Presentation and Status in Health Basket
Film Coated Tablets
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 the normal dosing schedule. If a patient misses a dose of Atripla by more than 12 hours and it is almost time for the 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 he/she does 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.
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 (AUC) will be approximately 30% lower following administration of Atripla on an empty stomach as compared to the individual component tenofovir disoproxil when taken with food. Data on the clinical translation of the decrease in pharmacokinetic exposure are not available. In virologically suppressed patients, the clinical relevance of this reduction can be expected to be limited.
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 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 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 to patients weighing 50 kg or more, an additional 200 mg/day (800 mg total) of efavirenz may be considered.
Elderly: Atripla should be administered with caution to elderly patients.
Renal impairment: 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 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 mild liver disease (Child-Pugh-Turcotte (CPT), Class A) 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 co-infected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis.
Paediatric population: The safety and efficacy of Atripla in children under the age of 18 years have not been established.
Method of administration Atripla tablets should be swallowed whole with water, once daily. There is no information available regarding the crushing/splitting of the product. It is recommended that the film-coated tablet is not chewed, split or crushed.
For use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
Hypersensitivity to the active substances or to any of the excipients.
Severe hepatic impairment (CPT, Class C).
Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine).
Co-administration with elbasvir/grazoprevir.
Co-administration with voriconazole.
Co-administration with herbal preparations containing St. John’s wort (Hypericum perforatum).
– a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.
– a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
– severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.
Co-administration with drugs that are known to prolong the QTc interval (proarrhythmic).
These drugs include:
– antiarrhythmics of classes IA and III,
– neuroleptics, antidepressive agents,
– certain antibiotics including some agents of the following classes: macrolides,
fluoroquinolones, imidazole and triazole antifungal agents,
– certain non-sedating antihistamines (terfenadine, astemizole),
– certain antimalarials,
See prescribing information for full details.
Co-administration with other medicinal products: As a fixed combination, Atripla should not be administered concomitantly with other medicinal products containing the same active components, emtricitabine or tenofovir disoproxil. Atripla should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin. 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 or with medicinal products containing tenofovir alafenamide.
Co-administration of Atripla and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil that may increase the risk of didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal have been reported.
Co-administration of Atripla and sofosbuvir/velpatasvir or sofosbuvir/ velpatasvir/voxilaprevir is not recommended since plasma concentrations of velpatasvir and voxilaprevir are expected to decrease following co-administration with efavirenz leading to reduced therapeutic effect of sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir.
No data are available on the safety and efficacy of Atripla in combination with other antiretroviral
Concomitant use of Ginkgo biloba extracts is not recommended.
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 this product 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 this product 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: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Effect of food: The administration of this product with food may increase efavirenz exposure and may lead to an increase in frequency of adverse reactions. It is recommended that this product be taken on an empty stomach, preferably at bedtime.
Liver disease: The pharmacokinetics, safety and efficacy of this product have not been established in patients with significant underlying liver disorders. This product is contraindicated in patients with severe hepatic impairment 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 this product 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.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease or persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with this product 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.
Hepatic events: Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. 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 CART are at an increased risk for severe and potentially fatal hepatic adverse reactions.
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 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: This product is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 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. Use of this product should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of this product 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.
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 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.
Skin reactions: Mild-to-moderate rash has been reported with the individual components of this product. 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 Stevens-Johnson syndrome was approximately 0.1%. This product 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. This product is not recommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking an NNRTI.
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 CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
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 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: This product should be avoided in patients with HIV-1 harbouring the K65R, M184V/I or K103N mutation.
Elderly: This product 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 this product.
See prescribing information for full details.
The most frequently reported adverse reactions considered possibly or probably related to Atripla among patients treated up to 48 weeks in study AI266073 were psychiatric disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).
Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures); severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported.
Rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have also been reported. Monitoring of renal function is recommended for patients receiving Atripla.
Discontinuation of Atripla therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis.
The administration of Atripla with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions.
See prescribing information for full details.
As Atripla contains efavirenz, emtricitabine and tenofovir disoproxil, 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 the components, emtricitabine or tenofovir disoproxil. Atripla should not be coadministered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin. 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 or with medicinal products containing tenofovir alafenamide.
Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with efavirenz.
Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observed in vitro and the net effect of co-administration with substrates of these enzymes is not clear.
Efavirenz exposure may be increased when given with medicinal products (for example ritonavir) or food (for example, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds or herbal preparations (for example Ginkgo biloba extracts and St. John’s wort) which induce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John’s wort is contraindicated. Concomitant use of Ginkgo biloba extracts is not recommended.
In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP-mediated interactions involving emtricitabine and tenofovir disoproxil 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 with some screening assays in uninfected and HIV infected subjects receiving efavirenz.
Confirmatory testing by a more specific method such as gas chromatography/ mass spectrometry is recommended in such cases.
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.
Elbasvir/grazoprevir: Co-administration of Atripla with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir.
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.
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.
QT Prolonging Drugs: Atripla is contraindicated with concomitant use of drugs that are known to prolong the QTc interval and could lead to Torsade de Pointes, such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain
non-sedating antihistaminics (terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone.
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.
Didanosine: Co-administration of Atripla and didanosine is not recommended.
Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir: Co-administration of Atripla and sofosbuvir/velpatasvir or sofosbuvir/ velpatasvir/voxilaprevir is not recommended.
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.
Other interactions: Interactions between Atripla or its individual component(s) and other medicinal products are listed in Table 1 at the attached doctor’s leaflet (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, 10 once daily as “q.d.” and once every 8 hours as “q8h”). If available, 90% confidence intervals are shown in parentheses.
See prescribing information for full details.
Pregnancy and Lactation
Pregnancy: This product should not be used during pregnancy unless the clinical condition of the woman requires treatment with efavirenz/ emtricitabine/tenofovir disoproxil fumarate.
Lactation: Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants. A risk to the infants cannot be excluded. Therefore Atripla should not be used during breast-feeding.
As a general rule, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV to the infant.
See prescribing information for full details.
Some patients accidentally taking 600 mg efavirenz twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
If overdose occurs, the patient must be monitored for evidence of toxicity, and
standard supportive treatment applied as necessary.
Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove significant quantities of it from blood.
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.