

Tenofovir 245 mg film-coated tablets are also indicated for the treatment of HIV-1 infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged 12 to < 18 years.

The choice of Tenofovir 245 mg film-coated tablets to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing

and/or treatment history of patients.

Hepatitis B infection

Tenofovir 245 mg film-coated tablets are indicated for the treatment of chronic

hepatitis B in adults with:

-    compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis (see section 5.1).

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

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

Tenofovir 245 mg film-coated tablets are indicated for the treatment of chronic

hepatitis B in adolescents 12 to < 18 years of age with:

-    compensated liver disease and evidence of immune active disease, i.e. active viral replication, persistently elevated serum ALT levels and histological evidence of active inflammation and/or fibrosis (see sections 4.4, 4.8 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV

infection and/or treatment of chronic hepatitis B.

Posology

Adults

The recommended dose of Tenofovir 245 mg film-coated tablets for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.

Chronic hepatitis B

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

-    In HBeAg positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.

-    In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.

Paediatric population HIV-1

In adolescents aged 12 to < 18 years and weighing > 35 kg, the recommended dose of Tenofovir 245 mg film-coated tablets is 245 mg (one tablet) once daily taken orally with food (see sections 4.8 and 5.1).

Reduced doses of tenofovir (the active ingredient of Tenofovir 245 mg film-coated tablets) are also used for treatment of HIV-1 infected paediatric patients aged 2 to

<    12 years. As Tenofovir 245 mg film-coated tablets are available only as 245 mg film-coated tablets, it is not suitable for the use in paediatric patients aged 2 < 12 years. Other suitable formulations are available.

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

Chronic hepatitis B

In adolescents aged 12 to < 18 years and weighing > 35 kg, the recommended dose of Tenofovir 245 mg film-coated tablets is 245 mg (one tablet) once daily, taken orally with food (see sections 4.8 and 5.1). The optimal duration of treatment is currently unknown.

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

Missed dose;

If a patient misses a dose of Tenofovir 245 mg film-coated tablets within 12 hours of the time it is usually taken, the patient should take Tenofovir 245 mg film-coated tablets with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Tenofovir 245 mg film-coated tablets by more than 12 hours and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Tenofovir 245 mg film-coated tablets another tablet should be taken. If the patient vomits more than 1 hour after taking Tenofovir 245 mg film-coated tablets they do not need to take another dose.

Special populations Elderly

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

Renal impairment

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

Adults

There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in adult patients with moderate and severe renal impairment (creatinine clearance

<    50 ml/min) and long-term safety data has not been evaluated for mild renal

impairment (creatinine clearance 50 - 80 ml/min). Therefore, in adult patients with renal impairment tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. Dose interval adjustments are recommended for adult patients with creatinine clearance < 50 ml/min.

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

Limited data from clinical studies support once daily dosing of 245 mg tenofovir disoproxil (as fumarate) in patients with mild renal impairment.

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

Administration of 245 mg tenofovir disoproxil (as fumarate) every 48 hours is recommended based on modelling of single-dose pharmacokinetic data in HIV-negative and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see sections 4.4 and 5.2).

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

patients:

Adequate dose adjustments cannot be applied due to lack of alternative tablet strengths, therefore use in this group of patients is not recommended. If no alternative treatment is available, prolonged dose intervals may be used as follows:

Severe renal impairment: 245 mg tenofovir disoproxil (as fumarate) may be administered every 72 - 96 hours (dosing twice a week). Haemodialysis patients:

245 mg tenofovir disoproxil (as fumarate) may be administered every 7 days following completion of a haemodialysis session*.

These dose interval adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Therefore clinical response to treatment and renal function should be closely monitored (see sections 4.4 and 5.2).

*Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.

No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance < 10 ml/min.

Paediatric population

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

Hepatic impairment

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

If Tenofovir 245 mg film-coated tablets are discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely

Method of administration

Tenofovir 245 mg film-coated tablets tablets should be taken once daily, orally with food.

In exceptional circumstances in patients having particular difficulty in swallowing, Tenofovir 245 mg film-coated tablets can be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape juice.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

General

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

HIV - 1

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Chronic hepatitis B

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

Co-administration of other medicinal products

-    Tenofovir 245 mg film-coated tablets should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.

-    Tenofovir 245 mg film-coated tablets should not be administered concomitantly with adefovir dipivoxil.

-    Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended.

-    Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40 - 60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir

disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

Triple therapy with nucleosides/nucleotides

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.

Renal and bone effects in adult population Renal effects

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

Renal monitoring

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil fumarate and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required.

Renal management

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any adult patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with tenofovir disoproxil fumarate in adult patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with tenofovir disoproxil fumarate should also be considered in case of progressive decline of renal function when no other cause has been identified.

Co-administration and risk of renal toxicity

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

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

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil fumarate in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients (see section 4.5). In patients with renal risk factors, the co-administration of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated.

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

Renal impairment

Renal safety with tenofovir disoproxil fumarate has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance

<    80 ml/min).

Adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients

There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function. Therefore, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance

<    30 ml/min) and in patients who require haemodialysis use of tenofovir disoproxil fumarate is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored (see sections 4.2 and 5.2).

Bone effects

In HIV infected patients, in a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naive adult patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups.

Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.

Bone abnormalities (infrequently contributing to fractures) may be associated with

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

Renal and bone effects in paediatric population

There are uncertainties associated with the long term effects of bone and renal toxicity. Moreover, the reversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach is recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide the appropriate monitoring during treatment (including decision for treatment withdrawal) and consider the need for supplementation.

Renal effects

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104-0352 (see sections 4.8 and 5.1).

Renal monitoring

Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, and monitored during treatment as in adults (see above).

Renal management

If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving tenofovir disoproxil fumarate renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). If renal abnormalities are suspected or detected then consultation with a nephrologist should be obtained to consider interruption of tenofovir disoproxil fumarate treatment.

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

Co-administration and risk of renal toxicity

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

Renal impairment

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

Bone effects

Tenofovir 245 mg film-coated tablets may cause a reduction in BMD. The effects of tenofovir disoproxil fumarate-associated changes in BMD on long-term bone health and future fracture risk are currently unknown (see section 5.1).

If bone abnormalities are detected or suspected in paediatric patients, consultation with an endocrinologist and/or nephrologist should be obtained.

Liver disease

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

There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in HBV infected patients with decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.

Exacerbations of hepatitis

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients (see section 4.8). In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

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

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

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

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see above Exacerbations of hepatitis.

Use with certain hepatitis C virus antiviral agents

Co-administration of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir has

been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of ledipasvir/sofosbuvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with coadministration of ledipasvir/sofosbuvir with tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil fumarate.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms.

Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Older people

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

Tenofovir 245 mg film-coated tablets contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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

Concomitant use not recommended

Tenofovir 245 mg film-coated tablets should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.

Tenofovir 245 mg film-coated tablets should not be administered concomitantly with adefovir dipivoxil.

Didanosine

Co-administration of tenofovir disoproxil fumarate 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 fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.

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

Given that tacrolimus can affect renal function, close monitoring is recommended

when it is co-administered with tenofovir disoproxil fumarate.

Other interactions

Interactions between tenofovir disoproxil fumarate and other medicinal products are listed in Table 1 below (increase is indicated as “t”, decrease as “ j”, no change as “^•”, twice daily as “b.i.d.”, and once daily as “q.d.”).

Table 1: Interactions between tenofovir disoproxil fumarate and other medicinal products

Medicinal product by therapeutic areas (dose in mg)	Effects on drug levels Mean percent change in AUC, Cmax, Cmin		Recommendation concerning Co-administration with 245 mg tenofovir disoproxil (as fumarate)
ANT1-1NFECT1VES
Antiretrovirals
Protease inhibitors
Atazanavir/Ritonavir (300 q.d./100 q.d./300 q.d.)	Atazanavir: AUC: j 25% Cmax: j 28% Cmin: j 26% Tenofovir: AUC: t 37% Cmax: t 34% Cmin: t 29%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).
Lopinavir/Ritonavir (400 b.i.d./100 b.i.d./300 q.d.)	Lopinavir/ritonavir: No significant effect on lopinavir/ritonavir PK parameters. Tenofovir: AUC: t 32% Cmax: ^ Cmin: t 51%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).
Darunavir/Ritonavir (300/100 b.i.d./300 q.d.)	Darunavir: No significant effect on darunavir/ritonavir PK parameters. Tenofovir: AUC: t 22% Cmin: t 37%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).

NRTTs
Didanosine	Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.	Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see section 4.4).
Adefovir dipivoxil	AUC: ^ Cmax-	Tenofovir disoproxil fumarate should not be administered concurrently with adefovir dipivoxil (see section 4.4).
Entecavir	AUC: ^ Cmax:	No clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with entecavir.

Hepatitis C virus antiviral agents
Ledipasvir/Sofosbuvir	Ledipasvir:	Increased plasma
(90 mg/400 mg q.d.) +	AUC: T 96%	concentrations of tenofovir
Atazanavir/Ritonavir	Cmax: T 68%	resulting from
(300 mg q.d./100 mg q.d.) +	Cmin: T 118%	co-administration of
Emtricitabine/Tenofovir		tenofovir disoproxil
disoproxil fumarate	Sofosbuvir:	fumarate,
(200 mg/300 mg q.d.)1	AUC: ^	ledipasvir/sofosbuvir and
	Cmax:	atazanavir/ritonavir may increase adverse reactions
	GS-3310072:	related to tenofovir disoproxil
	AUC: ^	fumarate, including renal
	Cmax:	disorders. The safety of
	Cmin: T 42%	tenofovir disoproxil fumarate when used with
	Atazanavir:	ledipasvir/sofosbuvir and a
	AUC: ^	pharmacokinetic enhancer
	Cmax:	(e.g. ritonavir or cobicistat)
	Cmin: T 63%	has not been established.
	Ritonavir:	The combination should be
	AUC: ^	used with caution with
	Cmax:	frequent renal monitoring, if
	Cmin: T 45% Emtricitabine: AUC: ^ Cmax: Cmin: Tenofovir: AUC: ^	other alternatives are not available (see section 4.4).

Ledipasvir/Sofosbuvir	Ledipasvir:	Increased plasma
(90 mg/400 mg q.d.) +	AUC: ^	concentrations of tenofovir
Darunavir/Ritonavir	Cmax:	resulting from
(800 mg q.d./100 mg q.d.) +	Cmin:	co-administration of
Emtricitabine/Tenofovir		tenofovir disoproxil
disoproxil fumarate	Sofosbuvir:	fumarate,
(200 mg/300 mg q.d.)1	AUC: | 27%	ledipasvir/sofosbuvir and
	Cmax: 1 37%	darunavir/ritonavir may increase adverse reactions
	GS-3310072:	related to tenofovir disoproxil
	AUC: ^	fumarate, including renal
	Cmax:	disorders. The safety of
	Cmin:	tenofovir disoproxil fumarate when used with
	Darunavir:	ledipasvir/sofosbuvir and a
	AUC: ^	pharmacokinetic enhancer
	Cmax:	(e.g. ritonavir or cobicistat)
	Cmin:	has not been established.
	Ritonavir:	The combination should be
	AUC: ^	used with caution with
	Cmax:	frequent renal monitoring, if
	Cmin: T 48% Emtricitabine: AUC: ^ Cmax: Cmin: Tenofovir: AUC: T 50%	other alternatives are not available (see section 4.4).

Ledipasvir/Sofosbuvir	Ledipasvir:	No dose adjustment is
(90 mg/400 mg q.d.) +	AUC: | 34%	recommended. The increased
Efavirenz/Emtricitabine/Tenofo	Cmax: 1 34%	exposure of tenofovir could
vir disoproxil fumarate	Cmin: I 34%	potentiate adverse reactions
(600 mg/200 mg/300 mg q.d.)		associated with tenofovir
	Sofosbuvir:	disoproxil fumarate,
	AUC: ^	including renal disorders.
	Cmax:	Renal function should be closely monitored (see
	GS-3310072: AUC: ^ Cmax: Cmin: Efavirenz: AUC: ^ Cmax: Cmin: Emtricitabine: AUC: ^ Cmax: Cmin:	section 4.4).

Tenofovir: AUC: T 98%

Ledipasvir/Sofosbuvir (90 mg/400 mg q.d.) + Emtricitabine/Rilpivirine/Teno fo vir disoproxil fumarate (200 mg/25 mg/300 mg q.d.)	Ledipasvir: AUC: ^ Cmax: Cmin: Sofosbuvir: AUC: ^ Cmax: GS-3310072: AUC: ^ Cmax: Cmin: Emtricitabine: AUC: ^ Cmax: Cmin: Rilpivirine: AUC: ^ Cmax: Cmin: Tenofovir: AUC: T 40% C : , *	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. Renal function should be closely monitored (see section 4.4).
Sofosbuvir (400 mg q.d.) + Efavirenz/Emtricitabine/T enof ovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.)	Sofosbuvir: AUC: ^ Cmax: i 19% GS-3310072: AUC: ^ Cmax: i 23% Efavirenz: AUC: ^ Cmax: Cmin: Emtricitabine: AUC: ^ Cmax: Cmin: Tenofovir: AUC: ^ Cmax: T 25%_	No dose adjustment is required.

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

The predominant circulating metabolite of sofosbuvir.

Studies conducted with other medicinal products

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300 - 1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil fumarate. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil fumarate may be considered during pregnancy, if necessary.

Breast-feeding

Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. Therefore Tenofovir 245 mg film-coated tablets should not be used during breast-feeding.

As a general rule, it is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant.

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.

4.8 Undesirable effects

Summary of the safety profile

HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and 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 245 mg film-coated tablets (see section 4.4).

HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil fumarate-treated adult patients discontinued treatment due to the gastrointestinal events.

Co-administration of Tenofovir 245 mg film-coated tablets and didanosine is not recommended as this may result in an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4).

Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil fumarate was nausea (5.4%).

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

Tabulated summary of adverse reactions

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

HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naive patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety profile of tenofovir disoproxil fumarate. After an initial decline of approximately-4.9ml/min (using Cockcroft-Gault equation) or -3.9ml/min/1.73m² (using modification of diet in renal disease [MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovir disoproxil fumarate treated patients was -1.41ml/min per year (using Cockcroft-Gault equation) and -0.74ml/min/1.73m² per year (using MDRD equation).

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

In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of > 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant differences between the combined tenofovir-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) of the tenofovir disoproxil fumarate group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil fumarate group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine > 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl.

At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil fumarate group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil fumarate group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 9% (2/22) in the entecavir group.

Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see section 4.4).

Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxil fumarate were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 lamivudine-resistant patients received treatment with tenofovir disoproxil fumarate (n = 141) or emtricitabine/tenofovir disoproxil fumarate (n = 139) for 240 weeks.

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

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

Frequency	Tenofovir disoproxil fumarate
Metabolism and nutrition disorders:
Very common:	hypophosphataemia1
Uncommon:	hypokalaemia1
Rare:	lactic acidosis
Nervous system disorders:
Very common:	dizziness
Common:	headache
Gastrointestinal disorders:

¹    This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the

absence of this condition.

2

This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials or the tenofovir disoproxil fumarate expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program (n = 7,319).

Description of selected adverse reactions HIV-1 and hepatitis B:

Renal impairment

As Tenofovir 245 mg film-coated tablets may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil fumarate discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil fumarate discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil fumarate discontinuation (see section 4.4).

HIV-1:

Interaction with didanosine

Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune reactivation syndrome

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

Osteonecrosis

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

Hepatitis B:

Exacerbations of hepatitis during treatment

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

Exacerbations of hepatitis after discontinuation of treatment

In HBV infected patients, clinical and laboratory evidence of exacerbations of

hepatitis have occurred after discontinuation of HBV therapy (see section 4.4).

Paediatric population HIV-1

Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received treatment with tenofovir disoproxil fumarate (n = 93) or placebo/active comparator (n = 91) in combination with other antiretroviral agents for 48 weeks (see section 5.1). The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical studies of tenofovir disoproxil fumarate in adults (see section 4.8 Tabulated summary of adverse reactions and 5.1).

Reductions in BMD have been reported in paediatric patients. In HIV-1 infected adolescents, the BMD Z-scores observed in subjects who received tenofovir disoproxil fumarate were lower than those observed in subjects who received placebo. In HIV-1 infected children, the BMD Z-scores observed in subjects who switched to tenofovir disoproxil fumarate were lower than those observed in subjects who remained on their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1).

In study GS-US-104-0352, 4 out of 89 paediatric patients exposed to tenofovir disoproxil fumarate (median tenofovir disoproxil fumarate exposure 312 weeks) discontinued due to adverse reactions consistent with proximal renal tubulopathy. Seven patients had estimated glomerular filtration rate (GRF) values between 70 and 90 mL/min/1.73 m². Among them, two patients experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of tenofovir disoproxil fumarate.

Chronic hepatitis B

Assessment of adverse reactions is based on one randomised study (study GS-US-174-0115) in 106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 52) or placebo (n = 54) for 72 weeks. The adverse reactions observed in adolescent patients who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical studies of tenofovir disoproxil fumarate in adults (see section 4.8 Tabulated summary of adverse reactions and 5.1).

Reductions in BMD have been observed in HBV infected adolescents. The BMD Z-scores observed in subjects who received tenofovir disoproxil fumarate were lower than those observed in subjects who received placebo (see sections 4.4 and 5.1).

Other special population(s)

Older people

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

Patients with renal impairment

Since tenofovir disoproxil fumarate can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with Tenofovir 245 mg film-coated tablets

(see sections 4.2, 4.4 and 5.2). The use of tenofovir disoproxil fumarate is not recommended in paediatric patients with renal impairment (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

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

Management

Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. It is not known whether tenofovir can be removed by peritoneal dialysis.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action and pharmacodynamic effects

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of cellular polymerases a, P, and y. At concentrations of up to 300 pmol/l, tenofovir has also shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro assays.

Data pertaining to HIV

HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the wild-type laboratory strain HIV-1 IIIB is 1 - 6 pmol/l in lymphoid cell lines and 1.1 pmol/l against primary HIV-1 subtype B isolates in PBMCs. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells. Tenofovir shows activity in vitro against HIV-2, with an EC50 of 4.9 pmol/l in MT-4 cells.

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

Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir disoproxil 245 mg (as fumarate) against strains of HIV-1 with resistance to nucleoside inhibitors. The results indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced response to tenofovir disoproxil 245 mg (as fumarate) therapy.

Clinical efficacy and safety

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

In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir disoproxil 245 mg (as fumarate) for 24 weeks. The mean baseline CD4 cell count was 427 cells/mm³, the mean baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of < 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years. Baseline genotypic analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase inhibitors.

At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels (DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 245 mg (as fumarate) recipients (p < 0.0001). A statistically significant difference in favour of tenofovir disoproxil 245 mg (as fumarate) was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 count (+13 cells/mm³ for tenofovir disoproxil 245 mg (as fumarate) versus -11 cells/mm3 for placebo, p-value = 0.0008). The antiviral response to tenofovir disoproxil fumarate was durable through 48 weeks (DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 50 copies/ml was 41% and 18% respectively). Eight (2%) tenofovir disoproxil 245 mg (as fumarate) treated patients developed the K65R mutation within the first 48 weeks.

The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) versus stavudine when used in combination with lamivudine and efavirenz in HIV-1 infected adult patients naive to antiretroviral therapy. The mean baseline CD4 cell count was 279 cells/mm³, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of patients had symptomatic HIV-1 infection and 18% had AIDS. Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads > 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml.

By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 84% and 80% in the stavudine arm. At 144 weeks, the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 64% and 63% in the stavudine arm.

The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm³ in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively). At 144 weeks of treatment, the average change from baseline remained similar in both treatment groups (-3.07 and -3.03 log10 copies/ml; +263 and +283 cells/mm in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively). A consistent response to treatment with tenofovir disoproxil 245 mg (as fumarate) was seen regardless of baseline HIV-1 RNA and CD4 count.

The K65R mutation occurred in a slightly higher percentage of patients in the

tenofovir disoproxil fumarate group than the active control group (2.7% versus 0.7%). Efavirenz or lamivudine resistance either preceded or was coincident with the development of K65R in all cases. Eight patients had HIV that expressed K65R in the tenofovir disoproxil 245 mg (as fumarate) arm, 7 of these occurred during the first 48 weeks of treatment and the last one at week 96. No further K65R development was observed up to week 144. One patient in the tenofovir disoproxil (as fumarate) arm developed the K70E substitution in the virus. From both the genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir.

Data pertaining to HBV

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

Resistance: No HBV mutations associated with tenofovir disoproxil fumarate resistance have been identified (see Clinical efficacy and safety). In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus. HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild- type virus. HBV strains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus. Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild-type virus.

Clinical efficacy and safety

The demonstration of benefit of tenofovir disoproxil fumarate in compensated and decompensated disease is based on virological, biochemical and serological responses in adults with HBeAg positive and HBeAg negative chronic hepatitis B. Treated patients included those who were treatment-naive, lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline. Benefit has also been demonstrated based on histological responses in compensated patients.

Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and GS-US-174-0103)

Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir disoproxil fumarate to adefovir dipivoxil in adult patients with compensated liver disease are presented in Table 3 below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) patients negative for HBeAg and positive for HBeAb.

In both of these studies tenofovir disoproxil fumarate was significantly superior to adefovir dipivoxil for the primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis). Treatment with tenofovir disoproxil 245 mg (as fumarate) was also associated with significantly greater proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg treatment. Both treatments produced similar results with regard to histological response (defined as Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis) at week 48 (see Table 3 below).

In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil fumarate group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 (see Table 3 below).

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

	Study 174-0102 (HBeAg negative)		Study 174-0103 (HBeAg positive)
Parameter	Tenofovir disoproxil 245 mg (as fumarate) n = 250	Adefovir dipivoxil 10 mg n = 125	Tenofovir disoproxil 245 mg (as fumarate) n = 176	Adefovir dipivoxil 10 mg n = 90
Complete response (%)a	71*	49	67*	12
Histology Histological response (%)b	72	69	74	68
Median HBV DNA reduction from baselinec	-4.7*	-4.0	-6.4*	-3.7
(log10 copies/ml)
HBV DNA (%)	93*	63	76*	13
< 400 copies/ml (< 69 IU/ml)
ALT (%)	76	77	68*	54
Normalised ALTd
Serology (%) HBeAg loss/seroconversion	n/a	n/a	22/21	18/18
HBsAg loss/seroconversion	0/0	0/0	3*/1	0/0

*p-value versus adefovir dipivoxil < 0.05,

^aComplete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis,

^bKnodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis,

^cMedian change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of detection (LOD) of the assay, ^dThe population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. n/a= not applicable.

Tenofovir disoproxil fumarate was associated with significantly greater proportions of patients with undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and study GS-US-174-0103; 69%, 9%), respectively.

Response to treatment with tenofovir disoproxil fumarate was comparable in nucleoside-experienced (n = 51) and nucleoside-naive (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT (n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined. Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naive patients achieved complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naive patients achieved HBV DNA suppression < 400 copies/ml. All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml.

Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 48 weeks (either tenofovir disoproxil 245 mg (as fumarate) or adefovir dipivoxil 10 mg), patients rolled over with no interruption in treatment to open-label tenofovir disoproxil fumarate. In studies GS-US-174-0102 and GS-US-174-0103,

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

At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses were maintained with continued tenofovir disoproxil fumarate 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 (as fumarate) n = 250	Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate)
Week	96b 144e 192g 240i 288l 384o	96c 144f 192= 240 288m 384p

HBV DNA (%) < 400 copies/ml (< 69 IU/ml)	90	87	84	83	80	74	89	88	87	84	84	76
ALT (%) Normalised ALTd	72	73	67	70	68	64	68	70	77	76	74	69
Serology (%)
HBeAg loss/ Seroconversion	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a
HBsAg loss/ seroconversion	0/0	0/0	0/0	0/0	0/0	1/1n	0/0	0/0	0/0	o o	1/1n	1/1n
aBased upon Long Term Eva			luation algorithm (LTE Ana					ysis)	- Patients who

discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. ^b48 weeks of double-blind tenofovir disoproxil fumarate followed by 48 weeks open-label.

^c48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil fumarate.

^dThe population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.

^e48 weeks of double-blind tenofovir disoproxil fumarate followed by 96 weeks open-label.

f

48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil fumarate.

^g48 weeks of double-blind tenofovir disoproxil fumarate followed by 144 weeks open-label.

^h48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil fumarate.

ⁱ48 weeks of double-blind tenofovir disoproxil fumarate followed by 192 weeks open-label,

^J48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil fumarate.

^kOne patient in this group became HBsAg negative for the first time at the 240 week

visit and was ongoing in the study at the time of the data cut-off. However, the

subject’s HBsAg loss was ultimately confirmed at the subsequent visit.

^l48 weeks of double-blind tenofovir disoproxil fumarate followed by 240 weeks open-

label.

^m48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil fumarate.

"Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil fumarate (KM-TDF).

^o48 weeks of double-blind tenofovir disoproxil fumarate followed by 336 weeks open-label.

^p48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil fumarate

n/a = not applicable.

^aBased upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator. ^b 48 weeks of double-blind tenofovir disoproxil fumarate followed by 48 weeks open-label.

^c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil fumarate.

^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 fumarate followed by 96 weeks open-label.

f

48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil fumarate.

^g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the addition of emtricitabine to open-label tenofovir disoproxil fumarate (KM-ITT).

^h 48 weeks of double-blind tenofovir disoproxil fumarate followed by 144 weeks open-label.

ⁱ 48 weeks double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil fumarate.

^j 48 weeks of double-blind tenofovir disoproxil fumarate followed by 192 weeks open-label.

^k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil fumarate.

^l Figures presented are cumulative percentages based upon a Kaplan Meier analysis

excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil fumarate (KM-TDF).

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

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

^o 48 weeks of double-blind tenofovir disoproxil fumarate followed by 336 weeks open-label.

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

Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below). Ninety-five percent (225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at baseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patients with cirrhosis at baseline (Ishak fibrosis score 5-6), 26% (24) experienced no change in Ishak fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak fibrosis score of at least 2 points.

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

	Study 174-0102 (HBeAg negative)		Study 174-0103 (HBeAg positive)
	Tenofovir disoproxil 245 mg (as fumarate) n = 250c	Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate) n = 125d	Tenofovir disoproxil 245 mg (as fumarate) n = 176c	Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate) n = 90d
Histological	88	85	90	92
responsea,b (%)	[130/148]	[63/74]	[63/70]	[36/39]
The population used for analysis of histology included on			ly 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).

^bKnodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score.

^c48 weeks double-blind tenofovir disoproxil fumarate followed by up to 192 weeks open-label.

^d48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil fumarate.

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 (as fumarate) in adult patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir arm were 9.45 log10 copies/ml (n = 27). Treatment with tenofovir disoproxil 245 mg (as fumarate) was associated with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week data, of -5.74 log10 copies/ml (n = 18). In addition, 61% of patients had normal ALT at week 48.

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

The efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) or tenofovir disoproxil 245 mg (as fumarate) plus 200 mg emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in HBeAg positive and HBeAg negative adult patients who had persistent viraemia (HBV DNA > 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks. At baseline, 57% of patients randomised to tenofovir disoproxil fumarate versus 60% of patients randomised to emtricitabine plus tenofovir disoproxil fumarate treatment group had previously been treated with lamivudine. Overall at week 24, treatment with tenofovir disoproxil fumarate resulted in 66% (35/53) of patients with HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine plus tenofovir disoproxil fumarate (p = 0.672). In addition 55% (29/53) of patients treated with tenofovir disoproxil fumarate had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus tenofovir disoproxil fumarate (p = 0.504). Comparisons between treatment groups beyond week 24 are difficult to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus tenofovir disoproxil. Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine plus tenofovir disoproxil fumarate in HBV monoinfected patients are ongoing.

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

Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety and efficacy of tenofovir disoproxil fumarate (n = 45), emtricitabine plus tenofovir disoproxil fumarate (n = 45), and entecavir (n = 22), in patients with decompensated liver disease. In the tenofovir disoproxil fumarate treatment arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum ALT of 61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 months of prior lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline. The co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine > 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl.

In patients with CPT scores < 9, 74% (29/39) of tenofovir disoproxil fumarate, and 94% (33/35) of emtricitabine plus tenofovir disoproxil fumarate treatment groups achieved HBV DNA < 400 copies/ml after 48 weeks of treatment.

Overall, the data derived from this study are too limited to draw any definitive conclusions on the comparison of emtricitabine plus tenofovir disoproxil fumarate versus tenofovir disoproxil fumarate, (see Table 7 below).

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

	Study 174-0108
Parameter	Tenofovir disoproxil 245 mg (as fumarate) (n = 45)	Emtricitabine 200 mg/ tenofovir disoproxil 245 mg (as fumarate) (n = 45)	Entecavir (0.5 mg or 1 mg) n = 22
Tolerability failure (permanent discontinuation of study drug due to a treatment emergent AE) n (%)a	3 (7%)	2 (4%)	2 (9%)
Confirmed increase in serum creatinine > 0.5 mg/dl from baseline or confirmed serum phosphate of < 2 mg/dl n (%)b	4 (9%)	3 (7%)	1 (5%)
HBV DNA n (%) < 400 copies/ml n (%)	31/44 (70%)	36/41 (88%)	16/22 (73%)
ALT n (%) Normal ALT	25/44 (57%)	31/41 (76%)	12/22 (55%)
> 2 point decrease in CPT from baseline n (%)	7/27 (26%)	12/25 (48%)	5/12 (42%)
Mean change from baseline in CPT score	-0.8	-0.9	-1.3
Mean change from baseline in MELD score	-1.8	-2.3	-2.6

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

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

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

Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir disoproxil fumarate, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil fumarate 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 (as fumarate) was evaluated in a randomised, double-blind study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with compensated liver disease, viraemia (HBV DNA > 1,000 IU/ml), and genotypic evidence of lamivudine resistance (rtM204I/V +/-rtL180M). Only five had adefovir-associated resistance mutations at baseline. One hundred forty-one and 139 adult subjects were randomised to a tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate treatment arm, respectively. Baseline demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and mean ALT was 79 U/l, respectively.

After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil fumarate had HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation. After 240 weeks of treatment with emtricitabine plus tenofovir disoproxil fumarate, 115 of 139 subjects (83%) had HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation. Among the HBeAg positive subjects randomised to tenofovir disoproxil fumarate, 16 of 65 subjects (25%) experienced HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240. In the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil fumarate, 13 of 68 subjects (19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion through week 240. Two subjects randomised to tenofovir disoproxil fumarate experienced HBsAg loss by Week 240, but not seroconversion to anti-HBs. OneFive subjects randomised to emtricitabine plus tenofovir disoproxil fumarate 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 doubleblind tenofovir disoproxil fumarate treatment and then switched to open-label tenofovir disoproxil fumarate treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 (n = 6) and 384 (n = 2) of tenofovir disoproxil fumarate monotherapy showed that no mutations associated with tenofovir disoproxil fumarate resistance have developed.

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

(GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir

dipivoxil treatment and then switched to open-label tenofovir disoproxil fumarate treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 (n = 1) and 384 (n = 2) of tenofovir disoproxil fumarate monotherapy showed that no mutations associated with tenofovir disoproxil fumarate resistance have developed.

In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline) received tenofovir disoproxil fumarate for up to 168 weeks.

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

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

In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance mutations at baseline) received tenofovir disoproxil fumarate for up to 72 weeks. Genotypic evaluations were performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 6) and week 72 (n = 5). No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates.

Paediatric population

HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years of age were treated with tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with an optimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovir disoproxil fumarate over placebo was not demonstrated based on plasma HIV-1 RNA levels at week 24. However, a benefit is expected for the adolescent population based on extrapolation of adult data and comparative pharmacokinetic data (see section 5.2).

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

Z-scores declined by -0.341 for lumbar spine and -0.458 for total body.

In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either replace stavudine or zidovudine with tenofovir disoproxil fumarate (n = 48) or continue on their original regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil fumarate treatment group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations < 400 copies/ml. The difference in the proportion of patients who maintained < 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil fumarate treatment group. When missing data were excluded, 91% of patients in the tenofovir disoproxil fumarate treatment group and 94% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations < 400 copies/ml at week 48.

Reductions in BMD have been reported in paediatric patients. In patients who received treatment with tenofovir disoproxil fumarate, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and -0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline. Mean changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil fumarate and stavudine or zidovudine groups, respectively. The mean rate of lumbar spine bone gain at week 48 was similar between the tenofovir disoproxil fumarate treatment group and the stavudine or zidovudine treatment group. Total body bone gain was less in the tenofovir disoproxil fumarate treatment group compared to the stavudine or zidovudine treatment group. One tenofovir disoproxil fumarate treated subject and no stavudine or zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48. BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil fumarate for 96 weeks. BMD Z-scores were not adjusted for height and weight.

In study GS-US-104-0352, 4 out of 89 paediatric patients exposed to tenofovir disoproxil fumarate discontinued due to adverse reactions consistent with proximal renal tubulopathy (median tenofovir disoproxil fumarate exposure 104 weeks).

Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients aged 12 to < 18 years with chronic HBV infection [HBV DNA > 10⁵ copies/ml, elevated serum ALT (> 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with tenofovir disoproxil 245 mg (as fumarate) (n = 52) or placebo (n = 54) for 72 weeks. Subjects must have been naive to tenofovir disoproxil fumarate, but could have received interferon based regimens (> 6 months prior to screening) or any other non-tenofovir disoproxil fumarate containing oral anti-HBV nucleoside/nucleotide therapy (> 16 weeks prior to screening). At week 72, overall 88% (46/52) of patients in the tenofovir disoproxil fumarate 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 fumarate group had normalised ALT at week 72 compared to 31% (13/42) in the placebo group. Response to treatment with tenofovir disoproxil fumarate was comparable in nucleos(t)ide-naive (n = 20) and nucleos(t)ide-experienced (n = 32) patients, including lamivudine- resistant patients (n = 6). Ninety-five percent of

nucleos(t)ide-naive patients, 84% of nucleos(t)ide- experienced patients, and 83% of lamivudine-resistant patients achieved HBV DNA < 400 copies/ml at week 72. Thirty-one of the 32 nucleos(t)ide-experienced patients had prior lamivudine experience. At week 72, 96% (27/28) of immune-active patients (HBV DNA > 10⁵ copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil fumarate treatment group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml. Seventy-five percent (21/28) of immune-active patients in the tenofovir disoproxil fumarate group had normal ALT at week 72 compared to 34% (11/32) in the placebo group.

No subjects met the primary safety endpoint of a 6% decrease in lumbar spine BMD. In subjects receiving tenofovir disoproxil fumarate or placebo, mean (SD) lumbar spine BMD Z-score was -0.43 (0.764) and -0.28 (0.813), and mean total body BMD Z-score was -0.20 (1.126) and -0.26 (0.878), respectively, at baseline. The mean (SD) change in lumbar spine BMD Z-score from baseline to week 72 in subjects receiving tenofovir disoproxil fumarate was -0.05 (0.310) and 0.07 (0.377) in those receiving placebo. The mean change in whole body BMD Z-score in subjects receiving tenofovir disoproxil fumarate was -0.15 (0.379) and 0.06 (0.361) in those receiving placebo.

BMD Z-scores were not adjusted for height and weight. The mean percentage increase in whole body and lumbar spine BMD from baseline to week 72 was 2.84% and 4.95%, respectively, in subjects receiving tenofovir disoproxil fumarate. These mean percentage increases in whole body and lumbar spine BMD were 2.53% and 3.19% less, respectively, when compared to subjects receiving placebo. Three subjects in the tenofovir disoproxil fumarate group and 2 subjects in the placebo group had a decrease of > 4% in spine BMD.

The European Medicines Agency has deferred the obligation to submit the results of studies with tenofovir disoproxil fumarate in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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

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

Absorption

Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil fumarate with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 326 (36.6%) ng/ml, 3,324 (41.2%) ng h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum tenofovir concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%. Administration of tenofovir disoproxil fumarate with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%. Following the first dose of tenofovir disoproxil fumarate in fed patients, the median C_max in serum ranged from 213 to 375 ng/ml. However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir.

Distribution

Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 pg/ml.

Biotransformation

In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil fumarate at a concentration of 100 pmol/l had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant interactions involving tenofovir disoproxil fumarate and medicinal products metabolised by CYP450 would occur.

Elimination

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70 - 80% of the dose excreted unchanged in urine following intravenous administration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration the terminal half-life of tenofovir is approximately 12 to 18 hours.

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

Linearity/non-linearity

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

Age

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

Gender

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

Ethnicity

Pharmacokinetics have not been specifically studied in different ethnic groups. Paediatric population

HIV-1: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight > 35 kg. Mean (± SD) Cmax and AUC_tau are 0.38 ± 0.13 pg/ml and 3.39 ± 1.22 pg h/ml, respectively. Tenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir disoproxil 245 mg (as fumarate) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg (as fumarate).

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 (as fumarate) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg (as fumarate).

Pharmacokinetic studies have not been performed with tenofovir disoproxil (as fumarate) 245 mg tablets in children under 12 years or with renal impairment.

Renal impairment

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30 - 49 ml/min and severe with CrCl = 10 - 29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ngh/ml in subjects with CrCl > 80 ml/min to respectively 3,064 (30%) ng h/ml, 6,009 (42%) ngh/ml and 15,985 (45%) ng h/ml in patients with mild, moderate and severe renal impairment. The dosing recommendations in patients with renal impairment, with increased dosing interval, are expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared with patients with normal renal function. The clinical implications of this are unknown.

In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean C_max of 1,032 ng/ml and a mean AUC0-48h of 42,857 ng h/ml.

It is recommended that the dosing interval for tenofovir disoproxil 245 mg (as fumarate) is modified in adult patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis (see section 4.2).

The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.

The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations (see sections

4.2    and 4.4).

Hepatic impairment

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUCO-ot values were 223 (34.8%) ng/ml and 2,050 (50.8%) ngh/ml, respectively, in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ngh/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ngh/ml in subjects with severe hepatic impairment.

Intracellular pharmacokinetics

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

5.3    Preclinical safety data

Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures > 5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (> 40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.

Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice. These tumours are unlikely to be of relevance to humans.

Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil fumarate reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Lactose monohydrate Povidone K-25 Croscarmellose sodium Microcrystalline cellulose (E-460)

Magnesium stearate

Film-coating:

Lactose monohydrate Hypromellose (E-464)

Titanium dioxide (E-171)

Triacetin (E-1518)

Indigo Carmine Aluminum Lake (E-132)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months

After first opening: 30 days

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a child-resistant cap and induction heat sealing (with aluminium foil), paper folding box.

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

Three OPA/Aluminium/PVC/Aluminium foil blisters, each containing 10 film-coated tablets, in one paper folding box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0573

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/05/2013

10    DATE OF REVISION OF THE TEXT

30/08/2016