Each film-coated tablet contains 123 mg of tenofovir disoproxil (as fumarate). Excipientwithknowneffect: Each tablet contains 82 mg lactose (as monohydrate). For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet (tablet). White, triangle-shaped, film-coated tablets, 8.5 mm in diameter, debossed on one side with "GILEAD" and on the other side with "150".

CLINICAL PARTICULARS

Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection. Posology The recommended dose for HIV-1 infected paediatric patients aged 6 to < 12 years weighing 17 kg to < 22 kg who are able to swallow film-coated tablets is one 123 mg tablet once daily taken orally with food. Please refer to the Summaries of Product Characteristics for Viread 163 mg and 204 mg film-coated tablets for the treatment of HIV-1 infected paediatric patients aged 6 to < 12 years weighing 22 kg to < 28 kg and 28 kg to < 35 kg, respectively. Viread is also available as 33 mg/g granules for use in HIV-1 infected paediatric patients aged 2 to < 12 years who weigh < 17 kg or who are unable to swallow film-coated tablets. Please refer to the Summary of Product Characteristics for Viread 33 mg/g granules.

If a patient misses a dose of Viread within 12 hours of the time it is usually taken, the patient should take Viread with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Viread 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 Viread, another tablet should be taken. If the patient vomits more than 1 hour after taking Viread they do not need to take another dose.

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

No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2). If Viread 123 mg film-coated tablets are discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

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. 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.

Contraindications

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

Special warnings and precautions for use

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.

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.

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.

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 safety with tenofovir has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance < 80 ml/min).

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. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8).

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 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).

It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all patients prior to initiating therapy with tenofovir disoproxil fumarate and that it is also monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.

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.

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. 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).

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.

Viread 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.

Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products. Discontinuation of Viread therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Viread should be closely monitored with both clinical and laboratory follow-up for at least 6 months after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Tenofovir and tenofovir disoproxil fumarate are not metabolised by liver enzymes. A pharmacokinetic study has been performed in non-HIV infected adult patients with various degrees of hepatic impairment. No significant pharmacokinetic alteration has been observed in these patients (see section 5.2). 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.

Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. The preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, a class effect of nucleoside analogues, is low for tenofovir disoproxil fumarate. However, as tenofovir is structurally related to nucleoside analogues, this risk cannot be excluded. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely.

CART has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8). Tenofovir is structurally related to nucleoside analogues hence the risk of lipodystrophy cannot be excluded. However, 144-week clinical data from antiretroviral-naive HIV infected adult patients indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered with lamivudine and efavirenz.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement. Viread 123 mg film-coated tablets contain 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.

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.

Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate. Viread should not be administered concomitantly with adefovir dipivoxil.

Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see section 4.4 and Table 1).

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.

Interactions between tenofovir disoproxil fumarate and protease inhibitors and antiretroviral agents other than protease inhibitors are listed in Table 1 below (increase is indicated as "|", decrease as "|", no change as "-", twice daily as "b.i.d. ", and once daily as "q.d. ").

Table 1: Interactions between tenofovir disoproxil fumarate and 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).

Fertility, pregnancy and lactation

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.

Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. Therefore Viread should not be used during breast-feeding. As a general rule, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV to the infant.

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.

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.

Undesirable effects

Summaryofthesafetyprofile

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 Viread (see section 4.4). 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. Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with tenofovir disoproxil fumarate (see sections 4.4 and 4.8 Description of selected adverse reactions). Co-administration of Viread 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). Discontinuation of Viread in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4).

Tabulatedsummaryofadversereactions

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. Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced adult 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 adult 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. 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:	hypophosphataemia 1
Uncommon:	hypokalaemia 1
Rare:	lactic acidosis 3
Nervous system disorders:
Very common:	dizziness
Gastrointestinal disorders:
Very common:	diarrhoea, vomiting, nausea
Common:	flatulence
Uncommon:	pancreatitis 3
Hepatobiliary disorders:
Common:	increased transaminases
Rare:	hepatic steatosis 3 , hepatitis
Skin and subcutaneous tissue disorders:
Very common:	rash
Rare:	angioedema
Musculoskeletal and connective tissue disorders:
Uncommon:	rhabdomyolysis 1 , muscular weakness 1
Rare:	osteomalacia (manifested as bone pain and infrequently contributing to fractures) 1, 2 , myopathy 1
Renal and urinary disorders:
Uncommon:	increased creatinine
Rare:	acute renal failure, renal failure, acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephritis (including acute interstitial nephritis) 2 , nephrogenic diabetes insipidus
General disorders and administration site conditions:
Very common:	asthenia

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.
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).
See section 4.8 Description of selected adverse reactions for more details.

Descriptionofselectedadversereactions

Renal impairment

As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile).

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.

Lipids, lipodystrophy and metabolic abnormalities

CART has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4). CART has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4). In a 144-week controlled clinical study in antiretroviral-naive adult patients that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz, patients who received tenofovir disoproxil had a significantly lower incidence of lipodystrophy compared with patients who received stavudine. The tenofovir disoproxil fumarate arm also had significantly smaller mean increases in fasting triglycerides and total cholesterol than the comparator arm.

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).

Lactic acidosis and severe hepatomegaly with steatosis

Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels (see section 4.4).

Paediatricpopulation

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). Of 89 patients (2 to < 12 years) who received tenofovir disoproxil fumarate in study GS-US-104-0352 (median exposure 104 weeks), 4 patients discontinued from the study due to adverse reactions consistent with proximal renal tubulopathy.

Otherspecialpopulation(s)

Patients with renal impairment

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

Exacerbations of hepatitis after discontinuation of treatment

In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have occurred after discontinuation of tenofovir disoproxil fumarate (see section 4.4).

Reportingofsuspectedadversereactions

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 thenationalreportingsystem listedinAppendixV.

Overdose

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.

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

Pharmacodynamic properties

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

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, b, and g. At concentrations of up to 300 umol/l, tenofovir has also shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro assays.

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

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/mm3 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. From both the genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir.

The antiviral activity of tenofovir disoproxil fumarate against hepatitis B virus (HBV) has been demonstrated in vitro and clinically in adults and adolescents. Please refer to the Summaries of Product Characteristics for Viread 245 mg film-coated tablets and Viread 33 mg/g granules.

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

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.

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 Cmax 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.

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 ug/ml.

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 umol/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.

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).

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.

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

Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight >= 35 kg and in 23 HIV-1 infected children aged 2 to < 12 years (see Table 3 below). Tenofovir exposure achieved in these paediatric patients receiving oral daily doses of tenofovir disoproxil 245 mg (as fumarate) or 6.5 mg/kg body weight tenofovir disoproxil (as fumarate) up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg (as fumarate).

Table 3: Mean (+- SD) tenofovir pharmacokinetic parameters by age groups for paediatric patients

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV infected adult patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and severe with CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ng *h/ml in subjects with CrCl > 80 ml/min to respectively 3,064 (30%) ng *h/ml, 6,009 (42%) ng *h/ml and 15,985 (45%) ng *h/ml in patients with mild, moderate and severe renal impairment. The pharmacokinetics of tenofovir in non-haemodialysis adult 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).

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUC0-[?] values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng *h/ml, respectively, in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng *h/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng *h/ml in subjects with severe hepatic impairment.

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.

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.

PHARMACEUTICAL PARTICULARS

List of excipients

Magnesium stearate (E572) Microcrystalline cellulose (E460) Starch pregelatinised

Glycerol triacetate (E1518) Hypromellose (E464) Lactose monohydrate Titanium dioxide (E171)

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 30 film-coated tablets and a silica gel desiccant. The following pack sizes are available: outer cartons containing 1 x 30 film-coated tablet and 3 x 30 film-coated tablet bottles. Not all pack sizes may be marketed.

Special precautions for disposal

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

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Medicinal product by therapeutic areas (dose in mg)	Effects on drug levels Mean percent change in AUC, C m ax , C m in	Recommendation concerning co-administration with 245 mg tenofovir disoproxil (as fumarate)
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors
Atazanavir/Ritonavir (300 q.d./100 q.d./300 q.d.)	Atazanavir: AUC: \| 25% C m ax : \| 28% C m in : \| 26% Tenofovir: AUC: \| 37% C m ax : \| 34% C m in : \| 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: \| 32% C max : - C m in : \| 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: \| 22% C m in : \| 37%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir-associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).
NRTIs
Didanosine	Co-administration of tenofovir disoproxil 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: - C m ax : -	Tenofovir disoproxil fumarate should not be administered concurrently with adefovir dipivoxil (see section 4.4).

Dose and formulation	245 mg film-coated tablet 12 to < 18 years (n = 8)	6.5 mg/kg granules 2 to < 12 years (n = 23)
C m ax (mg/ml)	0.38 +- 0.13	0.24 +- 0.13
AUC tau (mg *h/ml)	3.39 +- 1.22	2.59 +- 1.06

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION