1. Name Of The Medicinal Product
Atripla 600 mg/200 mg/245 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (as fumarate).
Excipient(s):
Each film-coated tablet contains 1 mmol (23.6 mg) of sodium.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Pink, capsule-shaped, film-coated tablet, of dimensions 20 mm x 10.4 mm, debossed with “123” on one side, plain on the other side.
4. Clinical Particulars
4.1 Therapeutic Indications
Atripla is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Atripla prior to initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).
The demonstration of the benefit of Atripla is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to Atripla (see section 5.1). No data are currently available from clinical studies with Atripla in treatment-naïve or in heavily pretreated patients.
No data are available to support the combination of Atripla and other antiretroviral agents.
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 Atripla is one tablet taken orally once daily.
If a patient misses a dose of Atripla within 12 hours of the time it is usually taken, the patient should take Atripla as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Atripla 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 Atripla, another tablet should be taken. If the patient vomits more than 1 hour after taking Atripla they do not need to take another dose.
It is recommended that Atripla be taken on an empty stomach since food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8). In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous system, bedtime dosing is recommended (see section 4.8).
It is anticipated that tenofovir exposure will be approximately 35% lower following administration of Atripla on an empty stomach as compared to the individual component tenofovir disoproxil fumarate when taken with food (see section 5.2). In virologically suppressed patients, the clinical relevance of this reduction can be expected to be limited (see section 5.1). Further data on the clinical translation of the decrease in pharmacokinetic exposure is awaited.
Where discontinuation of therapy with one of the components of Atripla is indicated or where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal products.
If therapy with Atripla is discontinued, consideration should be given to the long half-life of efavirenz (see section 5.2) and long intracellular half-lives of emtricitabine and tenofovir. Because of interpatient variability in these parameters and concerns regarding development of resistance, HIV treatment guidelines should be consulted, also taking into consideration the reason for discontinuation.
Dose adjustment: If Atripla is co-administered with rifampicin, an additional 200 mg/day (800 mg total) of efavirenz may be considered (see section 4.5).
Special populations
Elderly: Atripla should be administered with caution to elderly patients (see section 4.4).
Renal insufficiency: Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.4 and 5.2).
Hepatic impairment: The pharmacokinetics of Atripla have not been studied in patients with hepatic impairment. Patients with mild liver disease (Child-Pugh-Turcotte (CPT), Class A) may be treated with the normal recommended dose of Atripla (see sections 4.3, 4.4 and 5.2). Patients should be monitored carefully for adverse reactions, especially nervous system symptoms related to efavirenz (see sections 4.3 and 4.4).
If Atripla 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 Atripla in children under the age of 18 years have not been established (see section 5.2).
Method of administration
Atripla tablets should be swallowed whole with water, once daily.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Atripla must not be used in patients with severe hepatic impairment (CPT, Class C) (see section 5.2).
Atripla must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine), because competition for cytochrome P450 (CYP) 3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening undesirable effects (for example, cardiac arrhythmias, prolonged sedation or respiratory depression) (see section 4.5).
Efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations. Since Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and Atripla must not be co-administered (see section 4.5).
Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking Atripla due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5).
4.4 Special Warnings And Precautions For Use
Co-administration with other medicinal products: As a fixed combination, Atripla should not be administered concomitantly with other medicinal products containing any of the same active components, efavirenz, emtricitabine or tenofovir disoproxil fumarate. Due to similarities with emtricitabine, Atripla should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.5). Atripla should not be administered concomitantly with adefovir dipivoxil.
Co-administration of Atripla and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal have been reported.
No data are available on the safety and efficacy of Atripla in combination with other antiretroviral agents.
Switching from a PI-based antiretroviral regimen: Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switch to Atripla may lead to a reduction of the response to the therapy (see section 5.1). These patients should be carefully monitored for rises in viral load and, since the safety profile of efavirenz differs from that of protease inhibitors, for adverse reactions.
Opportunistic infections: Patients receiving Atripla 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 Atripla, 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.
Effect of food: The administration of Atripla with food may increase efavirenz exposure (see section 5.2) and may lead to an increase in frequency of adverse reactions (see section 4.8). It is recommended that Atripla be taken on an empty stomach, preferably at bedtime.
Liver disease: The pharmacokinetics, safety and efficacy of Atripla have not been established in patients with significant underlying liver disorders (see section 5.2). Atripla is contraindicated in patients with severe hepatic impairment (see section 4.3) and not recommended in patients with moderate hepatic impairment. Since efavirenz is principally metabolised by the cytochrome P450 (CYP450) system, caution should be exercised in administering Atripla to patients with mild hepatic impairment. These patients should be carefully monitored for efavirenz adverse reactions, especially nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at periodic intervals (see section 4.2).
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 or persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with Atripla needs to be weighed against the potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered (see section 4.8).
In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended.
Hepatic events: Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be considered for all patients independent of pre-existing hepatic dysfunction or other risk factors.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection: Patients with chronic hepatitis B or C and treated with combination 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 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 Atripla have not been studied 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 an anti-HBV activity when used in antiretroviral combination therapy to control HIV infection. Discontinuation of Atripla 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 Atripla must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Atripla. If appropriate, resumption of anti-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.
Psychiatric symptoms: Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions. In particular, severe depression was more common in those with a history of depression. There have also been post-marketing reports of severe depression, death by suicide, delusions and psychosis-like behaviour. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risk of continued therapy outweighs the benefits (see section 4.8).
Nervous system symptoms: Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mg daily in clinical studies. Dizziness was also seen in clinical studies with emtricitabine and tenofovir disoproxil fumarate. Headache has been reported in clinical studies with emtricitabine (see section 4.8). Nervous system symptoms associated with efavirenz usually begin during the first one or two days of therapy and generally resolve after the first two to four weeks. Patients should be informed that if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms.
Seizures: Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures.
Renal impairment: Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 30 ml/min). Patients with moderate or severe renal impairment require a dose adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.2 and 5.2). Use of Atripla should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of Atripla and nephrotoxic agents (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2) is unavoidable, renal function must be monitored weekly (see section 4.5).
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 Atripla 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 with a history of renal dysfunction or in patients who are at risk for renal dysfunction, 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 < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving Atripla, renal function must be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Since Atripla is a combination product and the dosing interval of the individual components cannot be altered, treatment with Atripla must be interrupted in patients with confirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Where discontinuation of therapy with one of the components of Atripla is indicated or where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil fumarate are available.
Bone: 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 the 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.
Skin reactions: Mild-to-moderate rash has been reported with the individual components of Atripla. The rash associated with the efavirenz component usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with efavirenz (see section 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Atripla must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Atripla is not recommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking an NNRTI.
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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).
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 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.
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.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to 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.
Patients with HIV-1 harbouring mutations: Atripla should be avoided in patients with HIV-1 harbouring the K65R, M184V/I or K103N mutation (see sections 4.1 and 5.1).
Elderly: Atripla has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased hepatic or renal function, therefore caution should be exercised when treating elderly patients with Atripla (see section 4.2).
Excipients: This medicinal product contains 1 mmol (23.6 mg) of sodium per dose which should be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No drug interaction studies have been performed using Atripla. As Atripla contains efavirenz, emtricitabine and tenofovir disoproxil fumarate, any interactions that have been identified with these agents individually may occur with Atripla. Interaction studies with these agents have only been performed in adults.
As a fixed combination, Atripla should not be administered concomitantly with other medicinal products containing any of the components, efavirenz, emtricitabine or tenofovir disoproxil as fumarate. Due to similarities with emtricitabine, Atripla should not be administered concomitantly with other cytidine analogues, such as lamivudine. Atripla should not be administered concomitantly with adefovir dipivoxil.
Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP450 isoenzymes including CYP3A4 (see section 5.2). Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz exposure may also be altered when given with medicinal products or food (for example, grapefruit juice) which affect CYP3A4 activity. 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.
Cannabinoid test interaction: Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received efavirenz. False positive test results have only been observed with the CEDIA DAU Multi-Level THC assay, which is used for screening, and have not been observed with other cannabinoid assays tested including tests used for confirmation of positive results.
Contraindications of concomitant use
Atripla must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious, life-threatening events (see section 4.3).
Voriconazole: Co-administration of standard doses of efavirenz and voriconazole is contraindicated. Since Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and Atripla must not be co-administered (see section 4.3 and Table 1).
St. John's wort (Hypericum perforatum): Co-administration of Atripla and St. John's wort or herbal preparations containing St. John's wort is contraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John's wort due to induction of drug metabolising enzymes and/or transport proteins by St. John's wort. If a patient is already taking St. John's wort, stop St. John's wort, check viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John's wort. The inducing effect of St. John's wort may persist for at least 2 weeks after cessation of treatment (see section 4.3).
Concomitant use not recommended
Atazanavir/ritonavir: Insufficient data are available to make a dosing recommendation for atazanavir/ritonavir in combination with Atripla. Therefore co-administration of atazanavir/ritonavir and Atripla is not recommended (see Table 1).
Didanosine: Co-administration of Atripla 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 Atripla 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 Atripla 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 Atripla and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “
Table 1: Interactions between the individual components of Atripla and other medicinal products
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