Truvada 200 mg/245 mg film-coated tablets

Each film-coated tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).

Excipient(s):

Each tablet contains 96 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Blue, capsule-shaped, film-coated tablet, of dimensions 19 mm x 8.5 mm, debossed on one side with “GILEAD” and on the other side with “701”.

Truvada is a fixed dose combination of emtricitabine and tenofovir disoproxil fumarate. It is indicated in antiretroviral combination therapy for the treatment of HIV-1 infected adults aged 18 years and over.

The demonstration of the benefit of the combination emtricitabine and tenofovir disoproxil fumarate in antiretroviral therapy is based solely on studies performed in treatment-naïve patients (see section 5.1).

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

Posology

Adults: The recommended dose of Truvada is one tablet, taken orally, once daily. In order to optimise the absorption of tenofovir, it is recommended that Truvada should be taken with food. Even a light meal improves absorption of tenofovir from the combination tablet (see section 5.2).

Where discontinuation of therapy with one of the components of Truvada is indicated or where dose modification is necessary, separate preparations of emtricitabine and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal products.

If a patient misses a dose of Truvada within 12 hours of the time it is usually taken, the patient should take Truvada with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Truvada 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 Truvada, another tablet should be taken. If the patient vomits more than 1 hour after taking Truvada 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. However, no adjustment in the recommended daily dose for adults should be required unless there is evidence of renal insufficiency.

Renal impairment: Emtricitabine and tenofovir are eliminated by renal excretion and the exposure to emtricitabine and tenofovir increases in patients with renal dysfunction. There are limited data on the safety and efficacy of Truvada in 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 patients with renal impairment Truvada should only be used if the potential benefits of treatment are considered to outweigh the potential risks. Patients with renal impairment may require close monitoring of renal function (see section 4.4). Dose interval adjustments are recommended for patients with creatinine clearance between 30 and 49 ml/min. These dose adjustments have not been confirmed in clinical studies and the clinical response to treatment should be closely monitored in these patients (see sections 4.4 and 5.2).

Mild renal impairment (creatinine clearance 50-80 ml/min): Limited data from clinical studies support once daily dosing of Truvada in patients with mild renal impairment (see section 4.4).

Moderate renal impairment (creatinine clearance 30-49 ml/min): Administration of Truvada every 48 hours is recommended, based on modelling of single-dose pharmacokinetic data for emtricitabine and tenofovir disoproxil fumarate in non-HIV infected subjects with varying degrees of renal impairment (see section 4.4).

Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients: Truvada is not recommended for patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis because appropriate dose reductions cannot be achieved with the combination tablet.

Hepatic impairment: The pharmacokinetics of Truvada and emtricitabine have not been studied in patients with hepatic impairment. The pharmacokinetics of tenofovir have been studied in patients with hepatic impairment and no dose adjustment is required for tenofovir disoproxil fumarate in these patients. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for Truvada in patients with hepatic impairment (see sections 4.4 and 5.2).

If Truvada is discontinued in patients co-infected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Paediatric population: The safety and efficacy of Truvada in children under the age of 18 years have not been established (see section 5.2).

Method of administration

Truvada tablets should be taken once daily, orally with food.

If patients have difficulty in swallowing, Truvada can be disintegrated in approximately 100 ml of water, orange juice or grape juice and taken immediately.

Hypersensitivity to the active substances or to any of the excipients.

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.

Triple nucleoside therapy: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. There is close structural similarity between lamivudine and emtricitabine and similarities in the pharmacokinetics and pharmacodynamics of these two agents. Therefore, the same problems may be seen if Truvada is administered with a third nucleoside analogue.

Opportunistic infections: Patients receiving Truvada or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Transmission of HIV: Patients must be advised that antiretroviral therapies, including Truvada, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.

Renal impairment: Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. 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).

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Truvada and renal function (creatinine clearance and serum phosphate) is also monitored every four weeks during the first year 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.

Patients with renal impairment (creatinine clearance < 80 ml/min), including haemodialysis patients: Renal safety with Truvada has only been studied to a very limited degree in patients with impaired renal function (creatinine clearance < 80 ml/min). Dose interval adjustments are recommended for patients with creatinine clearance 30-49 ml/min (see section 4.2). Limited clinical study data suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Furthermore, in a small clinical study, a subgroup of patients with creatinine clearance between 50 and 60 ml/min who received tenofovir disoproxil fumarate in combination with emtricitabine every 24 hours had a 2-4-fold higher exposure to tenofovir and worsening of renal function (see section 5.2). Therefore, a careful benefit-risk assessment is needed when Truvada is used in patients with creatinine clearance < 60 ml/min, and renal function should be closely monitored. In addition, the clinical response to treatment should be closely monitored in patients receiving Truvada at a prolonged dosing interval. The use of Truvada is not recommended in patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis since appropriate dose reductions cannot be achieved with the combination tablet (see sections 4.2 and 5.2).

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving Truvada, 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 Truvada in patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).

Use of Truvada should be avoided with concurrent or recent use of a nephrotoxic medicinal product (see section 4.5). If concomitant use of Truvada and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

Patients with HIV-1 harbouring mutations: Truvada should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see section 5.1).

Bone effects: In a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in bone mineral density of the hip and spine were observed in both treatment groups. Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in bone mineral density 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). If bone abnormalities are suspected then appropriate consultation should be obtained.

Patients with HIV and hepatitis B or C virus co-infection: Patients with chronic hepatitis B or C 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.

The safety and efficacy of Truvada have not been established for the treatment of chronic HBV infection. Emtricitabine and tenofovir individually and in combination have shown activity against HBV in pharmacodynamic studies (see section 5.1). Limited clinical experience suggests that emtricitabine and tenofovir disoproxil fumarate have anti-HBV activity when used in antiretroviral combination therapy to control HIV infection.

Discontinuation of Truvada 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 Truvada should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. 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 disease: The safety and efficacy of Truvada have not been established in patients with significant underlying liver disorders. The pharmacokinetics of Truvada and emtricitabine have not been studied in patients with hepatic impairment. The pharmacokinetics of tenofovir have been studied in patients with hepatic impairment and no dose adjustment is required in these patients. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for Truvada in patients with hepatic impairment (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 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.

Lipodystrophy: Combination antiretroviral therapy 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-naïve patients indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered with lamivudine and efavirenz.

Mitochondrial dysfunction: 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 reactions 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.

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (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.

HIV infected patients co-infected with hepatitis B virus may experience acute exacerbations of hepatitis associated with immune reactivation syndrome following the initiation of antiretroviral therapy.

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

Elderly: Truvada 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 Truvada.

Truvada contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each medicinal product dosed alone.

In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP450 mediated interactions involving emtricitabine and tenofovir disoproxil fumarate with other medicinal products is low.

Concomitant use not recommended:

Due to similarities with emtricitabine, Truvada should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4).

As a fixed combination, Truvada should not be administered concomitantly with other medicinal products containing any of the components, emtricitabine or tenofovir disoproxil fumarate.

Truvada should not be administered concomitantly with adefovir dipivoxil.

Didanosine: The co-administration of Truvada and didanosine is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Truvada with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of Truvada 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).

Other interactions:

Interactions between the components of Truvada and protease inhibitors and nucleoside reverse transcriptase 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.”). If available, 90% confidence intervals are shown in parentheses.

Table 1: Interactions between the individual components of Truvada and other medicinal products

Studies conducted with other medicinal products:

Emtricitabine: In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation.

There are no clinically significant pharmacokinetic interactions when emtricitabine is co-administered with indinavir, zidovudine, stavudine or famciclovir.

Tenofovir disoproxil fumarate: Co-administration of lamivudine, indinavir, efavirenz, nelfinavir or saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, adefovir dipivoxil or the hormonal contraceptive norgestimate/ethinyl oestradiol with tenofovir disoproxil fumarate did not result in any clinically significant pharmacokinetic interaction.

Truvada: Co-administration of tacrolimus with Truvada did not result in any clinically significant pharmacokinetic interaction.

Pregnancy

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

Breast-feeding

Emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants. Therefore Truvada should not be used during breast-feeding.

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

Fertility

No human data on the effect of Truvada are available. Animal studies do not indicate harmful effects of emtricitabine or tenofovir disoproxil fumarate on fertility.

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

a. Summary of the safety profile

The most frequently reported adverse reactions considered possibly or probably related to emtricitabine and/or tenofovir disoproxil fumarate were nausea (12%) and diarrhoea (7%) in an open-label randomised clinical trial (GS-01-934, see section 5.1). The safety profile of emtricitabine and tenofovir disoproxil fumarate in this study was consistent with the previous experience with these agents when each was administered with other antiretroviral agents.

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 Truvada (see section 4.4).

Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with tenofovir disoproxil fumarate and emtricitabine (see sections 4.4 and 4.8c).

Co-administration of tenofovir disoproxil fumarate 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 Truvada therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4).

b. Tabulated summary of adverse reactions

The adverse reactions considered at least possibly related to treatment with the components of Truvada from clinical trial and post-marketing experience are listed in Table 2, 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 the individual components of Truvada based on clinical study and post-marketing experience

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 See section c. Description of selected adverse reactions for more details.

³ Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.

⁴ This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials in adults or paediatric HIV clinical trials for emtricitabine or in randomised controlled clinical trials or the tenofovir disoproxil fumarate expanded access program for tenofovir disoproxil fumarate. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical trials (n = 1,563) or tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program (n = 7,319).

c. Description of selected adverse reactions

Renal impairment: As Truvada may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8a).

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: Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

Combination antiretroviral therapy 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).

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (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 combination antiretroviral therapy (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).

d. Paediatric population

Insufficient safety data are available for children below 18 years of age. Truvada is not recommended in this population (see section 4.2).

e. Other special population(s)

Elderly: Truvada 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 Truvada (see section 4.4).

Patients with renal impairment: Since tenofovir disoproxil fumarate can cause renal toxicity, close monitoring of renal function is recommended in any patient with renal impairment treated with Truvada (see sections 4.2, 4.4 and 5.2).

HIV/HBV or HCV co-infected patients: Only a limited number of patients were co-infected with HBV (n=13) or HCV (n=26) in study GS-01-934. The adverse reaction profile of emtricitabine and tenofovir disoproxil fumarate in patients co-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without co-infection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV infected population.

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 treatment (see section 4.4).

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

Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by haemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations. ATC code: J05AR03

Mechanism of action and pharmacodynamic effects: Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Both emtricitabine and tenofovir have activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain termination.

Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.

Antiviral activity in vitro: Synergistic antiviral activity was observed with the combination of emtricitabine and tenofovir in vitro. Additive to synergistic effects were observed in combination studies with protease inhibitors, and with nucleoside and non-nucleoside analogue inhibitors of HIV reverse transcriptase.

Resistance: Resistance has been seen in vitro and in some HIV-1 infected patients due to the development of the M184V/I mutation with emtricitabine or the K65R mutation with tenofovir. No other pathways of resistance to emtricitabine or tenofovir have been identified. Emtricitabine-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and zidovudine. The K65R mutation can also be selected by abacavir or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil fumarate should be avoided in patients with HIV-1 harbouring the K65R mutation.

Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate.

In vivo resistance (antiretroviral-naïve patients): In an open-label randomised clinical study (GS-01-934) in antiretroviral-naïve patients, genotyping was performed on plasma HIV-1 isolates from all patients with confirmed HIV RNA > 400 copies/ml at weeks 48, 96 or 144 or at the time of early study drug discontinuation. As of week 144:

• The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in the emtricitabine/tenofovir disoproxil fumarate/efavirenz group and in 10/29 (34.5%) isolates analysed from the lamivudine/zidovudine/efavirenz group (p-value < 0.05, Fisher's Exact test comparing the emtricitabine+tenofovir disoproxil fumarate group to the lamivudine/zidovudine group among all subjects).

• No virus analysed contained the K65R mutation.

• Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from 13/19 (68%) patients in the emtricitabine/tenofovir disoproxil fumarate/efavirenz group and in virus from 21/29 (72%) patients in the comparative group.

Clinical efficacy and safety: In an open-label randomised clinical study (GS-01-934), antiretroviral-naïve HIV-1 infected patients received either a once daily regimen of emtricitabine, tenofovir disoproxil fumarate and efavirenz (n=255) or a fixed combination of lamivudine and zidovudine (Combivir) administered twice daily and efavirenz once daily (n=254). Patients in the emtricitabine and tenofovir disoproxil fumarate group were given Truvada and efavirenz from week 96 to week 144. At baseline the randomised groups had similar median plasma HIV-1 RNA (5.02 and 5.00 log₁₀ copies/ml) and CD4 counts (233 and 241 cells/mm³). The primary efficacy endpoint for this study was the achievement and maintenance of confirmed HIV-1 RNA concentrations < 400 copies/ml over 48 weeks. Secondary efficacy analyses over 144 weeks included the proportion of patients with HIV-1 RNA concentrations < 400 or < 50 copies/ml, and change from baseline in CD4 cell count.

The 48-week primary endpoint data showed that the combination of emtricitabine, tenofovir disoproxil fumarate and efavirenz provided superior antiviral efficacy as compared with the fixed combination of lamivudine and zidovudine (Combivir) with efavirenz as shown in Table 3. The 144 week secondary endpoint data are also presented in Table 3.

Table 3: 48- and 144-week efficacy data from study GS-01-934 in which emtricitabine, tenofovir disoproxil fumarate and efavirenz were administered to antiretroviral-naïve patients with HIV-1 infection

* Patients receiving emtricitabine, tenofovir disoproxil fumarate and efavirenz were given Truvada plus efavirenz from week 96 to 144.

** The p-value based on the Cochran-Mantel-Haenszel Test stratified for baseline CD4 cell count

TLOVR=Time to Loss of Virologic Response

a: Van Elteren Test

In a separate randomised clinical study (M02-418), one hundred and ninety antiretroviral-naïve adults were also treated once daily with emtricitabine and tenofovir disoproxil fumarate in combination with lopinavir/ritonavir given once or twice daily. At 48 weeks, 70% and 64% of patients demonstrated HIV-1 RNA < 50 copies/ml with the once and twice daily regimens of lopinavir/ritonavir, respectively. The mean changes in CD4 cell count from baseline were +185 cells/mm³ and +196 cells/mm³ with the once and twice daily regimens of lopinavir/ritonavir, respectively.

Limited clinical experience in patients co-infected with HIV and HBV suggests that treatment with emtricitabine or tenofovir disoproxil fumarate in antiretroviral combination therapy to control HIV infection also results in a reduction in HBV DNA (3 log₁₀ reduction or 4 to 5 log₁₀ reduction, respectively) (see section 4.4).

Paediatric population: The safety and efficacy of Truvada in children under the age of 18 years have not been established.

Absorption: The bioequivalence of one Truvada film-coated tablet with one emtricitabine 200 mg hard capsule and one tenofovir disoproxil fumarate 245 mg film-coated tablet was established following single dose administration to fasting healthy subjects. Following oral administration of Truvada to healthy subjects, emtricitabine and tenofovir disoproxil fumarate are rapidly absorbed and tenofovir disoproxil fumarate is converted to tenofovir. Maximum emtricitabine and tenofovir concentrations are observed in serum within 0.5 to 3.0 h of dosing in the fasted state. Administration of Truvada with food resulted in a delay of approximately three quarters of an hour in reaching maximum tenofovir concentrations and increases in tenofovir AUC and C_max of approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In order to optimise the absorption of tenofovir, it is recommended that Truvada should be taken with food.

Distribution: Following intravenous administration the volume of distribution of emtricitabine and tenofovir was approximately 1.4 l/kg and 800 ml/kg, respectively. After oral administration of emtricitabine or tenofovir disoproxil fumarate, emtricitabine and tenofovir are widely distributed throughout the body. In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 µg/ml. In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/ml.

Biotransformation: There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation. Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.

Elimination: Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 ml/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

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. The apparent clearance of tenofovir averaged approximately 307 ml/min. Renal clearance has been estimated to be 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 elimination half-life of tenofovir is approximately 12 to 18 hours.

Age: Pharmacokinetic studies have not been performed with emtricitabine or tenofovir in the elderly (over 65 years of age).

Gender: Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

Ethnicity: No clinically important pharmacokinetic difference due to ethnicity has been identified for emtricitabine. The pharmacokinetics of tenofovir have not been specifically studied in different ethnic groups.

Paediatric population: In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months up to 18 years) are similar to those seen in adults. Pharmacokinetic studies have not been performed with tenofovir in children and adolescents (under 18 years of age).

Renal impairment: Limited pharmacokinetic data are available for emtricitabine and tenofovir after co-administration of separate preparations or as Truvada in patients with renal impairment. Pharmacokinetic parameters were mainly determined following administration of single doses of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected patients with varying degrees of renal impairment. The degree of renal impairment was defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild impairment with CrCl = 50-79 ml/min; moderate impairment with CrCl = 30-49 ml/min and severe impairment with CrCl = 10-29 ml/min).

The mean (%CV) emtricitabine drug exposure increased from 12 (25%) µg•h/ml in subjects with normal renal function, to 20 (6%) µg•h/ml, 25 (23%) µg•h/ml and 34 (6%) µg•h/ml, in patients with mild, moderate and severe renal impairment, respectively.

The mean (%CV) tenofovir drug exposure increased from 2,185 (12%) ng•h/ml in patients with normal renal function, to 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, respectively.

The increased dose interval for Truvada in patients with moderate renal impairment is expected to result in higher peak plasma concentrations and lower C_min levels as compared to patients with normal renal function. The clinical implications of this are unknown.

In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug exposures substantially increased over 72 hours to 53 (19%) µg•h/ml of emtricitabine, and over 48 hours to 42,857 (29%) ng•h/ml of tenofovir.

It is recommended that the dosing interval for Truvada is modified in patients with creatinine clearance between 30 and 49 ml/min. Truvada is not suitable for patients with CrCl < 30 ml/min or for those on haemodialysis (see section 4.2).

A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics of tenofovir disoproxil fumarate in combination with emtricitabine in HIV infected patients with renal impairment. A subgroup of patients with baseline creatinine clearance between 50 and 60 ml/min, receiving once daily dosing, had a 2-4-fold increase in tenofovir exposure and worsening renal function.

Hepatic impairment: The pharmacokinetics of Truvada have not been studied in patients with hepatic impairment. However, it is unlikely that a dose adjustment would be required for Truvada in patients with hepatic impairment.

The pharmacokinetics of emtricitabine have not been studied in non-HBV infected subjects with varying degrees of hepatic insufficiency. In general, emtricitabine pharmacokinetics in HBV infected subjects were similar to those in healthy subjects and in HIV infected subjects.

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected 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 C_max and AUC_0- 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.

Tenofovir disoproxil fumarate: Non-clinical safety pharmacology studies on tenofovir disoproxil fumarate reveal no special hazard for humans. 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 toxicity 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.

Combination of emtricitabine and tenofovir disoproxil fumarate: Genotoxicity and repeated dose toxicity studies of one month or less with the combination of these two components found no exacerbation of toxicological effects compared to studies with the separate components.

Tablet core:

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Pregelatinised starch (gluten free)

Film-coating:

Glycerol triacetate (E1518)

Hypromellose (E464)

Indigo carmine aluminium lake (E132)

Lactose monohydrate

Titanium dioxide (E171)

Not applicable.

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.

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

Gilead Sciences International Limited

Cambridge

CB21 6GT

United Kingdom

EU/1/04/305/002

Date of first authorisation: 21 February 2005

Date of latest renewal: 20 January 2010

07/2011

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