1. Name Of The Medicinal Product
Truvada 200 mg/245 mg film-coated tablets
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
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”.
4. Clinical Particulars
4.1 Therapeutic Indications
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).
4.2 Posology And Method Of Administration
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.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Co-administration of other medicinal products: Truvada should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate) or other cytidine analogues, such as lamivudine (see section 4.5). Truvada should not be administered concomitantly with adefovir dipivoxil.
Co-administration of tenofovir disoproxil fumarate and didanosine: Is not recommended. Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations.
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.
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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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
As Truvada contains emtricitabine and tenofovir disoproxil fumarate, any interactions that have been identified with these agents individually may occur with Truvada. Interaction studies have only been performed in adults.
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 “
Table 1: Interactions between the individual components of Truvada and other medicinal products
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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.
4.6 Pregnancy And Lactation
Pregnancy
A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with 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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with both emtricitabine and tenofovir disoproxil fumarate.
4.8 Undesirable Effects
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 (
Table 2: Tabulated summary of adverse reactions associated with the individual components of Truvada based on clinical study and post-marketing experience
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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 fo
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