ATRIPLA 600mg / 200mg / 245mg film-coated tablets medication leaflet

Atripla 600 mg/200 mg/245 mg film-coated tablets

Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg oftenofovir disoproxil (as fumarate).

For the full list of excipients, see section 6.1

Film-coated tablet.

Pink, capsule-shaped, film-coated tablet, of dimensions 20 mm x 10.4 mm, debossed with “123” onone side, plain on the other side.

Atripla is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. It isindicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their currentcombination antiretroviral therapy for more than three months. Patients must not have experiencedvirological failure on any prior antiretroviral therapy and must be known not to have harboured virusstrains 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 inwhich 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 intreatment-naïve 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 HIV infection.

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 shouldtake 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 themissed 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 patientvomits 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 efavirenzexposure 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 nervoussystem, bedtime dosing is recommended (see section 4.8).

It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower followingadministration of Atripla on an empty stomach as compared to the individual component tenofovirdisoproxil when taken with food (see section 5.2). Data on the clinical translation of the decrease inpharmacokinetic exposure are not available. In virologically suppressed patients, the clinicalrelevance of this reduction can be expected to be limited (see section 5.1).

Where discontinuation of therapy with one of the components of Atripla is indicated or where dosemodification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxilare 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 ofinterpatient variability in these parameters and concerns regarding development of resistance, HIVtreatment 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, anadditional 200 mg/day (800 mg total) of efavirenz may be considered (see section 4.5).

Atripla should be administered with caution to elderly patients (see section 4.4).

Atripla is not recommended for patients with moderate or severe renal impairment (creatinineclearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require doseinterval adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with thecombination tablet (see sections 4.4 and 5.2).

The pharmacokinetics of Atripla have not been studied in patients with hepatic impairment. Patientswith mild liver disease (Child-Pugh-Turcotte (CPT), Class A) may be treated with the normalrecommended dose of Atripla (see sections pct. 4.3, pct. 4.4 and 5.2). Patients should be monitored carefullyfor adverse reactions, especially nervous system symptoms related to efavirenz (see sections 4.3and 4.4).

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

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

Atripla tablets should be swallowed whole with water, once daily.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Severe hepatic impairment (CPT, Class C) (see section 5.2).

Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil,or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine).

Competition for cytochrome P450 (CYP) 3A4 by efavirenz could result in inhibition of metabolismand create the potential for serious and/or life-threatening adverse reactions (for example, cardiacarrhythmias, prolonged sedation or respiratory depression) (see section 4.5).

Co-administration with elbasvir/grazoprevir due to the expected significant decreases in plasmaconcentrations of elbasvir and grazoprevir. This effect is due to induction of CYP3A4 or P-gp byefavirenz and may result in loss of therapeutic effect of elbasvir/grazoprevir (see section 4.5).

Co-administration with voriconazole. Efavirenz significantly decreases voriconazole plasmaconcentrations while voriconazole also significantly increases efavirenz plasma concentrations. Since

Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered (see section 4.5).

Co-administration with herbal preparations containing St. John’s wort (Hypericum perforatum) due tothe risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5).

Administration to patients with:

- a family history of sudden death or of congenital prolongation of the QTc interval onelectrocardiograms, or with any other clinical condition known to prolong the QTc interval.

- a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or withcongestive 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),

- cisapride,

- flecainide,

- certain antimalarials,

- methadone (see sections 4.4, 4.5 and 5.1).

Co-administration with other medicinal products

As a fixed combination, Atripla should not be administered concomitantly with other medicinalproducts containing the same active components, emtricitabine or tenofovir disoproxil. Atripla shouldnot be co-administered with products containing efavirenz unless needed for dose adjustment e.g. withrifampicin (see section 4.2). Due to similarities with emtricitabine, Atripla should not be administeredconcomitantly with other cytidine analogues, such as lamivudine (see section 4.5). Atripla should notbe administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofoviralafenamide.

Co-administration of Atripla and didanosine is not recommended (see section 4.5).

Co-administration of Atripla and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is notrecommended since plasma concentrations of velpatasvir and voxilaprevir are expected to decreasefollowing co-administration with efavirenz leading to reduced therapeutic effect ofsofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.5).

No data are available on the safety and efficacy of Atripla in combination with other antiretroviralagents.

Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5).

Switching from a PI-based antiretroviral regimen

Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switchto Atripla may lead to a reduction of the response to the therapy (see section 5.1). These patientsshould be carefully monitored for rises in viral load and, since the safety profile of efavirenz differsfrom that of protease inhibitors, for adverse reactions.

Patients receiving Atripla or any other antiretroviral therapy may continue to develop opportunisticinfections and other complications of HIV infection, and therefore should remain under close clinicalobservation by physicians experienced in the treatment of patients with HIV associated diseases.

While effective viral suppression with antiretroviral therapy has been proven to substantially reducethe risk of sexual transmission, a residual risk cannot be excluded. Precautions to preventtransmission should be taken in accordance with national guidelines.

The administration of Atripla with food may increase efavirenz exposure (see section 5.2) and maylead to an increase in frequency of adverse reactions (see section 4.8). It is recommended that Atriplabe taken on an empty stomach, preferably at bedtime.

The pharmacokinetics, safety and efficacy of Atripla have not been established in patients withsignificant underlying liver disorders (see section 5.2). Atripla is contraindicated in patients withsevere hepatic impairment (see section 4.3) and not recommended in patients with moderate hepaticimpairment. Since efavirenz is principally metabolised by the CYP system, caution should beexercised in administering Atripla to patients with mild hepatic impairment. These patients should becarefully monitored for efavirenz adverse reactions, especially nervous system symptoms. Laboratorytests 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 increasedfrequency of liver function abnormalities during combination antiretroviral therapy (CART) andshould be monitored according to standard practice. If there is evidence of worsening liver disease orpersistent elevations of serum transaminases to greater than 5 times the upper limit of the normalrange, the benefit of continued therapy with Atripla needs to be weighed against the potential risks ofsignificant liver toxicity. In such patients, interruption or discontinuation of treatment must beconsidered (see section 4.8).

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

Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic diseaseor other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be considered forall 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 andpotentially 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 Summaryof 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 inpharmacodynamic studies (see section 5.1). Limited clinical experience suggests that emtricitabineand tenofovir disoproxil have an anti-HBV activity when used in antiretroviral combination therapy tocontrol HIV infection. Discontinuation of Atripla therapy in patients co-infected with HIV and HBVmay 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-upfor 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, treatmentdiscontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepaticdecompensation.

QTc Prolongation

QTc prolongation has been observed with the use of efavirenz (see sections 4.5 and 5.1). For patientsat increased risk of Torsade de Pointes or who are receiving drugs with a known risk for Torsade de

Pointes, consider alternatives to Atripla.

Psychiatric symptoms

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with aprior history of psychiatric disorders appear to be at greater risk of serious psychiatric adversereactions. 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,psychosis-like behaviour, and catatonia. Patients should be advised that if they experience symptomssuch as severe depression, psychosis or suicidal ideation, they should contact their doctor immediatelyto assess the possibility that the symptoms may be related to the use of efavirenz, and if so, todetermine 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 andabnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mgdaily in clinical studies. Dizziness was also seen in clinical studies with emtricitabine and tenofovirdisoproxil. 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 oftherapy and generally resolve after the first two to four weeks. Patients should be informed that if theydo occur, these common symptoms are likely to improve with continued therapy and are not predictiveof subsequent onset of any of the less frequent psychiatric symptoms.

Convulsions have been observed in patients receiving efavirenz, generally in the presence of a knownmedical history of seizures. Patients who are receiving concomitant anticonvulsant medicinalproducts primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, mayrequire periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasmaconcentrations 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.

Atripla is not recommended for patients with moderate or severe renal impairment (creatinineclearance < 50 ml/min). Patients with moderate or severe renal impairment require a dose adjustmentof emtricitabine and tenofovir disoproxil 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 anephrotoxic 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).

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatorydrugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factorsfor renal dysfunction. If Atripla is co-administered with an NSAID, renal function should bemonitored adequately.

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinicalpractice (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 after two tofour weeks of treatment, after three months of treatment and every three to six months thereafter inpatients without renal risk factors. In patients with a history of renal dysfunction or in patients whoare at risk of renal dysfunction, a more frequent monitoring of renal function is required.

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min inany patient receiving Atripla, renal function must be re-evaluated within one week, includingmeasurements 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 theindividual components cannot be altered, treatment with Atripla must be interrupted in patients withconfirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl(0.32 mmol/l). Interrupting treatment with Atripla should also be considered in case of progressivedecline of renal function when no other cause has been identified. Where discontinuation of therapywith one of the components of Atripla is indicated or where dose modification is necessary, separatepreparations of efavirenz, emtricitabine and tenofovir disoproxil are available.

Bone effects

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone painand, which can infrequently contribute to fractures may be associated with tenofovirdisoproxil-induced proximal renal tubulopathy (see section 4.8).

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD). In a 144-weekcontrolled clinical study that compared tenofovir disoproxil with stavudine in combination withlamivudine and efavirenz in antiretroviral-naïve patients, small decreases in BMD of the hip and spinewere observed in both treatment groups. Decreases in bone mineral density of spine and changes inbone biomarkers from baseline were significantly greater in the tenofovir disoproxil treatment group at144 weeks. Decreases in bone mineral density of the hip were significantly greater in this group until96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant boneabnormalities over 144 weeks in this study.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seenin patients treated with tenofovir disoproxil as part of a regimen containing a boosted proteaseinhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and thelimitations of long term data on the impact of tenofovir disoproxil on bone health and fracture risk,alternative treatment regimens should be considered for patients with osteoporosis that are at a highrisk for fractures.

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Mild-to-moderate rash has been reported with the individual components of Atripla. The rashassociated with the efavirenz component usually resolves with continued therapy. Appropriateantihistamines 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 than1% 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 patientsdeveloping severe rash associated with blistering, desquamation, mucosal involvement or fever.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI classis limited. Atripla is not recommended for patients who have had a life-threatening cutaneous reaction(e.g., Stevens-Johnson syndrome) while taking an NNRTI.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown etiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirusretinitis, 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 tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

Although the etiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported 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, jointstiffness 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).

Atripla has not been studied in patients over the age of 65. Elderly patients are more likely to havedecreased hepatic or renal function, therefore caution should be exercised when treating elderlypatients with Atripla (see section 4.2).

As Atripla contains efavirenz, emtricitabine and tenofovir disoproxil, any interactions that have beenidentified with these agents individually may occur with Atripla. Interaction studies with these agentshave only been performed in adults.

As a fixed combination, Atripla should not be administered concomitantly with other medicinalproducts containing the components, emtricitabine or tenofovir disoproxil. Atripla should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. withrifampicin (see section 4.2). Due to similarities with emtricitabine, Atripla should not be administeredconcomitantly with other cytidine analogues, such as lamivudine. Atripla should not be administeredconcomitantly 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 ofthese 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 observedin vitro and the net effect of co-administration with substrates of these enzymes is not clear (seesection 5.2).

Co-administration of efavirenz with metamizole, which is an inducer of metabolising enzymesincluding CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of efavirenz withpotential decrease in clinical efficacy. Therefore, caution is advised when metamizole and efavirenzare administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

Efavirenz exposure may be increased when given with medicinal products (for example ritonavir) orfood (for example, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds orherbal preparations (for example Ginkgo biloba extracts and St. John’s wort) which induce theseenzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of

St. John’s wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is notrecommended (see section 4.4).

In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP-mediatedinteractions 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 havebeen 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 isrecommended 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 (see section 4.3).

Elbasvir/grazoprevir: Co-administration of Atripla with elbasvir/grazoprevir is contraindicatedbecause it may lead to loss of virologic response to elbasvir/grazoprevir (see section 4.3 and Table 1).

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 herbalpreparations containing St. John’s wort is contraindicated. Plasma levels of efavirenz can be reducedby concomitant use of St. John’s wort due to induction of drug metabolising enzymes and/or transportproteins by St. John’s wort. If a patient is already taking St. John’s wort, stop St. John’s wort, checkviral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John’swort. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation oftreatment (see section 4.3).

QT Prolonging Drugs: Atripla is contraindicated with concomitant use of drugs that are known toprolong the QTc interval and could lead to Torsade de Pointes, such as: antiarrhythmics of classes IAand III, neuroleptics and antidepressant agents, certain antibiotics including some agents of thefollowing classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certainnon-sedating antihistaminics (terfenadine, astemizole), cisapride, flecainide, certain antimalarials andmethadone (see section 4.3).

Atazanavir/ritonavir: Insufficient data are available to make a dosing recommendation foratazanavir/ritonavir in combination with Atripla. Therefore co-administration of atazanavir/ritonavirand Atripla is not recommended (see Table 1).

Didanosine: Co-administration of Atripla and didanosine is not recommended (see Table 1).

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir: Co-administration of Atripla andsofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended (see section 4.4 and

Table 1)

Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated bythe kidneys, co-administration of Atripla with medicinal products that reduce renal function orcompete for active tubular secretion (e.g. cidofovir) may increase serum concentrations ofemtricitabine, 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).

Interactions between Atripla or its individual component(s) and other medicinal products are listed in

Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”,once daily as “q.d.” and once every 8 hours as “q8h”). If available, 90% confidence intervals areshown in parentheses.

Table 1: Interactions between Atripla or its individual components and other medicinalproducts

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

ANTI-INFECTIVES

HIV antivirals

Protease inhibitors

Atazanavir/ritonavir/Tenofovir disoproxil Atazanavir: Co-administration of(300 mg q.d./100 mg q.d./245 mg q.d.) AUC: ↓ 25% (↓ 42 to ↓ 3) atazanavir/ritonavir and

Cmax: ↓ 28% (↓ 50 to ↑ 5) Atripla is not

Cmin: ↓ 26% (↓ 46 to ↑ 10) recommended.

Co-administration ofatazanavir/ritonavir with tenofovirresulted in increased exposure totenofovir. Higher tenofovirconcentrations could potentiatetenofovir-associated adverse events,including renal disorders.

Atazanavir/ritonavir/Efavirenz Atazanavir (pm):

(400 mg q.d./100 mg q.d./600 mg q.d., all AUC: ↔* (↓ 9% to ↑ 10%)administered with food) Cmax: ↑ 17%* (↑ 8 to ↑ 27)

Cmin: ↓ 42%* (↓ 31 to ↓ 51)

Atazanavir/ritonavir/Efavirenz Atazanavir (pm):

(400 mg q.d./200 mg q.d./600 mg q.d., all AUC: ↔*/** (↓ 10% to ↑ 26%)administered with food) Cmax: ↔*/** (↓ 5% to ↑ 26%)

Cmin: ↑ 12%*/** (↓ 16 to ↑ 49)(CYP3A4 induction).

* When compared to atazanavir300 mg/ritonavir 100 mg q.d. in theevening without efavirenz. Thisdecrease in atazanavir Cmin mightnegatively impact the efficacy ofatazanavir.

** based on historical comparison.

Co-administration of efavirenz withatazanavir/ritonavir is notrecommended.

Atazanavir/ritonavir/Emtricitabine Interaction not studied.

Darunavir/ritonavir/Efavirenz Darunavir: Atripla in combination(300 mg b.i.d.*/100 mg b.i.d./600 mg AUC: ↓ 13% with darunavir/ritonavirq.d.) Cmin: ↓ 31% 800/100 mg once daily

Cmax: ↓ 15% may result in suboptimal

*lower than recommended doses; similar (CYP3A4 induction) darunavir Cmin. If Atriplafindings are expected with recommended is to be used indoses. Efavirenz: combination with

AUC: ↑ 21% darunavir/ritonavir, the

Cmin: ↑ 17% darunavir/ritonavir

Cmax: ↑ 15% 600/100 mg twice daily(CYP3A4 inhibition) regimen should be used.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Darunavir/ritonavir/Tenofovir disoproxil Darunavir: Darunavir/ritonavir(300 mg b.i.d.*/100 mg b.i.d./245 mg q.d.) AUC: ↔ should be used with

Cmin: ↔ caution in combination

*lower than recommended dose with Atripla. See

Tenofovir: ritonavir row below.

AUC: ↑ 22% Monitoring of renal

Cmin: ↑ 37% function may be

Darunavir/ritonavir/Emtricitabine Interaction not studied. Based on the indicated, particularly indifferent elimination pathways, no patients with underlyinginteraction is expected. systemic or renal disease,or in patients takingnephrotoxic agents.

Fosamprenavir/ritonavir/Efavirenz No clinically significant Atripla and(700 mg b.i.d./100 mg b.i.d./600 mg q.d.) pharmacokinetic interaction. fosamprenavir/ritonavir

Fosamprenavir/ritonavir/Emtricitabine Interaction not studied. can be co-administered

Fosamprenavir/ritonavir/Tenofovir Interaction not studied. without dose adjustment.

disoproxil See ritonavir row below.

Indinavir/Efavirenz Efavirenz: Insufficient data are(800 mg q8h/200 mg q.d.) AUC: ↔ available to make a

Cmax: ↔ dosing recommendation

Cmin: ↔ for indinavir when dosedwith Atripla. While the

Indinavir: clinical significance of

AUC: ↓ 31% (↓ 8 to ↓ 47) decreased indinavir

Cmin: ↓ 40% concentrations has notbeen established, the

A similar reduction in indinavir magnitude of theexposures was observed when observedindinavir 1,000 mg q8h was given pharmacokineticwith efavirenz 600 mg q.d. interaction should be(CYP3A4 induction) taken into consideration

For co-administration of efavirenz when choosing a regimenwith low-dose ritonavir in containing bothcombination with a protease inhibitor, efavirenz, a componentsee section on ritonavir below. of Atripla, and indinavir.

Indinavir/Emtricitabine Indinavir:

(800 mg q8h/200 mg q.d.) AUC: ↔

Cmax: ↔

AUC: ↔

Cmax: ↔

Indinavir/Tenofovir disoproxil Indinavir:

(800 mg q8h/245 mg q.d.) AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Lopinavir/ritonavir/Tenofovir disoproxil Lopinavir/Ritonavir: Insufficient data are(400 mg b.i.d./100 mg b.i.d./245 mg q.d.) AUC: ↔ available to make a

Cmax: ↔ dosing recommendation

Cmin: ↔ for lopinavir/ritonavirwhen dosed with Atripla.

Tenofovir: Co-administration of

AUC: ↑ 32% (↑ 25 to ↑ 38) lopinavir/ritonavir and

Cmax: ↔ Atripla is not

Cmin: ↑ 51% (↑ 37 to ↑ 66) recommended.

Higher tenofovir concentrations couldpotentiate tenofovir-associatedadverse events, including renaldisorders.

Lopinavir/ritonavir soft capsules or oral Substantial decrease in lopinavirsolution/Efavirenz exposure, necessitating dosageadjustment of lopinavir/ritonavir.

When used in combination withefavirenz and two NRTIs, 533/133 mglopinavir/ritonavir (soft capsules)twice daily yielded similar lopinavirplasma concentrations as compared tolopinavir/ritonavir (soft capsules)400/100 mg twice daily withoutefavirenz (historical data).

Lopinavir/ritonavir tablets/Efavirenz Lopinavir concentrations: ↓ 30-40%(400/100 mg b.i.d./600 mg q.d.)(500/125 mg b.i.d./600 mg q.d.) Lopinavir concentrations: similar tolopinavir/ritonavir 400/100 mg twicedaily without efavirenz. Dosageadjustment of lopinavir/ritonavir isnecessary when given with efavirenz.

For co-administration of efavirenzwith low-dose ritonavir incombination with a protease inhibitor,see section on ritonavir below.

Lopinavir/ritonavir/Emtricitabine Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Ritonavir/Efavirenz Ritonavir: Co-administration of(500 mg b.i.d./600 mg q.d.) Morning AUC: ↑ 18% (↑ 6 to ↑ 33) ritonavir at doses of

Evening AUC: ↔ 600 mg and Atripla is not

Morning Cmax: ↑ 24% (↑ 12 to ↑ 38) recommended. When

Evening Cmax: ↔ using Atripla with

Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) low-dose ritonavir, the

Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) possibility of an increasein the incidence of

Efavirenz: efavirenz-associated

AUC: ↑ 21% (↑ 10 to ↑ 34) adverse events should be

Cmax: ↑ 14% (↑ 4 to ↑ 26) considered, due to

Cmin: ↑ 25% (↑ 7 to ↑ 46) possible(inhibition of CYP-mediated pharmacodynamicoxidative metabolism) interaction.

When efavirenz was given withritonavir 500 mg or 600 mg twicedaily, the combination was not welltolerated (for example, dizziness,nausea, paraesthesia and elevatedliver enzymes occurred). Sufficientdata on the tolerability of efavirenzwith low-dose ritonavir (100 mg, onceor twice daily) are not available.

Ritonavir/Emtricitabine Interaction not studied.

Ritonavir/Tenofovir disoproxil Interaction not studied.

Saquinavir/ritonavir/Efavirenz Interaction not studied. For Insufficient data areco-administration of efavirenz with available to make alow-dose ritonavir in combination dosing recommendationwith a protease inhibitor, see section for saquinavir/ritonaviron ritonavir above. when dosed with Atripla.

Saquinavir/ritonavir/Tenofovir disoproxil There were no clinically significant Co-administration ofpharmacokinetic interactions when saquinavir/ritonavir andtenofovir disoproxil was Atripla is notco-administered with ritonavir recommended. Use ofboosted saquinavir. Atripla in combination

Saquinavir/ritonavir/Emtricitabine Interaction not studied. with saquinavir as thesole protease inhibitor isnot recommended.

CCR5 antagonist

Maraviroc/Efavirenz Maraviroc: Refer to the Summary of(100 mg b.i.d./600 mg q.d.) AUC12h: ↓ 45% (↓ 38 to ↓ 51) Product Characteristics

Cmax: ↓ 51% (↓ 37 to ↓ 62) for the medicinal productcontaining maraviroc.

Efavirenz concentrations notmeasured, no effect is expected.

Maraviroc/Tenofovir disoproxil Maraviroc:

(300 mg b.i.d./245 mg q.d.) AUC12h: ↔

Cmax: ↔

Tenofovir concentrations notmeasured, no effect is expected.

Maraviroc/Emtricitabine Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Integrase strand transfer inhibitor

Raltegravir/Efavirenz Raltegravir: Atripla and raltegravir(400 mg single dose/-) AUC: ↓ 36% can be co-administered

C12h: ↓ 21% without dose adjustment.

Cmax: ↓ 36%(UGT1A1 induction)

Raltegravir/Tenofovir disoproxil Raltegravir:

(400 mg b.i.d./-) AUC: ↑ 49%

C12h: ↑ 3%

Cmax: ↑ 64%(mechanism of interaction unknown)

Tenofovir:

AUC: ↓ 10%

C12h: ↓ 13%

Cmax: ↓ 23%

Raltegravir/Emtricitabine Interaction not studied.

NRTIs and NNRTIs

NRTIs/Efavirenz Specific interaction studies have not Due to the similaritybeen performed with efavirenz and between lamivudine and

NRTIs other than lamivudine, emtricitabine, azidovudine and tenofovir disoproxil. component of Atripla,

Clinically significant interactions Atripla should not behave not been found and would not be administeredexpected since the NRTIs are concomitantly withmetabolised via a different route than lamivudineefavirenz and would be unlikely to (see section 4.4).

compete for the same metabolicenzymes and elimination pathways.

NNRTIs/Efavirenz Interaction not studied. Since use of two NNRTIsproved not beneficial interms of efficacy andsafety, co-administrationof Atripla and another

NNRTI is notrecommended.

Didanosine/Tenofovir disoproxil Co-administration of tenofovir Co-administration ofdisoproxil and didanosine results in a Atripla and didanosine is40-60% increase in systemic exposure not recommended.

to didanosine. Increased systemic

Didanosine/Efavirenz Interaction not studied. exposure to didanosine

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Didanosine/Emtricitabine Interaction not studied. may increase didanosinerelated adverse reactions.

Rarely, pancreatitis andlactic acidosis,sometimes fatal, havebeen reported.

Co-administration oftenofovir disoproxil anddidanosine at a dose of400 mg daily has beenassociated with asignificant decrease in

CD4 cell count, possiblydue to an intracellularinteraction increasingphosphorylated (i.e.

active) didanosine. Adecreased dosage of250 mg didanosineco-administered withtenofovir disoproxiltherapy has beenassociated with reports ofhigh rates of virologicalfailure within severaltested combinations forthe treatment of

HIV-1 infection.

Hepatitis C antivirals

Elbasvir/Grazoprevir + Elbasvir: Co-administration of

Efavirenz AUC: ↓ 54% Atripla with

Cmax: ↓ 45% elbasvir/grazoprevir is(CYP3A4 or P-gp induction - effect contraindicated because iton elbasvir) may lead to loss ofvirologic response to

Grazoprevir: elbasvir/grazoprevir.

AUC: ↓ 83% This loss is due to

Cmax: ↓ 87% significant decreases in(CYP3A4 or P-gp induction - effect elbasvir/grazopreviron grazoprevir) plasma concentrationscaused by CYP3A4 or

Efavirenz: P-gp induction. Refer to

AUC: ↔ the Summary of Product

Cmax: ↔ Characteristics forelbasvir/grazoprevir formore information.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Glecaprevir/Pibrentasvir/Efavirenz Expected: Concomitant

Glecaprevir: ↓ administration of

Pibrentasvir: ↓ glecaprevir/pibrentasvirwith efavirenz, acomponent of Atripla,may significantlydecrease plasmaconcentrations ofglecaprevir andpibrentasvir, leading toreduced therapeuticeffect. Coadministrationofglecaprevir/pibrentasvirwith Atripla is notrecommended. Refer tothe prescribinginformation forglecaprevir/pibrentasvirfor more information.

Ledipasvir/Sofosbuvir Ledipasvir: No dose adjustment is(90 mg/400 mg q.d.) + AUC: ↓ 34% (↓ 41 to ↓ 25) recommended. The

Efavirenz/Emtricitabine/Tenofovir Cmax: ↓ 34% (↓ 41 to ↑ 25) increased exposure ofdisoproxil Cmin: ↓ 34% (↓ 43 to ↑ 24) tenofovir could potentiate(600 mg/200 mg/245 mg q.d.) adverse reactions

Sofosbuvir: associated with tenofovir

AUC: ↔ disoproxil, including

Cmax: ↔ renal disorders. Renalfunction should be

GS-3310071: closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98% (↑ 77 to ↑ 123)

Cmax: ↑ 79% (↑ 56 to ↑ 104)

Cmin: ↑ 163% (↑ 137 to ↑ 197)

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Sofosbuvir/Velpatasvir Sofosbuvir: Concomitant(400 mg/100 mg q.d.) + AUC: ↔ administration of Atripla

Efavirenz/Emtricitabine/Tenofovir Cmax: ↑ 38% (↑ 14 to ↑ 67) anddisoproxil sofosbuvir/velpatasvir or(600 mg/200 mg/245 mg q.d.) GS-3310071: sofosbuvir/velpatasvir/

AUC: ↔ voxilaprevir is expected

Cmax: ↔ to decrease plasma

Cmin: ↔ concentrations ofvelpatasvir and

Velpatasvir: voxilaprevir.

AUC: ↓ 53% (↓ 61 to ↓ 43) Co-administration of

Cmax: ↓ 47% (↓ 57 to ↓ 36) Atripla with

Cmin: ↓ 57% (↓ 64 to ↓ 48) sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/

Efavirenz: voxilaprevir is not

AUC: ↔ recommended (see

Cmax: ↔ section 4.4).

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81% (↑ 68 to ↑ 94)

Cmax: ↑ 77% (↑ 53 to ↑ 104)

Cmin: ↑ 121% (↑ 100 to ↑ 143)

Sofosbuvir/Velpatasvir/Voxilaprevir Interaction only studied with(400 mg/100 mg/100 mg q.d.) + sofosbuvir/velpatasvir.

Efavirenz/Emtricitabine/Tenofovirdisoproxil Expected:(600 mg/200 mg/245 mg q.d.) Voxilaprevir:↓

Sofosbuvir Sofosbuvir: Atripla and sofosbuvir(400 mg q.d.) + AUC: ↔ can be co-administered

Efavirenz/Emtricitabine/Tenofovir Cmax: ↓ 19% (↓ 40 to ↑ 10) without dose adjustment.

disoproxil(600 mg/200 mg/245 mg q.d.) GS-3310071:

AUC: ↔

Cmax: ↓ 23% (↓ 30 to ↑ 16)

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 25% (↑ 8 to ↑ 45)

Cmin: ↔

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Antibiotics

Clarithromycin/Efavirenz Clarithromycin: The clinical significance(500 mg b.i.d./400 mg q.d.) AUC: ↓ 39% (↓ 30 to ↓ 46) of these changes in

Cmax: ↓ 26% (↓ 15 to ↓ 35) clarithromycin plasmalevels is not known.

Clarithromycin Alternatives to14-hydroxymetabolite: clarithromycin (e.g.

AUC: ↑ 34% (↑ 18 to ↑ 53) azithromycin) may be

Cmax: ↑ 49% (↑ 32 to ↑ 69) considered. Othermacrolide antibiotics,

Efavirenz: such as erythromycin,

AUC: ↔ have not been studied in

Cmax: ↑ 11% (↑ 3 to ↑ 19) combination with Atripla.

(CYP3A4 induction)

Rash developed in 46% of uninfectedvolunteers receiving efavirenz andclarithromycin.

Clarithromycin/Emtricitabine Interaction not studied.

Clarithromycin/Tenofovir disoproxil Interaction not studied.

Antimycobacterials

Rifabutin/Efavirenz Rifabutin: The daily dose of(300 mg q.d./600 mg q.d.) AUC: ↓ 38% (↓ 28 to ↓ 47) rifabutin should be

Cmax: ↓ 32% (↓ 15 to ↓ 46) increased by 50% when

Cmin: ↓ 45% (↓ 31 to ↓ 56) given with Atripla.

Consider doubling the

Efavirenz: rifabutin dose in

AUC: ↔ regimens where rifabutin

Cmax: ↔ is given 2 or 3 times a

Cmin: ↓ 12% (↓ 24 to ↑ 1) week in combination(CYP3A4 induction) with Atripla. The clinical

Rifabutin/Emtricitabine Interaction not studied. effect of this dose

Rifabutin/Tenofovir disoproxil Interaction not studied. adjustment has not beenadequately evaluated.

Individual tolerabilityand virological responseshould be consideredwhen making the doseadjustment (seesection 5.2).

Rifampicin/Efavirenz Efavirenz: When Atripla is taken(600 mg q.d./600 mg q.d.) AUC: ↓ 26% (↓ 15 to ↓ 36) with rifampicin in

Cmax: ↓ 20% (↓ 11 to ↓ 28) patients weighing 50 kg

Cmin: ↓ 32% (↓ 15 to ↓ 46) or greater, an additional(CYP3A4 and CYP2B6 induction) 200 mg/day (800 mg

Rifampicin/Tenofovir disoproxil Rifampicin: total) of efavirenz may(600 mg q.d./245 mg q.d.) AUC: ↔ provide exposure similar

Cmax: ↔ to a daily efavirenz doseof 600 mg when taken

Tenofovir: without rifampicin. The

AUC: ↔ clinical effect of this dose

Cmax: ↔ adjustment has not been

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Rifampicin/Emtricitabine Interaction not studied. adequately evaluated.

Individual tolerabilityand virological responseshould be consideredwhen making the doseadjustment(see section 5.2). Nodose adjustment ofrifampicin isrecommended whengiven with Atripla.

Antifungals

Itraconazole/Efavirenz Itraconazole: Since no dose(200 mg b.i.d./600 mg q.d.) AUC: ↓ 39% (↓ 21 to ↓ 53) recommendation can be

Cmax: ↓ 37% (↓ 20 to ↓ 51) made for itraconazole

Cmin: ↓ 44% (↓ 27 to ↓ 58) when used with Atripla,(decrease in itraconazole an alternative antifungalconcentrations: CYP3A4 induction) treatment should beconsidered.

Hydroxyitraconazole:

AUC: ↓ 37% (↓ 14 to ↓ 55)

Cmax: ↓ 35% (↓ 12 to ↓ 52)

Cmin: ↓ 43% (↓ 18 to ↓ 60)

AUC: ↔

Cmax: ↔

Cmin: ↔

Itraconazole/Emtricitabine Interaction not studied.

Itraconazole/Tenofovir disoproxil Interaction not studied.

Posaconazole/Efavirenz Posaconazole: Concomitant use of(-/400 mg q.d.) AUC: ↓ 50% posaconazole and Atripla

Cmax: ↓ 45% should be avoided unless(UDP-G induction) the benefit to the patient

Posaconazole/Emtricitabine Interaction not studied. outweighs the risk.

Posaconazole/Tenofovir disoproxil Interaction not studied.

Voriconazole/Efavirenz Voriconazole: Since Atripla is a fixed-(200 mg b.i.d./400 mg q.d.) AUC: ↓ 77% dose combination

Cmax: ↓ 61% product, the dose ofefavirenz cannot be

Efavirenz: altered; therefore,

AUC: ↑ 44% voriconazole and Atripla

Cmax: ↑ 38% must not be(competitive inhibition of oxidative co-administered.

metabolism)

Co-administration of standard dosesof efavirenz and voriconazole iscontraindicated (see section 4.3).

Voriconazole/Emtricitabine Interaction not studied.

Voriconazole/Tenofovir disoproxil Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Antimalarials

Artemether/Lumefantrine/Efavirenz Artemether: Since decreased(20/120 mg tablet, 6 doses of 4 tablets AUC: ↓ 51% concentrations ofeach over 3 days/600 mg q.d.) Cmax: ↓ 21% artemether,dihydroartemisinin, or

Dihydroartemisinin (active lumefantrine may resultmetabolite): in a decrease of

AUC: ↓ 46% antimalarial efficacy,

Cmax: ↓ 38% caution is recommendedwhen Atripla and

Lumefantrine: artemether/lumefantrine

AUC: ↓ 21% tablets are

Cmax: ↔ co-administered.

AUC: ↓ 17%

Cmax: ↔(CYP3A4 induction)

Artemether/Lumefantrine/Emtricitabine Interaction not studied.

Artemether/Lumefantrine/Tenofovir Interaction not studied.

disoproxil

Atovaquone and proguanil Atovaquone: Concomitanthydrochloride/Efavirenz AUC: ↓ 75% (↓ 62 to ↓ 84) administration of(250/100 mg single dose/600 mg q.d.) Cmax: ↓ 44% (↓ 20 to ↓ 61) atovaquone/proguanilwith Atripla should be

Proguanil: avoided.

AUC: ↓ 43% (↓ 7 to ↓ 65)

Cmax: ↔

Atovaquone and proguanil Interaction not studied.

hydrochloride/Emtricitabine

Atovaquone and proguanil Interaction not studied.

hydrochloride/Tenofovir disoproxil

ANTICONVULSANTS

Carbamazepine/Efavirenz Carbamazepine: No dose recommendation(400 mg q.d./600 mg q.d.) AUC: ↓ 27% (↓ 20 to ↓ 33) can be made for the use

Cmax: ↓ 20% (↓ 15 to ↓ 24) of Atripla with

Cmin: ↓ 35% (↓ 24 to ↓ 44) carbamazepine. Analternative anticonvulsant

Efavirenz: should be considered.

AUC: ↓ 36% (↓ 32 to ↓ 40) Carbamazepine plasma

Cmax: ↓ 21% (↓ 15 to ↓ 26) levels should be

Cmin: ↓ 47% (↓ 41 to ↓ 53) monitored periodically.

(decrease in carbamazepineconcentrations: CYP3A4 induction;decrease in efavirenz concentrations:

CYP3A4 and CYP2B6 induction)

Co-administration of higher doses ofeither efavirenz or carbamazepine hasnot been studied.

Carbamazepine/Emtricitabine Interaction not studied.

Carbamazepine/Tenofovir disoproxil Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Phenytoin, Phenobarbital, and other Interaction not studied with efavirenz, When Atripla is co-anticonvulsants that are substrates of CYP emtricitabine, or tenofovir disoproxil. administered with anisozymes There is a potential for reduction or anticonvulsant that is aincrease in the plasma concentrations substrate of CYPof phenytoin, phenobarbital and other isozymes, periodicanticonvulsants that are substrates of monitoring of

CYP isozymes with efavirenz. anticonvulsant levelsshould be conducted.

Valproic acid/Efavirenz No clinically significant effect on Atripla and valproic acid(250 mg b.i.d./600 mg q.d.) efavirenz pharmacokinetics. Limited can be co-administereddata suggest there is no clinically without dose adjustment.

significant effect on valproic acid Patients should bepharmacokinetics. monitored for seizure

Valproic acid/Emtricitabine Interaction not studied. control.

Valproic acid/Tenofovir disoproxil Interaction not studied.

Vigabatrin/Efavirenz Interaction not studied. Clinically Atripla and vigabatrin or

Gabapentin/Efavirenz significant interactions are not gabapentin can be co-expected since vigabatrin and administered withoutgabapentin are exclusively eliminated dose adjustment.

unchanged in the urine and areunlikely to compete for the samemetabolic enzymes and eliminationpathways as efavirenz.

Vigabatrin/Emtricitabine Interaction not studied.

Gabapentin/Emtricitabine

Vigabatrin/Tenofovir disoproxil Interaction not studied.

Gabapentin/Tenofovir disoproxil

ANTICOAGULANTS

Warfarin/Efavirenz Interaction not studied. Plasma Dose adjustment of

Acenocoumarol/Efavirenz concentrations and effects of warfarin warfarin oror acenocoumarol are potentially acenocoumarol may beincreased or decreased by efavirenz. required whenco-administered with

Atripla.

ANTIDEPRESSANTS

Selective Serotonin Reuptake Inhibitors (SSRIs)

Sertraline/Efavirenz Sertraline: When co-administered(50 mg q.d./600 mg q.d.) AUC: ↓ 39% (↓ 27 to ↓ 50) with Atripla, sertraline

Cmax: ↓ 29% (↓ 15 to ↓ 40) dose increases should be

Cmin: ↓ 46% (↓ 31 to ↓ 58) guided by clinicalresponse.

AUC: ↔

Cmax: ↑ 11% (↑ 6 to ↑ 16)

Cmin: ↔(CYP3A4 induction)

Sertraline/Emtricitabine Interaction not studied.

Sertraline/Tenofovir disoproxil Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Paroxetine/Efavirenz Paroxetine: Atripla and paroxetine(20 mg q.d./600 mg q.d.) AUC: ↔ can be co-administered

Cmax: ↔ without dose adjustment.

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Paroxetine/Emtricitabine Interaction not studied.

Paroxetine/Tenofovir disoproxil Interaction not studied.

Fluoxetine/Efavirenz Interaction not studied. Since Atripla and fluoxetinefluoxetine shares a similar metabolic can be co-administeredprofile with paroxetine, i.e. a strong without dose adjustment.

CYP2D6 inhibitory effect, a similarlack of interaction would be expectedfor fluoxetine.

Fluoxetine/Emtricitabine Interaction not studied.

Fluoxetine/Tenofovir disoproxil Interaction not studied.

Norepinephrine and dopamine reuptake inhibitor

Bupropion/Efavirenz Bupropion: Increases in bupropion[150 mg single dose (sustained AUC: ↓ 55% (↓ 48 to ↓ 62) dosage should be guidedrelease)/600 mg q.d.] Cmax: ↓ 34% (↓ 21 to ↓ 47) by clinical response, butthe maximum

Hydroxybupropion: recommended dose of

AUC: ↔ bupropion should not be

Cmax: ↑ 50% (↑ 20 to ↑ 80) exceeded. No dose(CYP2B6 induction) adjustment is necessary

Bupropion/Emtricitabine Interaction not studied. for efavirenz.

Bupropion/Tenofovir disoproxil Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

CARDIOVASCULAR AGENTS

Calcium Channel Blockers

Diltiazem/Efavirenz Diltiazem: Dose adjustments of(240 mg q.d./600 mg q.d.) AUC: ↓ 69% (↓ 55 to ↓ 79) diltiazem when co-

Cmax: ↓ 60% (↓ 50 to ↓ 68) administered with Atripla

Cmin: ↓ 63% (↓ 44 to ↓ 75) should be guided byclinical response (refer to

Desacetyl diltiazem: the Summary of Product

AUC: ↓ 75% (↓ 59 to ↓ 84) Characteristics for

Cmax: ↓ 64% (↓ 57 to ↓ 69) diltiazem).

Cmin: ↓ 62% (↓ 44 to ↓ 75)

N-monodesmethyl diltiazem:

AUC: ↓ 37% (↓ 17 to ↓ 52)

Cmax: ↓ 28% (↓ 7 to ↓ 44)

Cmin: ↓ 37% (↓ 17 to ↓ 52)

AUC: ↑ 11% (↑ 5 to ↑ 18)

Cmax: ↑ 16% (↑ 6 to ↑ 26)

Cmin: ↑ 13% (↑ 1 to ↑ 26)(CYP3A4 induction)

The increase in efavirenzpharmacokinetic parameters is notconsidered clinically significant.

Diltiazem/Emtricitabine Interaction not studied.

Diltiazem/Tenofovir disoproxil Interaction not studied.

Verapamil, Felodipine, Nifedipine and Interaction not studied with efavirenz, Dose adjustments of

Nicardipine emtricitabine, or tenofovir disoproxil. calcium channel blockers

When efavirenz is co-administered when co-administeredwith a calcium channel blocker that is with Atripla should bea substrate of the CYP3A4 enzyme, guided by clinicalthere is a potential for reduction in the response (refer to theplasma concentrations of the calcium Summary of Productchannel blocker. Characteristics for thecalcium channel blocker).

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A Reductase Inhibitors

Atorvastatin/Efavirenz Atorvastatin: Cholesterol levels should(10 mg q.d./600 mg q.d.) AUC: ↓ 43% (↓ 34 to ↓ 50) be periodically

Cmax: ↓ 12% (↓ 1 to ↓ 26) monitored. Dosageadjustments of2-hydroxy atorvastatin: atorvastatin may be

AUC: ↓ 35% (↓ 13 to ↓ 40) required when

Cmax: ↓ 13% (↓ 0 to ↓ 23) co-administered with

Atripla (refer to the4-hydroxy atorvastatin: Summary of Product

AUC: ↓ 4% (↓ 0 to ↓ 31) Characteristics for

Cmax: ↓ 47% (↓ 9 to ↓ 51) atorvastatin).

Total active HMG Co-A reductaseinhibitors:

AUC: ↓ 34% (↓ 21 to ↓ 41)

Cmax: ↓ 20% (↓ 2 to ↓ 26)

Atorvastatin/Emtricitabine Interaction not studied.

Atorvastatin/Tenofovir disoproxil Interaction not studied.

Pravastatin/Efavirenz Pravastatin: Cholesterol levels should(40 mg q.d./600 mg q.d.) AUC: ↓ 40% (↓ 26 to ↓ 57) be periodically

Cmax: ↓ 18% (↓ 59 to ↑ 12) monitored. Dosage

Pravastatin/Emtricitabine Interaction not studied. adjustments of

Pravastatin/Tenofovir disoproxil Interaction not studied. pravastatin may berequired whenco-administered with

Atripla (refer to the

Summary of Product

Characteristics forpravastatin).

Simvastatin/Efavirenz Simvastatin: Cholesterol levels should(40 mg q.d./600 mg q.d.) AUC: ↓ 69% (↓ 62 to ↓ 73) be periodically

Cmax: ↓ 76% (↓ 63 to ↓ 79) monitored. Dosageadjustments of

Simvastatin acid: simvastatin may be

AUC: ↓ 58% (↓ 39 to ↓ 68) required when

Cmax: ↓ 51% (↓ 32 to ↓ 58) co-administered with

Atripla (refer to the

Total active HMG Co-A reductase Summary of Productinhibitors: Characteristics for

AUC: ↓ 60% (↓ 52 to ↓ 68) simvastatin).

Cmax: ↓ 62% (↓ 55 to ↓ 78)(CYP3A4 induction)

Co-administration of efavirenz withatorvastatin, pravastatin, orsimvastatin did not affect efavirenz

AUC or Cmax values.

Simvastatin/Emtricitabine Interaction not studied.

Simvastatin/Tenofovir disoproxil Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Rosuvastatin/Efavirenz Interaction not studied. Rosuvastatin Atripla and rosuvastatinis largely excreted unchanged via the can be co-administeredfaeces, therefore interaction with without dose adjustment.

efavirenz is not expected.

Rosuvastatin/Emtricitabine Interaction not studied.

Rosuvastatin/Tenofovir disoproxil Interaction not studied.

HORMONAL CONTRACEPTIVES

Oral: Ethinyloestradiol: A reliable method of

Ethinyloestradiol+Norgestimate/Efavirenz AUC: ↔ barrier contraception(0.035 mg+0.25 mg q.d./600 mg q.d.) Cmax: ↔ must be used in addition

Cmin: ↓ 8% (↑ 14 to ↓ 25) to hormonalcontraceptives

Norelgestromin (active metabolite): (see section 4.6).

AUC: ↓ 64% (↓ 62 to ↓ 67)

Cmax: ↓ 46% (↓ 39 to ↓ 52)

Cmin: ↓ 82% (↓ 79 to ↓ 85)

Levonorgestrel (active metabolite):

AUC: ↓ 83% (↓ 79 to ↓ 87)

Cmax: ↓ 80% (↓ 77 to ↓ 83)

Cmin: ↓ 86% (↓ 80 to ↓ 90)(induction of metabolism)

Efavirenz: no clinically significantinteraction.

The clinical significance of theseeffects is not known.

Ethinyloestradiol/Tenofovir disoproxil Ethinyloestradiol:

(-/245 mg q.d.) AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Norgestimate/Ethinyloestradiol/ Interaction not studied.

Injection: In a 3-month drug interaction study, Because of the limited

Depomedroxyprogesterone acetate no significant differences in MPA information available, a(DMPA)/Efavirenz pharmacokinetic parameters were reliable method of barrier(150 mg IM single dose DMPA) found between subjects receiving contraception must beefavirenz-containing antiretroviral used in addition totherapy and subjects receiving no hormonal contraceptivesantiretroviral therapy. Similar results (see section 4.6).

were found by other investigators,although the MPA plasma levels weremore variable in the second study. Inboth studies, plasma progesteronelevels for subjects receiving efavirenzand DMPA remained low consistentwith suppression of ovulation.

DMPA/Tenofovir disoproxil Interaction not studied.

DMPA/Emtricitabine Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Implant: Decreased exposure of etonogestrel A reliable method of

Etonogestrel/Efavirenz may be expected (CYP3A4 barrier contraceptioninduction). There have been must be used in additionoccasional post-marketing reports of to hormonalcontraceptive failure with etonogestrel contraceptivesin efavirenz-exposed patients. (see section 4.6).

Etonogestrel/Tenofovir disoproxil Interaction not studied.

Etonogestrel/Emtricitabine Interaction not studied.

IMMUNOSUPPRESSANTS

Immunosuppressants metabolised by Interaction not studied. Dose adjustments of the

CYP3A4 (e.g. cyclosporine, tacrolimus, ↓ exposure of the immunosuppressant immunosuppressant maysirolimus)/Efavirenz may be expected (CYP3A4 be required. Closeinduction). monitoring of

These immunosuppressants are not immunosuppressantanticipated to impact exposure of concentrations for at leastefavirenz. two weeks (until stable

Tacrolimus/Emtricitabine/Tenofovir Tacrolimus: concentrations aredisoproxil AUC: ↔ reached) is recommended(0.1 mg/kg q.d./200 mg/245 mg q.d.) Cmax: ↔ when starting or stopping

C24h: ↔ treatment with Atripla.

AUC: ↔

Cmax: ↔

C24h: ↔

Tenofovir disoproxil:

AUC: ↔

Cmax: ↔

C24h: ↔

OPIOIDS

Methadone/Efavirenz Methadone: Concomitant(35-100 mg q.d./600 mg q.d.) AUC: ↓ 52% (↓ 33 to ↓ 66) administration with

Cmax: ↓ 45% (↓ 25 to ↓ 59) Atripla should be avoided(CYP3A4 induction) due to the risk for QTcprolongation (see section

In a study of HIV infected intravenous 4.3).

drug users, co-administration ofefavirenz with methadone resulted indecreased plasma levels of methadoneand signs of opiate withdrawal. Themethadone dose was increased by amean of 22% to alleviate withdrawalsymptoms.

Methadone/Tenofovir disoproxil Methadone:

(40-110 mg q.d./245 mg q.d.) AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Methadone/Emtricitabine Interaction not studied.

Medicinal product by therapeutic areas Effects on drug levels Recommendation

Mean percent change in AUC, Cmax, concerning

Cmin with 90% confidence intervals co-administration withif available Atripla(mechanism) (efavirenz 600 mg,emtricitabine 200 mg,tenofovir disoproxil245 mg)

Buprenorphine/naloxone/Efavirenz Buprenorphine: Despite the decrease in

AUC: ↓ 50% buprenorphine exposure,no patients exhibited

Norbuprenorphine: withdrawal symptoms.

AUC: ↓ 71% Dose adjustment ofbuprenorphine may not

Efavirenz: be necessary when

No clinically significant co-administered withpharmacokinetic interaction. Atripla.

Buprenorphine/naloxone/Emtricitabine Interaction not studied.

Buprenorphine/naloxone/Tenofovir Interaction not studied.

disoproxil1 The predominant circulating metabolite of sofosbuvir.

There were no clinically significant pharmacokinetic interactions when efavirenz was administeredwith azithromycin, cetirizine, fosamprenavir/ritonavir, lorazepam, zidovudine, aluminium/magnesiumhydroxide antacids, famotidine or fluconazole. The potential for interactions with efavirenz and otherazole antifungals, such as ketoconazole, has not been studied.

There were no clinically significant pharmacokinetic interactions when emtricitabine was administeredwith stavudine, zidovudine or famciclovir. There were no clinically significant pharmacokineticinteractions when tenofovir disoproxil was co-administered with emtricitabine or ribavirin.

Women of childbearing potential (see below and section 5.3)

Pregnancy should be avoided in women receiving Atripla. Women of childbearing potential shouldundergo pregnancy testing before initiation of Atripla.

Barrier contraception should always be used in combination with other methods of contraception (forexample, oral or other hormonal contraceptives, see section 4.5) while on therapy with Atripla.

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks afterdiscontinuation of Atripla is recommended.

Efavirenz: There have been seven retrospective reports of findings consistent with neural tube defects,including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding anyefavirenz-containing fixed-dose combination tablets) in the first trimester. Two additional cases(1 prospective and 1 retrospective) including events consistent with neural tube defects have beenreported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovirdisoproxil. A causal relationship of these events to the use of efavirenz has not been established, andthe denominator is unknown. As neural tube defects occur within the first 4 weeks of foetaldevelopment (at which time neural tubes are sealed), this potential risk would concern women exposedto efavirenz during the first trimester of pregnancy.

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of904 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 livebirths. One child was reported to have a neural tube defect, and the frequency and pattern of otherbirth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, aswell as those in HIV negative controls. The incidence of neural tube defects in the general populationranges from 0.5-1 case per 1,000 live births.

Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3).

Emtricitabine and tenofovir disoproxil: A large amount of data on pregnant women (more than 1000pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated withemtricitabine and tenofovir disoproxil. Animal studies on emtricitabine and tenofovir disoproxil donot indicate reproductive toxicity (see section 5.3).

Atripla should not be used during pregnancy unless the clinical condition of the woman requirestreatment with efavirenz/emtricitabine/tenofovir disoproxil.

Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There isinsufficient 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 orderto avoid transmission of HIV to the infant.

No human data on the effect of Atripla are available. Animal studies do not indicate harmful effectsof efavirenz, emtricitabine or tenofovir disoproxil on fertility.

No studies on the effects on the ability to drive and use machines have been performed. However,dizziness has been reported during treatment with efavirenz, emtricitabine and tenofovir disoproxil.

Efavirenz may also cause impaired concentration and/or somnolence. Patients should be instructedthat if they experience these symptoms they should avoid potentially hazardous tasks such as drivingand operating machinery.

The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patientseither as the fixed-dose combination tablet Atripla (study AI266073) or as the component products(study GS-01-934). Adverse reactions were generally consistent with those seen in previous studies ofthe individual components. The most frequently reported adverse reactions considered possibly orprobably related to Atripla among patients treated up to 48 weeks in study AI266073 were psychiatricdisorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).

Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatricadverse 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 tofractures) have also been reported. Monitoring of renal function is recommended for patientsreceiving Atripla (see section 4.4).

Discontinuation of Atripla therapy in patients co-infected with HIV and HBV may be associated withsevere acute exacerbations of hepatitis (see section 4.4).

The administration of Atripla with food may increase efavirenz exposure and may lead to an increasein the frequency of adverse reactions (see sections 4.4 and 5.2).

The adverse reactions from clinical study and post-marketing experience with Atripla and theindividual components of Atripla in antiretroviral combination therapy are listed in Table 2 below bybody system organ class, frequency and the component(s) of Atripla to which the adverse reactions areattributable. Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Adverse reactions associated with the use of Atripla: Treatment-emergent adverse reactionsconsidered possibly or probably related to Atripla reported in study AI266073 (over 48 weeks;n = 203), which have not been associated with one of the individual components of Atripla, include:

Common: - anorexia

Uncommon: - dry mouth

- incoherent speech

- increased appetite

- libido decreased

- myalgia

Table 2: Adverse reactions associated with Atripla listed by the component(s) of Atripla towhich the adverse reactions are attributable

Atripla

Efavirenz Emtricitabine Tenofovir disoproxil

Common neutropenia

Uncommon anaemia1

Common allergic reaction

Uncommon hypersensitivity

Very common hypophosphataemia2

Common hypertriglyceridaemia3 hyperglycaemia,hypertriglyceridaemia

Uncommon hypercholesterolaemia3 hypokalaemia2

Rare lactic acidosis

Atripla

Efavirenz Emtricitabine Tenofovir disoproxil

Common depression (severe in abnormal dreams,1.6%)3, anxiety3, insomniaabnormal dreams3,insomnia3

Uncommon suicide attempt3, suicideideation3, psychosis3,mania3, paranoia3,hallucination3, euphoricmood3, affect lability3,confusional state3,aggression3, catatonia3

Rare completed suicide3,4,delusion3,4, neurosis3,4

Very common headache dizziness

Common cerebellar coordination dizziness headacheand balancedisturbances3,somnolence (2.0%)3,headache (5.7%)3,disturbance in attention(3.6%)3, dizziness(8.5%)3

Uncommon convulsions3, amnesia3,thinking abnormal3,ataxia3, coordinationabnormal3, agitation3,tremor

Uncommon vision blurred

Ear and labyrinth disorders:

Uncommon tinnitus, vertigo

Uncommon flushing

Very common diarrhoea, nausea diarrhoea, vomiting,nausea

Common diarrhoea, vomiting, elevated amylase abdominal pain,abdominal pain, nausea including elevated abdominal distension,pancreatic amylase, flatulenceelevated serum lipase,vomiting, abdominalpain, dyspepsia

Uncommon pancreatitis pancreatitis

Common elevated aspartate elevated serum AST increased transaminasesaminotransferase (AST), and/or elevated serumelevated alanine ALT,aminotransferase (ALT), hyperbilirubinaemiaelevated gamma-glutamyltransferase(GGT)

Uncommon hepatitis acute

Rare hepatic failure3,4 hepatic steatosis,hepatitis

Very common rash (moderate-severe, rash11.6%, all grades, 18%)3

Atripla

Efavirenz Emtricitabine Tenofovir disoproxil

Common pruritus vesiculobullous rash,pustular rash,maculopapular rash,rash, pruritus, urticaria,skin discolouration(increasedpigmentation)1

Uncommon Stevens-Johnson angioedema4syndrome, erythemamultiforme3, severe rash(< 1%)

Rare photoallergic dermatitis angioedema

Very common elevated creatine kinase

Uncommon rhabdomyolysis2,muscular weakness2

Rare osteomalacia (manifestedas bone pain andinfrequently contributingto fractures)2,4,myopathy2

Uncommon increased creatinine,proteinuria, proximalrenal tubulopathyincluding Fanconisyndrome

Rare renal failure (acute andchronic), acute tubularnecrosis, nephritis(including acuteinterstitial nephritis)4,nephrogenic diabetesinsipidus

Uncommon gynaecomastia

Very common asthenia

Common fatigue pain, asthenia1 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine wasadministered to paediatric patients.2 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causallyassociated with tenofovir disoproxil in the absence of this condition.

3 See section 4.8 Description of selected adverse reactions for more details.

4 This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovirdisoproxil. The frequency category was estimated from a statistical calculation based on the total number of patientstreated with efavirenz in clinical trials (n = 3,969) or exposed to emtricitabine in randomised controlled clinical trials(n = 1,563) or exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded accessprogramme (n = 7,319).

Rash: In clinical trials of efavirenz, rashes were usually mild-to-moderate maculopapular skineruptions that occurred within the first two weeks of initiating therapy with efavirenz. In most patientsrash resolved with continuing therapy with efavirenz within one month. Atripla can be reinitiated inpatients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroidsis recommended when Atripla is restarted.

Psychiatric symptoms: Patients with a history of psychiatric disorders appear to be at greater risk ofserious psychiatric adverse reactions listed in the efavirenz column of Table 2.

Nervous system symptoms: Nervous system symptoms are common with efavirenz, one of thecomponents of Atripla. In clinical controlled studies of efavirenz, nervous system symptoms ofmoderate to severe intensity were experienced by 19% (severe 2%) of patients, and 2% of patientsdiscontinued therapy due to such symptoms. They usually begin during the first one or two days ofefavirenz therapy and generally resolve after the first two to four weeks. They may occur morefrequently when Atripla is taken concomitantly with meals possibly due to increased efavirenz plasmalevels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms(see section 4.2).

Hepatic failure with efavirenz: Hepatic failure, including cases in patients with no pre-existing hepaticdisease or other identifiable risk factors, as reported post-marketing, were sometimes characterised bya fulminant course, progressing in some cases to transplantation or death.

Renal impairment: As Atripla may cause renal damage, monitoring of renal function is recommended(see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generallyresolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declinesin creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation.

Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIVdisease, or patients receiving concomitant nephrotoxic medications) are at increased risk ofexperiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (seesection 4.4).

Lactic acidosis: Cases of lactic acidosis have been reported with tenofovir disoproxil alone or incombination with other antiretrovirals. Patients with predisposing factors such as severe hepaticimpairment (CPT, Class C) (see section 4.3), or patients receiving concomitant medications known toinduce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovirdisoproxil treatment, including fatal outcomes.

Metabolic parameters: Weight and levels of blood lipids and glucose may increase duringantiretroviral therapy (see section 4.4).

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the timeof initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infectionsmay arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also beenreported; however, the reported time to onset is more variable and these events can occur manymonths after initiation of treatment (see section 4.4).

Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generallyacknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency ofthis is unknown (see section 4.4).

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

Elderly: Atripla has not been studied in patients over the age of 65. Elderly patients are more likely tohave decreased hepatic or renal function, therefore caution should be exercised when treating elderlypatients with Atripla (see section 4.2).

Patients with renal impairment: Since tenofovir disoproxil can cause renal toxicity, close monitoringof renal function is recommended in any patient with mild renal impairment treated with Atripla(see sections 4.2, pct. 4.4 and 5.2).

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

HIV infected population.

Exacerbations of hepatitis after discontinuation of treatment: In HIV infected patients co-infectedwith HBV, clinical and laboratory evidence of hepatitis may occur after discontinuation of treatment(see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Some patients accidentally taking 600 mg efavirenz twice daily have reported increased nervoussystem symptoms. One patient experienced involuntary muscle contractions.

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

Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is nospecific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis isunlikely 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 byhaemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritonealdialysis.

Pharmacotherapeutic group: Antiviral for systemic use, antivirals for treatment of HIV infections,combinations, ATC code: J05AR06

Mechanism of action and pharmacodynamic effects

Efavirenz is an NNRTI of HIV-1. Efavirenz non-competitively inhibits HIV-1 reverse transcriptase(RT) and does not significantly inhibit human immunodeficiency virus-2 (HIV-2) RT or cellulardeoxyribonucleic acid (DNA) polymerases (α, β, γ, and δ). Emtricitabine is a nucleoside analogue ofcytidine. Tenofovir disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate(nucleotide) analogue of adenosine monophosphate.

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

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

The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebocontrolled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjectsenriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmaxobserved in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenzconcentration and QTc prolongation was observed. Based on the concentration-QTc relationship, themean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms insubjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days(see section 4.5).

Efavirenz demonstrated antiviral activity against most non-clade B isolates (subtypes A, AE, AG, C,

D, F, G, J, and N) but had reduced antiviral activity against group O viruses. Emtricitabine displayedantiviral activity against HIV-1 clades A, B, C, D, E, F, and G. Tenofovir displayed antiviral activityagainst HIV-1 clades A, B, C, D, E, F, G, and O. Both emtricitabine and tenofovir showed strainspecific activity against HIV-2 and antiviral activity against HBV.

In combination studies evaluating the in vitro antiviral activity of efavirenz and emtricitabine together,efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergisticantiviral effects were observed.

Resistance to efavirenz can be selected in vitro and resulted in single or multiple amino acidsubstitutions in HIV-1 RT, including L100I, V108I, V179D, and Y181C. K103N was the mostfrequently observed RT substitution in viral isolates from patients who experienced rebound in viralload during clinical studies of efavirenz. Substitutions at RT positions 98, 100, 101, 108, 138, 188,190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N.

Cross-resistance profiles for efavirenz, nevirapine and delavirdine in vitro demonstrated that the

K103N substitution confers loss of susceptibility to all three NNRTIs.

The potential for cross-resistance between efavirenz and NRTIs is low because of the different bindingsites on the target and mechanism of action. The potential for cross-resistance between efavirenz and

PIs is low because of the different enzyme targets involved.

Resistance to emtricitabine or tenofovir has been seen in vitro and in some HIV-1 infected patients dueto the development of an M184V or M184I substitution in RT with emtricitabine or a K65Rsubstitution in RT with tenofovir. Emtricitabine-resistant viruses with the M184V/I mutation werecross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir andzidovudine. The K65R mutation can also be selected by abacavir or didanosine and results in reducedsusceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxilshould be avoided in patients with HIV-1 harbouring the K65R mutation. Both the K65R and

M184V/I mutation remain fully susceptible to efavirenz. In addition, a K70E substitution in HIV-1

RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir,emtricitabine, lamivudine and tenofovir.

Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) thatincluded either an M41L or an L210W substitution in RT showed reduced susceptibility to tenofovirdisoproxil.

In vivo resistance (antiretroviral-naïve patients): In a 144-week open-label randomised clinical study(GS-01-934) in antiretroviral-naïve patients, where efavirenz, emtricitabine and tenofovir disoproxilwere used as individual formulations (or as efavirenz and the fixed combination of emtricitabine andtenofovir disoproxil (Truvada) from week 96 to 144), genotyping was performed on plasma

HIV-1 isolates from all patients with confirmed HIV RNA > 400 copies/ml at week 144 or early studydrug discontinuation (see section on Clinical experience). As of week 144:

* The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in theefavirenz + emtricitabine + tenofovir disoproxil group and in 10/29 (34.5%) isolates analysedfrom the efavirenz + lamivudine/zidovudine group (p-value < 0.05, Fisher’s Exact testcomparing the emtricitabine + tenofovir disoproxil group to the lamivudine/zidovudine groupamong all subjects).

* No virus analysed contained the K65R or K70E mutation.

* Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from13/19 (68%) patients in the efavirenz + emtricitabine + tenofovir disoproxil group and in virusfrom 21/29 (72%) patients in the efavirenz + lamivudine/zidovudine group. A summary ofresistance mutation development is shown in Table 3.

Table 3: Development of resistance in study GS-01-934 through week 144

Efavirenz+ Efavirenz+lamivudine/zidoemtricitabine+ vudinetenofovir disoproxil (N=243)(N=244)

Resistance analysis by week 144 19 31

On-therapy genotypes 19 (100%) 29 (100%)

Efavirenz resistance1 13 (68%) 21 (72%)

K103N 8 (42%) 18* (62%)

K101E 3 (16%) 3 (10%)

G190A/S 2 (10.5%) 4 (14%)

Y188C/H 1 (5%) 2 (7%)

V108I 1 (5%) 1 (3%)

P225H 0 2 (7%)

M184V/I 2 (10.5%) 10* (34.5%)

K65R 0 0

K70E 0 0

TAMs2 0 2 (7%)

* p-value < 0.05, Fisher’s Exact test comparing efavirenz + emtricitabine + tenofovir disoproxil group to efavirenz +lamivudine/zidovudine group among all patients.

1 Other efavirenz resistance mutations included A98G (n=1), K103E (n=1), V179D (n=1), and M230L (n=1).

2 Thymidine analogue associated mutations included D67N (n=1) and K70R (n=1).

In the open-label extended phase of study GS-01-934, where patients received Atripla on an emptystomach, 3 additional cases of resistance were seen. All 3 subjects had received a fixed dosecombination of lamivudine and zidovudine (Combivir) and efavirenz for 144 weeks and then switchedto Atripla. Two subjects with confirmed virologic rebound developed NNRTI resistance-associatedsubstitutions to efavirenz including K103N, V106V/I/M and Y188Y/C reverse transcriptasesubstitutions at week 240 (96 weeks on Atripla) and week 204 (60 weeks on Atripla). A third subjecthad pre-existing NNRTI resistance-associated substitutions to efavirenz and the M184V reversetranscriptase resistance-associated substitution to emtricitabine at entry into the Atripla extensionphase and experienced a suboptimal virologic response, and developed K65K/R, S68N and K70K/E

NRTI resistance-associated substitutions at week 180 (36 weeks on Atripla).

Please refer to the Summary of Product Characteristics for the individual components for additionalinformation regarding in vivo resistance with these medicinal products.

In a 144-week open-label randomised clinical study (GS-01-934) antiretroviral treatment-naïve

HIV-1 infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovirdisoproxil or a fixed combination of lamivudine and zidovudine (Combivir) administered twice dailyand efavirenz once daily (please refer to the Summary of Product Characteristics for Truvada).

Patients who completed 144 weeks of treatment with either treatment arm in study GS-01-934 weregiven the option to continue in an open-label extended phase of the study with Atripla on an emptystomach. Data are available from 286 patients who switched to Atripla: 160 had previously receivedefavirenz, emtricitabine and tenofovir disoproxil, and 126 had previously received Combivir andefavirenz. High rates of virologic suppression were maintained by subjects from both initial treatmentgroups who then received Atripla in the open-label extended phase of the study. After 96 weeks of

Atripla treatment, HIV-1 RNA plasma concentrations remained < 50 copies/ml in 82% of patients and< 400 copies/ml in 85% of patients (intention to treat analysis (ITT), missing=failure).

Study AI266073 was a 48-week open-label randomised clinical study in HIV infected patientscomparing the efficacy of Atripla to antiretroviral therapy consisting of at least two nucleoside ornucleotide reverse transcriptase inhibitors (NRTIs) with a protease inhibitor or non-nucleoside reversetranscriptase inhibitor; however not a regimen containing all Atripla components (efavirenz,emtricitabine and tenofovir disoproxil). Atripla was administered on an empty stomach(see section 4.2). Patients had never experienced virological failure on a previous antiretroviraltherapy, had no known HIV-1 mutations that confer resistance to any of the three components within

Atripla, and had been virologically suppressed for at least three months at baseline. Patients eitherchanged to Atripla (N=203) or continued on their original antiretroviral treatment regimen (N=97).

Forty-eight week data showed that high levels of virologic suppression, comparable to the originaltreatment regimen, were maintained in patients who were randomised to change to Atripla(see Table 4).

Table 4: 48-week efficacy data from study AI266073 in which Atripla was administered tovirologically suppressed patients on combination antiretroviral therapy

Treatment group

Endpoint Atripla (N=203) Stayed on original Difference between Atriplan/N (%) treatment regimen (N=97) and original treatmentn/N (%) regimen (95%CI)patients with HIV-1 RNA < 50 copies/ml

PVR (KM) 94.5% 85.5% 8.9% (-7.7% to 25.6%)

M=Excluded 179/181 (98.9%) 85/87 (97.7%) 1.2% (-2.3% to 6.7%)

M=Failure 179/203 (88.2%) 85/97 (87.6%) 0.5% (-7.0% to 9.3%)

Modified LOCF 190/203 (93.6%) 94/97 (96.9%) -3.3 (-8.3% to 2.7%)patients with HIV-1 RNA < 200 copies/ml

PVR (KM) 98.4% 98.9% -0.5% (-3.2% to 2.2%)

M=Excluded 181/181 (100%) 87/87 (100%) 0% (-2.4% to 4.2%)

M=Failure 181/203 (89.2%) 87/97 (89.7%) -0.5% (-7.6% to 7.9%)

PVR (KM): Pure virologic response assessed using the Kaplan Meier (KM) method

M: Missing

Modified LOCF: Post-hoc analysis where patients who failed virologically or discontinued for adverse events were treated asfailures; for other drop-outs, the LOCF (last observation carried forward) method was applied

When the two strata were analysed separately, response rates in the stratum with prior PI-treatmentwere numerically lower for patients switched to Atripla [92.4% versus 94.0% for the PVR (sensitivityanalysis) for Atripla and SBR patients respectively; a difference (95%CI) of -1.6% (-10.0%, 6.7%). Inthe prior-NNRTI stratum, response rates were 98.9% vs 97.4% for Atripla and SBR patientsrespectively; a difference (95%CI) of 1.4% (-4.0%, 6.9%)].

A similar trend was observed in a sub-group analysis of treatment-experienced patients with baseline

HIV-1 RNA < 75 copies/ml from a retrospective cohort study (data collected over 20 months, see

Table 5).

Table 5: Maintenance of pure virologic response (Kaplan Meier % (Standard Error) [95%CI])at week 48 for treatment-experienced patients with baseline HIV-1 RNA < 75 copies/ml who hadtherapy switched to Atripla according to the type of prior antiretroviral regimen (Kaiser

Permanente patient database)

Prior Atripla components Prior NNRTI-based regimen Prior PI-based regimen(N=299) (N=104) (N=34)98.9% (0.6%) 98.0% (1.4%) 93.4% (4.5%)[96.8%, 99.7%] [92.3%, 99.5%] [76.2%, 98.3%]

No data are currently available from clinical studies with Atripla in treatment-naïve patients or inheavily pretreated patients. There is no clinical experience with Atripla in patients who areexperiencing virological failure in a first-line antiretroviral treatment regimen or in combination withother antiretroviral agents.

Patients coinfected with HIV and HBV

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

The safety and efficacy of Atripla in children under the age of 18 years have not been established.

The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil were used todetermine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil, administeredseparately in HIV infected patients. The bioequivalence of one Atripla film-coated tablet with oneefavirenz 600 mg film-coated tablet plus one emtricitabine 200 mg hard capsule plus one tenofovirdisoproxil 245 mg film-coated tablet (equivalent to 300 mg tenofovir disoproxil fumarate)administered together, was established following single dose administration to fasting healthy subjectsin study GS-US-177-0105 (see Table 6).

Table 6: Summary of pharmacokinetic data from study GS-US-177-0105

Efavirenz Emtricitabine Tenofovir disoproxil(n=45) (n=45) (n=45)

GMR (%) GMR (%) GMR (%)

Parameters Test Reference (90%CI) Test Reference (90%CI) Test Reference (90%CI)98.79 88.84 91.462,264.3 2,308.6 2,130.6 2,384.4 325.1 352.9

Cmax (ng/ml) (92.28, (84.02, (84.64,(26.8) (30.3) (25.3) (20.4) (34.2) (29.6)105.76) 93.94) 98.83)95.84 97.98 99.29

AUC0-last 125,623.6 132,795.7 10,682.6 10,874.4 1,948.8 1,969.0(90.73, (94.90, (91.02,(ng∙h/ml) (25.7) (27.0) (18.1) (14.9) (32.9) (32.8)101.23) 101.16) 108.32)95.87 97.96 100.45

AUCinf 146,074.9 155,518.6 10,854.9 11,054.3 2,314.0 2,319.4(89.63, (94.86, (93.22,(ng∙h/ml) (33.1) (34.6) (17.9) (14.9) (29.2) (30.3)102.55) 101.16) 108.23)

T1/2 180.6 182.5 14.5 14.6 18.9 17.8(h) (45.3) (38.3) (53.8) (47.8) (20.8) (22.6)

Test: single fixed-dose combination tablet taken under fasted conditions.

Reference: single dose of a 600 mg efavirenz tablet, 200 mg emtricitabine capsule and 300 mg tenofovir disoproxil tablettaken under fasted conditions.

Values for Test and Reference are mean (% coefficient of variation).

GMR=geometric least-squares mean ratio, CI=confidence interval

In HIV infected patients, peak efavirenz plasma concentrations were attained by 5 hours andsteady-state concentrations reached in 6 to 7 days. In 35 patients receiving efavirenz 600 mg oncedaily, steady-state peak concentration (Cmax) was 12.9 ± 3.7 µM (29%) [mean ± standard deviation(S.D.) (coefficient of variation (%CV))], steady-state Cmin was 5.6 ± 3.2 µM (57%), and AUC was184 ± 73 µM*h (40%).

Emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours post-dose.

Following multiple dose oral administration of emtricitabine to 20 HIV infected patients, steady-state

Cmax was 1.8 ± 0.7 µg/ml (mean ± S.D.) (39%CV), steady-state Cmin was 0.09 ± 0.07 µg/ml (80%) andthe AUC was 10.0 ± 3.1 µg*h/ml (31%) over a 24 hour dosing interval.

Following oral administration of a single 300 mg dose of tenofovir disoproxil to HIV-1 infectedpatients in the fasted state, maximum tenofovir concentrations were achieved within one hour and the

Cmax and AUC (mean ± S.D.) (%CV) values were 296 ± 90 ng/ml (30%) and 2,287 ± 685 ng*h/ml(30%), respectively. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted patientswas approximately 25%.

Atripla has not been evaluated in the presence of food.

Administration of efavirenz capsules with a high fat meal increased the mean AUC and Cmax ofefavirenz by 28% and 79%, respectively, compared to administration in a fasted state. Compared tofasted administration, dosing of tenofovir disoproxil and emtricitabine in combination with either ahigh fat meal or a light meal increased the mean AUC of tenofovir by 43.6% and 40.5%, and Cmax by16% and 13.5%, respectively without affecting emtricitabine exposures.

Atripla is recommended for administration on an empty stomach since food may increase efavirenzexposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8).

It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower followingadministration of Atripla on an empty stomach as compared to the individual component tenofovirdisoproxil when taken with food (see section 5.1).

Efavirenz is highly bound (> 99%) to human plasma proteins, predominantly albumin.

In vitro binding of emtricitabine to human plasma proteins is < 4% and independent of concentrationsover the range of 0.02 to 200 µg/ml. Following intravenous administration the volume of distributionof emtricitabine was approximately 1.4 l/kg. After oral administration, emtricitabine is widelydistributed throughout the body. The mean plasma to blood concentration ratio was approximately 1.0and the mean semen to plasma concentration ratio was approximately 4.0.

In vitro binding of tenofovir to human plasma or serum protein is < 0.7% and 7.2%, respectively overthe tenofovir concentration range 0.01 to 25 µg/ml. Following intravenous administration the volumeof distribution of tenofovir was approximately 800 ml/kg. After oral administration, tenofovir iswidely distributed throughout the body.

Studies in humans and in vitro studies using human liver microsomes have demonstrated thatefavirenz is principally metabolised by the CYP system to hydroxylated metabolites with subsequentglucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against

HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsiblefor efavirenz metabolism and that it inhibits CYP isozymes 2C9, 2C19, and 3A4. In in vitro studiesefavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations wellabove those achieved clinically.

Efavirenz plasma exposure may be increased in patients with homozygous G516T genetic variant ofthe CYP2B6 isozyme. The clinical implications of such an association are unknown; however, thepotential for an increased frequency and severity of efavirenz-associated adverse events cannot beexcluded.

Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its ownmetabolism, which may be clinically relevant in some patients. In uninfected volunteers, multipledoses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation(22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to76 hours). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1substrate) are reduced in the presence of efavirenz (see section 4.5, Table 1). Although in vitro datasuggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictory reports of bothincreased and decreased exposures to substrates of these enzymes when co-administered withefavirenz in vivo. The net effect of co-administration is not clear.

There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includesoxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) andconjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitrostudies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the

CYP enzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated byany of the major human CYP isoforms involved in drug biotransformation. Also, emtricitabine didnot inhibit uridine 5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.

Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses (see also datafrom bioequivalence study described above) and 40 to 55 hours after multiple doses. Approximately14 to 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dosewas excreted in urine as unchanged efavirenz.

Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabinedose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged307 ml/min.

Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.

Tenofovir is primarily excreted by the kidneys by both filtration and an active tubular transport systemwith approximately 70 to 80% of the dose excreted unchanged in urine following intravenousadministration. The apparent clearance of tenofovir averaged approximately 307 ml/min. Renalclearance has been estimated to be approximately 210 ml/min, which is in excess of the glomerularfiltration rate. This indicates that active tubular secretion is an important part of the elimination oftenofovir.

Pharmacokinetic studies have not been performed with efavirenz, emtricitabine or tenofovir in elderlypatients (over 65 years of age).

The pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients. Limiteddata suggest that females may have higher exposure to efavirenz but they do not appear to be lesstolerant of efavirenz.

Limited data suggest that Asian and Pacific Island patients may have higher exposure to efavirenz butthey do not appear to be less tolerant of efavirenz.

Pharmacokinetic studies have not been performed with Atripla in infants and children under 18 yearsof age (see section 4.2).

The pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil after co-administration ofthe separate pharmaceutical forms or as Atripla have not been studied in HIV infected patients withrenal impairment.

Pharmacokinetic parameters were determined following administration of single doses of theindividual preparations of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infectedpatients with varying degrees of renal impairment. The degree of renal impairment was definedaccording to baseline creatinine clearance (normal renal function when creatinineclearance > 80 ml/min; mild impairment with creatinine clearance=50 to 79 ml/min; moderateimpairment with creatinine clearance=30 to 49 ml/min and severe impairment with creatinineclearance=10 to 29 ml/min).

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

The mean (%CV) tenofovir exposure increased from 2,185 ng*h/ml (12%) in patients with normalrenal function, to 3,064 ng*h/ml (30%), 6,009 ng*h/ml (42%) and 15,985 ng*h/ml (45%) in patientswith mild, moderate and severe renal impairment, respectively.

In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drugexposures substantially increased over 72 hours to 53 µg*h/ml (19%) of emtricitabine, and over48 hours to 42,857 ng*h/ml (29%) of tenofovir.

The pharmacokinetics of efavirenz have not been studied in patients with renal impairment. However,less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renalimpairment on exposure to efavirenz is likely to be minimal.

Atripla is not recommended for patients with moderate or severe renal impairment(creatinine clearance < 50 ml/min). Patients with moderate or severe renal impairment require doseinterval adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with thecombination tablet (see sections 4.2 and 4.4).

The pharmacokinetics of Atripla have not been studied in HIV infected patients with hepaticimpairment. Atripla should be administered with caution to patients with mild hepatic impairment(see sections 4.3 and 4.4).

Atripla must not be used in patients with severe hepatic impairment (see section 4.3) and is notrecommended for patients with moderate hepatic impairment. In a single-dose study of efavirenz,half-life was doubled in the single patient with severe hepatic impairment (Child-Pugh-Turcotte

Class C), indicating a potential for a much greater degree of accumulation. A multiple-dose study ofefavirenz showed no significant effect on efavirenz pharmacokinetics in patients with mild hepaticimpairment (Child-Pugh-Turcotte Class A) compared with controls. There were insufficient data todetermine whether moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C) affectsefavirenz pharmacokinetics.

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

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected patients withvarying degrees of hepatic impairment defined according to CPT classification. Tenofovirpharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that nodose adjustment of tenofovir disoproxil is required in these subjects.

Efavirenz: Non-clinical safety pharmacology studies on efavirenz reveal no special hazard for humans.

In repeated-dose toxicity studies, biliary hyperplasia was observed in cynomolgus monkeys givenefavirenz for ≥ 1 year at a dose resulting in mean AUC values approximately 2-fold greater than thosein humans given the recommended dose. The biliary hyperplasia regressed upon cessation of dosing.

Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed in some monkeysreceiving efavirenz for ≥ 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than thosein humans given the recommended dose.

Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays. Carcinogenicitystudies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not inmale mice. The mechanism of tumour formation and the potential relevance for humans are notknown. Carcinogenicity studies in male mice, male and female rats were negative.

Reproductive toxicity studies showed increased foetal resorptions in rats. No malformations wereobserved in foetuses from efavirenz-treated rats and rabbits. However, malformations were observedin 3 of 20 foetuses/newborns from efavirenz-treated cynomolgus monkeys given doses resulting inplasma efavirenz concentrations similar to those seen in humans. Anencephaly and unilateralanophthalmia with secondary enlargement of the tongue were observed in one foetus,microophthalmia was observed in another foetus and cleft palate was observed in a third foetus.

Emtricitabine: Non-clinical data on emtricitabine reveal no special hazard for humans based onconventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicpotential, and toxicity to reproduction and development.

Tenofovir disoproxil: Non-clinical safety pharmacology studies on tenofovir disoproxil reveal nospecial hazard for humans. Findings in repeated-dose toxicity studies in rats, dogs and monkeys atexposure levels greater than or equal to clinical exposure levels and with possible relevance to clinicaluse include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicitywas diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs).

The bone toxicity in young adult rats and dogs occurred at exposures ≥ 5-fold the exposure inpaediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very highexposures following subcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat andmonkey studies indicated that there was a substance-related decrease in intestinal absorption ofphosphate with potential secondary reduction in BMD.

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal resultsin one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rathepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.

Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at anextremely high dose in mice. These tumours are unlikely to be of relevance to humans.

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy orfoetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups inperi-postnatal toxicity studies at maternally toxic doses.

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

Croscarmellose sodium

Hyprolose

Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Sodium laurilsulfate

Iron oxide black

Iron oxide red

Macrogol 3350

Poly(vinyl alcohol)

Talc

Titanium dioxide (E171)

Not applicable.

4 years.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing30 film-coated tablets and silica gel desiccant.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/07/430/001

EU/1/07/430/002

Date of first authorisation: 13 December 2007

Date of latest renewal: 17 September 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.