Atripla 600 mg/200 mg/245 mg filmcoated tablets

Film coated tablet. Pink, capsule shaped, filmcoated tablet, debossed with “123” on one side, plain on the other side.

Atripla is a fixeddose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. It is indicated for the treatment of human immunodeficiency virus1 (HIV1) infection in adults with virologic suppression to HIV1 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. The demonstration of the benefit of Atripla is primarily based on 48week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to Atripla. No data are currently available from clinical studies with Atripla in treatmentnaïve or in heavily pretreated patients. No data are available to support the combination of Atripla and other antiretroviral agents.

Therapy should be initiated by a physician experienced in the management of human immunodeficiency virus (HIV) infection.

Posology

Adults: the recommended dose of Atripla is one tablet taken orally once daily.

Method of administration

It is recommended that Atripla be swallowed whole with water.

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. In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous system, bedtime dosing is recommended.

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. In virologically suppressed patients, the clinical relevance of this reduction can be expected to be limited. Further data on the clinical translation of the decrease in pharmacokinetic exposure is awaited.

Dose adjustment: if Atripla is coadministered with rifampicin, an additional 200 mg/day (800 mg total) of efavirenz is recommended.

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.

Hepatic impairment: the pharmacokinetics of Atripla have not been studied in patients with hepatic impairment. Patients with mildtomoderate liver disease (ChildPughTurcotte (CPT), Grade A or B) may be treated with the normal recommended dose of Atripla. Patients should be monitored carefully for adverse reactions, especially nervous system symptoms related to efavirenz.

If Atripla is discontinued in patients coinfected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis.

It is important to take Atripla on a regular dosing schedule to avoid missing doses. Patients should be told that if they forget to take Atripla, they should take the missed dose right away, unless it is less than 12 hours until the next day's dose. In this case, patients should be told not to take the missed dose and to take their next dose at the usual time.

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 and long intracellular half-lives of tenofovir and emtricitabine. 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.

Children and adolescents: Atripla is not recommended for use in children below 18 years of age due to lack of data on safety and efficacy.

Elderly: insufficient numbers of elderly patients have been evaluated in clinical studies of the components of Atripla to determine whether they respond differently than younger patients. Caution should be exercised when prescribing Atripla to the elderly, keeping in mind the greater frequency of decreased hepatic or renal function in these patients.

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

Atripla must not be used in patients with severe hepatic impairment (CPT Grade C).

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 lifethreatening undesirable effects (for example, cardiac arrhythmias, prolonged sedation or respiratory depression).

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.

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 coadministered.

General: 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. Atripla should not be administered concomitantly with adefovir dipivoxil.

Currently available data indicate a trend that in patients on a PIbased antiretroviral regimen the switch to Atripla may lead to a reduction of the response to the therapy  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.

Liver disease: the pharmacokinetics, safety and efficacy of Atripla have not been established in patients with significant underlying liver disorders. Atripla is contraindicated in patients with severe hepatic impairment. Since efavirenz is principally metabolised by the cytochrome P450 (CYP450) system, caution should be exercised in administering Atripla to patients with mildtomoderate liver disease. 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.

Patients with preexisting 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.

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended.

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. Limited clinical experience suggests that emtricitabine and tenofovir disoproxil fumarate have an antiHBV 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 followup 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.

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. 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. 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. 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. 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.

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.

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, consideration must 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 reevaluated 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.

Skin reactions: mildtomoderate 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. The incidence of erythema multiforme or StevensJohnson syndrome was approximately 0.1%. Atripla must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. Patients who discontinued treatment with other nonnucleoside reverse transcriptase inhibitors due to rash may be at higher risk of developing rash during treatment with Atripla.

Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The longterm consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PI) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drugrelated 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.

Effect of food: the administration of Atripla with food may increase efavirenz exposure and may lead to an increase in frequency of adverse reactions. It is recommended that Atripla be taken on an empty stomach, preferably at bedtime.

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 lateonset 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 followup 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 pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). 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.

Bone: in a 144week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviralnaïve 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. If bone abnormalities are suspected then appropriate consultation should be obtained.

Other antiretroviral agents: no data are available on the safety and efficacy of Atripla in combination with other antiretroviral agents.

Didanosine: coadministration of Atripla and didanosine is not recommended since exposure to didanosine is significantly increased following coadministration with tenofovir disoproxil fumarate.

Patients with HIV1 harbouring mutations: Atripla should be avoided in patients with HIV1 harbouring the K65R, M184V/I or K103N mutation.

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.

Assessment of adverse reactions for the fixed combination Atripla is based on experience from:

• a 48week clinical study of Atripla (see Table 2)
• a clinical study in which efavirenz, emtricitabine and tenofovir disoproxil fumarate were co-administered (see Table 3)
• clinical study and postmarketing experience with the individual components of Atripla (see Table 4).

In Tables 2, 3 and 4 undesirable effects are presented in order of decreasing seriousness within each frequency grouping. Frequencies are defined as very common ( 1/10), common ( 1/100, < 1/10) or uncommon ( 1/1,000, < 1/100).

Adverse reactions from clinical study experience with Atripla

In a 48week open-label randomised clinical study in HIV infected patients with successful virological suppression on their current antiretroviral regimen, patients either changed to Atripla (n=203) or continued on their original antiretroviral treatment regimen (n=97). Treatment-emergent adverse reactions considered possibly or probably related to study drugs reported in patients who received Atripla in study AI266073 are listed by body system organ class and frequency in Table 2.

Table 2: All treatment-emergent adverse reactions considered possibly or probably related to Atripla reported in study AI266073 (over 48 weeks)

Adverse reactions from clinical study experience with efavirenz + emtricitabine + tenofovir disoproxil fumarate

The following data are derived from a clinical study (GS01934) in which efavirenz, emtricitabine and tenofovir disoproxil fumarate were coadministered without regard to food as individual formulations or as a dual fixed combination of emtricitabine and tenofovir disoproxil fumarate with efavirenz.

Selected treatmentemergent adverse reactions considered possibly or probably related to study drugs from this study reported in patients after 144 weeks of treatment are listed by body system organ class and frequency in Table 3.

Table 3: Selected treatmentemergent adverse reactions considered possibly or probably related to study drugs (efavirenz, emtricitabine and tenofovir disoproxil fumarate) in clinical study GS01934 over 144 weeks

Laboratory test abnormalities: Liver enzymes: in a 144week clinical study (GS01934), elevations of aspartate aminotransferase (AST > 5 times ULN (upper limit of normal)) and of alanine aminotransferase (ALT > 5 times ULN) were reported in 3% and 2% of patients treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate (n=257) and 3% and 3% of patients treated with efavirenz and fixeddose zidovudine/lamivudine (n=254), respectively.

Adverse reactions associated with the individual components of Atripla

The adverse reactions from clinical study and postmarketing experience with the individual components of Atripla in antiretroviral combination therapy are listed in Table 4 below by body system organ class and frequency.

The most notable adverse reactions that have been reported in clinical studies with efavirenz are rash and nervous system symptoms. The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions. There have been post-marketing reports in association with tenofovir disoproxil fumarate of renal and urinary disorders including renal failure, proximal tubulopathy (including Fanconi syndrome), acute tubular necrosis and nephrogenic diabetes insipidus.

Table 4: Adverse reactions associated with the individual components of Atripla based on clinical study and postmarketing safety experience

* These adverse reactions have been identified through postmarketing safety surveillance and the frequency is not known.

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy and hypophosphataemia. These events are not considered to be causally associated with tenofovir disoproxil fumarate therapy in the absence of proximal renal tubulopathy.

Rash with efavirenz: rashes are usually mildtomoderate maculopapular skin eruptions that occur within the first two weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with efavirenz within one month. In clinical studies, 1.7% of patients treated with efavirenz discontinued therapy because of rash. Efavirenz can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is restarted.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the nonnucleoside reverse transcriptase inhibitor (NNRTI) class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mildtomoderate rash while receiving therapy with efavirenz, and two discontinued because of rash.

Psychiatric symptoms with efavirenz: patients with a history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse reactions listed in the efavirenz column of Table 4 with the frequency of events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation.

Nervous system symptoms with efavirenz: in clinical controlled studies, nervous system symptoms of moderatetosevere intensity were experienced by 19.4% of patients compared to 9.0% of patients receiving control regimens. These symptoms were severe in 2.0% of patients receiving efavirenz 600 mg daily and in 1.3% of patients receiving control regimens. In clinical studies 2.1% of patients treated with 600 mg of efavirenz discontinued therapy because of nervous system symptoms.

Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first two to four weeks. Nervous system symptoms may occur more frequently when efavirenz is taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms.

Analysis of longterm data from a clinical study (median followup 180 weeks, 102 weeks and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of newonset nervous system symptoms among efavirenztreated patients were generally similar to those in the control arm.

Lactic acidosis: lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues.

HIV/HBV or HCV coinfected patients: Only a limited number of patients were coinfected with HBV (n=13) or HCV (n=26) in study GS01934. The adverse reaction profile of efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients coinfected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without coinfection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV infected population.

Amylase: in clinical studies, asymptomatic increases in serum amylase levels > 1.5 times the ULN were seen in 10% of patients treated with efavirenz and 6% of patients treated with control regimens. The clinical significance of asymptomatic increases in serum amylase is unknown.

Lipids, lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulinresistance, hyperglycaemia and hyperlactataemia.

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 intraabdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump)

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

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 MultiLevel 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.

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.

Gilead Sciences Ltd

POM

08 June 2009