EFAVIRENZ/EMTRICITABINA/TENOFOVIR DISOPROXIL MYLAN 600mg / 200mg / 245mg tablets medication leaflet

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan 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 maleate).

Each film-coated tablet contains 7.5 mg of sodium metabisulfite and 105.5 mg of lactosemonohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Pink capsule-shaped, biconvex, beveled-edge film-coated tablet, approximately 21 mm x 11 mm anddebossed with ‘M’ on one side and ‘TME’ on the other side.

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is a fixed-dose combination of efavirenz,emtricitabine and tenofovir disoproxil. It is indicated for the treatment of human immunodeficiencyvirus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNAlevels of < 50 copies/ml on their current combination antiretroviral therapy for more than threemonths. Patients must not have experienced virological failure on any prior antiretroviral therapy andmust be known not to have harboured virus strains with mutations conferring significant resistance toany of the three components contained in Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan prior toinitiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).

The demonstration of the benefit of efavirenz/emtricitabine/tenofovir disoproxil is primarily based on48-week data from a clinical study in which patients with stable virologic suppression on acombination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovir disoproxil (seesection 5.1). No data are currently available from clinical studies withefavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve or in heavily pretreated patients.

No data are available to support the combination of efavirenz/emtricitabine/tenofovir disoproxil andother antiretroviral agents

Therapy should be initiated by a physician experienced in the management of HIV infection.

The recommended dose of Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is one tablet takenorally once daily.

If a patient misses a dose of Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan within 12 hours ofthe time it is usually taken, the patient should take Efavirenz/Emtricitabine/Tenofovir disoproxil

Mylan as soon as possible and resume the normal dosing schedule. If a patient misses a dose of

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan by more than 12 hours and it is almost time forthe next dose, the patient should not take the missed dose and simply resume the usual dosingschedule.

If the patient vomits within 1 hour of taking Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan,another tablet should be taken. If the patient vomits more than 1 hour after taking

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan he/she does not need to take another dose.

It is recommended that Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan be taken on an emptystomach since food may increase efavirenz exposure and may lead to an increase in the frequency ofadverse reactions (see sections 4.4 and 4.8). In order to improve the tolerability to efavirenz withrespect to undesirable effects on the nervous system, bedtime dosing is recommended (see section4.8).

It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower followingadministration of Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan on an empty stomach ascompared to the individual component tenofovir disoproxil when taken with food (see section 5.2).

Data on the clinical translation of the decrease in pharmacokinetic exposure are not available. Invirologically suppressed patients, the clinical relevance of this reduction can be expected to be limited(see section 5.1).

Where discontinuation of therapy with one of the components of Efavirenz/Emtricitabine/Tenofovirdisoproxil Mylan is indicated or where dose modification is necessary, separate preparations ofefavirenz, emtricitabine and tenofovir disoproxil are available. Please refer to the Summary of Product

Characteristics for these medicinal products.

If therapy with Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is discontinued, considerationshould be given to the long half-life of efavirenz (see section 5.2) and long intracellular half-lives ofemtricitabine and tenofovir. Because of interpatient variability in these parameters and concernsregarding development of resistance, HIV treatment guidelines should be consulted, also taking intoconsideration the reason for discontinuation.

If Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is co-administered with rifampicin to patientsweighing 50 kg or more, an additional 200 mg/day (800 mg total) of efavirenz may be considered (seesection 4.5).

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan should be administered with caution to elderlypatients (see section 4.4).

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is not recommended for patients with moderateor severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate orsevere renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxilthat cannot be achieved with the combination tablet (see sections 4.4 and 5.2).

The pharmacokinetics of efavirenz/emtricitabine/tenofovir disoproxil have not been studied inpatients with hepatic impairment. Patients with mild liver disease (Child-Pugh-Turcotte (CPT), Class

A) may be treated with the normal recommended dose of Efavirenz/Emtricitabine/Tenofovirdisoproxil Mylan (see sections pct. 4.3, pct. 4.4 and 5.2). Patients should be monitored carefully for adversereactions, especially nervous system symptoms related to efavirenz (see sections 4.3 and 4.4).

If Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is discontinued in patients co-infected with

HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis(see section 4.4).

The safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil in children under the age of18 years have not been established (see section 5.2).

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan 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

Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is a fixed-dose combination product, the dose ofefavirenz 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 medicinal products that are known to prolong the QTc interval(proarrhythmic).

These medicinal products 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, efavirenz/emtricitabine/tenofovir disoproxil should not be administeredconcomitantly with other medicinal products containing the same active components, emtricitabine ortenofovir disoproxil. Efavirenz/emtricitabine/tenofovir disoproxil should not be co-administered withproducts containing efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2).

Due to similarities with emtricitabine, efavirenz/emtricitabine/tenofovir disoproxil should not beadministered concomitantly with other cytidine analogues, such as lamivudine (see section 4.5).

Efavirenz/emtricitabine/tenofovir disoproxil should not be administered concomitantly with adefovirdipivoxil or with medicinal products containing tenofovir alafenamide.

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and didanosine is not recommended(see section 4.5).

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir is not recommended since plasma concentrations of velpatasvirand voxilaprevir are expected to decrease following co-administration with efavirenz leading toreduced therapeutic effect of sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir (see section4.5).

No data are available on the safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil incombination with other antiretroviral agents.

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

Switching from a Protease Inhibitor (PI)-based antiretroviral regimen

Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen theswitch to efavirenz/emtricitabine/tenofovir disoproxil may lead to a reduction of the response to thetherapy (see section 5.1). These patients should be carefully monitored for rises in viral load and,since the safety profile of efavirenz differs from that of protease inhibitors, for adverse reactions.

Patients receiving efavirenz/emtricitabine/tenofovir disoproxil or any other antiretroviral therapy maycontinue to develop opportunistic infections and other complications of HIV infection, and thereforeshould remain under close clinical observation by physicians experienced in the treatment of patientswith HIV associated diseases.

The administration of efavirenz/emtricitabine/tenofovir disoproxil with food may increase efavirenzexposure (see section 5.2) and may lead to an increase in frequency of adverse reactions (see section4.8). It is recommended that efavirenz/emtricitabine/tenofovir disoproxil be taken on an emptystomach, preferably at bedtime.

The pharmacokinetics, safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil have notbeen established in patients with significant underlying liver disorders (see section 5.2).

Efavirenz/emtricitabine/tenofovir disoproxil is contraindicated in patients with severe hepaticimpairment (see section 4.3) and not recommended in patients with moderate hepatic impairment.

Since efavirenz is principally metabolised by the CYP system, caution should be exercised inadministering efavirenz/emtricitabine/tenofovir disoproxil to patients with mild hepatic impairment.

These patients should be carefully monitored for efavirenz adverse reactions, especially nervoussystem symptoms. Laboratory tests should be performed to evaluate their liver disease at periodicintervals (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 efavirenz/emtricitabine/tenofovir disoproxil needs to beweighed against the potential risks of significant liver toxicity. In such patients, interruption ordiscontinuation of treatment must be considered (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 HIVinfection 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 efavirenz/emtricitabine/tenofovir disoproxil have not been studied for thetreatment of chronic HBV infection. Emtricitabine and tenofovir individually and in combination haveshown activity against HBV in pharmacodynamic studies (see section 5.1). Limited clinicalexperience suggests that emtricitabine and tenofovir disoproxil have an anti-HBV activity when usedin antiretroviral combination therapy to control HIV infection. Discontinuation ofefavirenz/emtricitabine/tenofovir disoproxil therapy in patients co-infected with HIV and HBV maybe associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBVwho discontinue efavirenz/emtricitabine/tenofovir disoproxil must be closely monitored with bothclinical and laboratory follow-up for at least four months after stopping treatment withefavirenz/emtricitabine/tenofovir disoproxil. If appropriate, resumption of anti-hepatitis B therapymay be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation isnot recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

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 medicinal products with a known risk for

Torsade de Pointes, consider alternatives to efavirenz/emtricitabine/tenofovir disoproxil.

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 notpredictive of 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 medicinal productsprimarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may requireperiodic monitoring of plasma levels. In a medicinal product interaction study, carbamazepine plasmaconcentrations were decreased when carbamazepine was co-administered with efavirenz (see section4.5). Caution must be taken in any patient with a history of seizures.

Efavirenz/emtricitabine/tenofovir disoproxil is not recommended for patients with moderate or severerenal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renalimpairment require a dose adjustment of emtricitabine and tenofovir disoproxil that cannot beachieved with the combination tablet (see sections 4.2 and 5.2). Use of

Efavirenz/emtricitabine/tenofovir disoproxil should be avoided with concurrent or recent use of anephrotoxic medicinal product. If concomitant use of efavirenz/emtricitabine/tenofovir disoproxil andnephrotoxic agents (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine,vancomycin, cidofovir, interleukin-2) is unavoidable, renal function must be monitored weekly (seesection 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 efavirenz/emtricitabine/tenofovir disoproxil is co-administered with an

NSAID, renal function should be monitored 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 withefavirenz/emtricitabine/tenofovir disoproxil and renal function (creatinine clearance and serumphosphate) is also monitored after two to four weeks of treatment, after three months of treatment andevery three to six months thereafter in patients without renal risk factors. In patients with a history ofrenal dysfunction or in patients who are at risk of renal dysfunction, a more frequent monitoring ofrenal 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 efavirenz/emtricitabine/tenofovir disoproxil, renal function must be re-evaluatedwithin one week, including measurements of blood glucose, blood potassium and urine glucoseconcentrations (see section 4.8, proximal tubulopathy). Since efavirenz/emtricitabine/tenofovirdisoproxil is a combination product and the dosing interval of the individual components cannot bealtered, treatment with efavirenz/emtricitabine/tenofovir disoproxil must be interrupted in patientswith confirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl(0.32 mmol/l). Interrupting treatment with efavirenz/emtricitabine/tenofovir disoproxil should also beconsidered in case of progressive decline of renal function when no other cause has been identified.

Where discontinuation of therapy with one of the components of efavirenz/emtricitabine/tenofovirdisoproxil is indicated or where dose modification is necessary, separate preparations 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 tenofovir disoproxil-induced proximal renal tubulopathy (see section 4.8).

Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil inrandomized controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients.

These BMD decreases generally improved after treatment discontinuation.

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 or with a history ofbone 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 ofefavirenz/emtricitabine/tenofovir disoproxil. The rash associated with the efavirenz componentusually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids mayimprove tolerability and hasten the resolution of rash. Severe rash associated with blistering, moistdesquamation or ulceration has been reported in less than 1% of patients treated with efavirenz (seesection 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately0.1%. Efavirenz/emtricitabine/tenofovir disoproxil must be discontinued in patients developing severerash associated with blistering, desquamation, mucosal involvement or fever. Experience withefavirenz in patients who discontinued other antiretroviral agents of the non-nucleoside reversetranscriptase inhibitors (NNRTI) class is limited. Efavirenz/emtricitabine/tenofovir disoproxil is notrecommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnsonsyndrome) 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;these have predominantly concerned treatment with regimens containing zidovudine. The mainadverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolicdisorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onsetneurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. These findingsshould be considered for any child exposed in utero to nucleos(t)ide analogues, who present withsevere clinical findings of unknown etiology, particularly neurologic findings. These findings do notaffect current national recommendations to use antiretroviral therapy in pregnant women to preventvertical transmission 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

Efavirenz/emtricitabine/tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the

K65R, M184V/I or K103N mutation (see sections 4.1 and 5.1).

Efavirenz/emtricitabine/tenofovir disoproxil has not been studied in patients over the age of 65.

Elderly patients are more likely to have decreased hepatic or renal function, therefore caution shouldbe exercised when treating elderly patients with efavirenz/emtricitabine/tenofovir disoproxil (seesection 4.2).

This medicinal product contains 7.5 mg of sodium metabisulfite per dose, which may rarely causesevere hypersensitivity reactions and bronchospasm.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

This medicinal product contains 105.5 mg of lactose. Patients with rare hereditary problems ofgalactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take thismedicinal product.

As Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan contains efavirenz, emtricitabine andtenofovir disoproxil, any interactions that have been identified with these agents individually mayoccur with Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan. Interaction studies with these agentshave only been performed in adults.

As a fixed combination, efavirenz/emtricitabine/tenofovir disoproxil should not be administeredconcomitantly with other medicinal products containing the components, emtricitabine or tenofovirdisoproxil. Efavirenz/emtricitabine/tenofovir disoproxil should not be co-administered with productscontaining efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2). Due tosimilarities with emtricitabine, efavirenz/emtricitabine/tenofovir disoproxil should not beadministered concomitantly with other cytidine analogues, such as lamivudine.

Efavirenz/emtricitabine/tenofovir disoproxil should not be administered concomitantly with adefovirdipivoxil 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/emtricitabine/tenofovir disoproxil with metamizole, which is aninducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasmaconcentrations of efavirenz/emtricitabine/tenofovir disoproxil with potential decrease in clinicalefficacy. Therefore, caution is advised when metamizole and efavirenz/emtricitabine/tenofovirdisoproxil are administered concurrently; clinical response and/or medicinal product levels should bemonitored 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 or herbalpreparations (for example Ginkgo biloba extracts and St. John's wort) which induce these enzymesmay give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John's wort iscontraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not recommended (seesection 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 receivingefavirenz. Confirmatory testing by a more specific method such as gas chromatography/massspectrometry is recommended in such cases.

Contraindications of concomitant use

Efavirenz/emtricitabine/tenofovir disoproxil 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 theirmetabolism may lead to serious, life-threatening events (see section 4.3).

Elbasvir/grazoprevir: Co administration of efavirenz/emtricitabine/tenofovir disoproxil withelbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response toelbasvir/grazoprevir (see section 4.3 and Table 1).

Voriconazole: Co-administration of standard doses of efavirenz and voriconazole is contraindicated.

Since efavirenz/emtricitabine/tenofovir disoproxil is a fixed-dose combination product, the dose ofefavirenz cannot be altered; therefore, voriconazole and efavirenz/emtricitabine/tenofovir disoproxilmust not be co-administered (see section 4.3 and Table 1).

St. John's wort (Hypericum perforatum): Co-administration of efavirenz/emtricitabine/tenofovirdisoproxil and St. John's wort or herbal preparations containing St. John's wort is contraindicated.

Plasma levels of efavirenz can be reduced by concomitant use of St. John's wort due to induction ofmedicinal product metabolising enzymes and/or transport proteins by St. John's wort. If a patient isalready taking St. John's wort, stop St. John's wort, check viral levels and if possible efavirenz levels.

Efavirenz levels may increase on stopping St. John's wort. The inducing effect of St. John's wort maypersist for at least 2 weeks after cessation of treatment (see section 4.3).

QT Prolonging medicinal products: efavirenz/emtricitabine/tenofovir disoproxil is contraindicatedwith concomitant use of medicinal products that are known to prolong the QTc interval and could leadto Torsade de Pointes, such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressantagents, certain antibiotics including some agents of the following classes: macrolides,fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics(terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3).

Atazanavir/ritonavir: Insufficient data are available to make a dosing recommendation foratazanavir/ritonavir in combination with efavirenz/emtricitabine/tenofovir disoproxil. Therefore co-administration of atazanavir/ritonavir and efavirenz/emtricitabine/tenofovir disoproxil is notrecommended (see Table 1).

Didanosine: Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and didanosine is notrecommended (see Table 1).

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir: Co-administration ofefavirenz/emtricitabine/tenofovir disoproxil and sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir is not recommended (see section 4.4 and Table 1).

Praziquantel: Concomitant use of efavirenz with praziquantel is not recommended due to significantdecrease in plasma concentrations of praziquantel, with risk of treatment failure due to increasedhepatic metabolism by efavirenz. In case the combination is needed, an increased dose of praziquantelcould be considered.

Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated bythe kidneys, co-administration of efavirenz/emtricitabine/tenofovir disoproxil with medicinal productsthat reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serumconcentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of efavirenz/emtricitabine/tenofovir disoproxil should be avoided with concurrent or recent use ofa nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides,amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (seesection 4.4).

Interactions between efavirenz/emtricitabine/tenofovir disoproxil or its individual component(s) andother medicinal products are listed in Table 1 below (increase is indicated as ‘↑’, decrease as ‘↓’, nochange as ‘↔’, twice daily as ‘b.i.d.’, once daily as ‘q.d.’ and once every 8 hours as ‘q8h’). Ifavailable, 90% confidence intervals are shown in parentheses.

Table 1: Interactions between efavirenz/emtricitabine/tenofovir disoproxil or its individualcomponents and other medicinal products

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

ANTI-INFECTIVES

HIV antivirals

Protease inhibitors

Atazanavir/ritonavir/Tenofovir Atazanavir: Co-administration ofdisoproxil AUC: ↓ 25% (↓ 42 to ↓ 3) atazanavir/ritonavir and(300 mg q.d./100 mg q.d./245 mg q.d.) Cmax: ↓ 28% (↓ 50 to ↑ 5) efavirenz/emtricitabine/tenofovir

Cmin: ↓ 26% (↓ 46 to ↑ 10) disoproxil is not recommended.

Co-administration ofatazanavir/ritonavir withtenofovir resulted in increasedexposure to tenofovir. Highertenofovir concentrations couldpotentiate tenofovir-associatedadverse events, including renaldisorders.

Atazanavir/ritonavir/Efavirenz Atazanavir (pm):

(400 mg q.d./100 mg q.d./600 mg q.d., AUC: ↔* (↓ 9% to ↑ 10%)all 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., AUC: ↔*/** (↓ 10% to ↑ 26%)all administered with food) Cmax: ↔*/** (↓ 5% to ↑ 26%)

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

* When compared to atazanavir300 mg/ritonavir 100 mg q.d. inthe evening without efavirenz.

This decrease in atazanavir Cminmight negatively impact theefficacy of atazanavir.

** based on historicalcomparison.

Co-administration of efavirenzwith atazanavir/ritonavir is notrecommended.

Atazanavir/ritonavir/Emtricitabine Interaction not studied.

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Darunavir/ritonavir/Efavirenz Darunavir: Efavirenz/emtricitabine/tenofovir(300 mg b.i.d.*/100 mg b.i.d./600 mg AUC: ↓ 13% disoproxil in combination withq.d.) Cmin: ↓ 31% darunavir/ritonavir 800/100 mg once

Cmax: ↓ 15% daily may result in suboptimal

*lower than recommended doses; similar (CYP3A4 induction) darunavir Cmin. Iffindings are expected with recommended Efavirenz: efavirenz/emtricitabine/tenofovirdoses. AUC: ↑ 21% disoproxil is to be used in

Cmin: ↑ 17% combination with darunavir/ritonavir,

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

Darunavir/ritonavir/Tenofovir disoproxil Darunavir: Darunavir/ritonavir should be used(300 mg b.i.d.*/100 mg b.i.d./245 mg AUC: ↔ with caution in combination withq.d.) Cmin: ↔ efavirenz/emtricitabine/tenofovir

Tenofovir: disoproxil. See ritonavir row below.

AUC: ↑ 22% Monitoring of renal function may be

*lower than recommended dose C : ↑ 37% indicated, particularly in patients withminunderlying systemic or renal disease,

Darunavir/ritonavir/Emtricitabine Interaction not studied. Based onor in patients taking nephrotoxicthe different eliminationagents.pathways, no interaction isexpected.

Fosamprenavir/ritonavir/Efavirenz No clinically significant Efavirenz/emtricitabine/tenofovir(700 mg b.i.d./100 mg b.i.d./600 mg pharmacokinetic interaction. disoproxil andq.d.) fosamprenavir/ritonavir can be co-

Fosamprenavir/ritonavir/Emtricitabine Interaction not studied. administered without doseadjustment.

Fosamprenavir/ritonavir/Tenofovir Interaction not studied.

See ritonavir row below.disoproxil

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

Cmax: ↔ indinavir when dosed with

Cmin: ↔ efavirenz/emtricitabine/tenofovir

Indinavir: disoproxil. While the clinical

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

Cmin: ↓ 40% concentrations has not been

A similar reduction in indinavir established, the magnitude of theexposures was observed when observed pharmacokinetic interactionindinavir 1,000 mg q8h was should be taken into considerationgiven with efavirenz 600 mg q.d. when choosing a regimen containing(CYP3A4 induction). both efavirenz, a component of

For co-administration of efavirenz/emtricitabine/tenofovirefavirenz with low-dose disoproxil, and indinavir.

ritonavir in combination with a

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)protease inhibitor, see section onritonavir below.

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: ↔

Lopinavir/ritonavir/Tenofovir disoproxil Lopinavir/Ritonavir: Insufficient data are available to(400 mg b.i.d./100 mg b.i.d./245 mg AUC: ↔ make a dosing recommendation forq.d.) Cmax: ↔ lopinavir/ritonavir when dosed with

Cmin: ↔ efavirenz/emtricitabine/tenofovir

Tenofovir: disoproxil. Co-administration of

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

Cmax: ↔ efavirenz/emtricitabine/tenofovir

Cmin: ↑ 51% (↑ 37 to ↑ 66) disoproxil is not recommended.

Higher tenofovir concentrationscould potentiate tenofovir-associated adverse events,including renal disorders.

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

When used in combination withefavirenz and two NRTIs,533/133 mg lopinavir/ritonavir(soft capsules) twice dailyyielded similar lopinavir plasmaconcentrations as compared tolopinavir/ritonavir (softcapsules) 400/100 mg twicedaily without efavirenz(historical data).

Lopinavir/ritonavir tablets/Efavirenz(400/100 mg b.i.d./600 mg q.d.)

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Lopinavir concentrations: ↓ 30-(500/125 mg b.i.d./600 mg q.d.) 40%

Lopinavir concentrations:

similar to lopinavir/ritonavir400/100 mg twice daily withoutefavirenz. Dose adjustment oflopinavir/ritonavir is necessarywhen given with efavirenz. Forco-administration of efavirenzwith low-dose ritonavir incombination with a proteaseinhibitor, see section on ritonavirbelow.

Lopinavir/ritonavir/Emtricitabine Interaction not studied.

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

Evening AUC: ↔ disoproxil is not recommended.

Morning Cmax: ↑ 24% (↑ 12 to When using↑ 38) efavirenz/emtricitabine/enofovir

Evening Cmax: ↔ disoproxil with low-dose ritonavir,

Morning Cmin: ↑ 42% (↑ 9 to the possibility of an increase in the↑ 86) incidence of efavirenz-associated

Evening Cmin: ↑ 24% (↑ 3 to adverse events should be considered,↑ 50) due to possible pharmacodynamic

Efavirenz: interaction.

AUC: ↑ 21% (↑ 10 to ↑ 34)

Cmax: ↑ 14% (↑ 4 to ↑ 26)

Cmin: ↑ 25% (↑ 7 to ↑ 46)(inhibition of CYP-mediatedoxidative metabolism)

When efavirenz was given withritonavir 500 mg or 600 mgtwice daily, the combination wasnot well tolerated (for example,dizziness, nausea, paraesthesiaand elevated liver enzymesoccurred). Sufficient data on thetolerability of efavirenz withlow-dose ritonavir (100 mg,once or twice daily) are notavailable.

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Ritonavir/Emtricitabine Interaction not studied.

Ritonavir/Tenofovir disoproxil Interaction not studied.

Saquinavir/ritonavir/Efavirenz Interaction not studied. For co- Insufficient data are available toadministration of efavirenz with make a dosing recommendation forlow-dose ritonavir in saquinavir/ritonavir when dosed withcombination with a protease efavirenz/emtricitabine/tenofovirinhibitor, see section on ritonavir disoproxil. Co-administration ofabove. saquinavir/ritonavir and

Saquinavir/ritonavir/Tenofovir There were no clinically efavirenz/emtricitabine/tenofovirdisoproxil significant pharmacokinetic disoproxil is not recommended. Useinteractions when tenofovir of efavirenz/emtricitabine/tenofovirdisoproxil was co-administered disoproxil in combination withwith ritonavir boosted saquinavir as the sole proteasesaquinavir. inhibitor is not recommended.

Saquinavir/ritonavir/Emtricitabine Interaction not studied.

CCR5 antagonist

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

Cmax: ↓ 51% (↓ 37 to ↓ 62) product containing 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.

Integrase strand transfer inhibitor

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

C12h: ↓ 21% administered without dose

Cmax: ↓ 36% adjustment.

(UGT1A1 induction)

Raltegravir/Tenofovir disoproxil Raltegravir:

(400 mg b.i.d./-) AUC: ↑ 49%

C12h: ↑ 3%

Cmax: ↑ 64%(mechanism of interactionunknown)

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Tenofovir:

AUC: ↓ 10%

C12h: ↓ 13%

Cmax: ↓ 23%

Raltegravir/Emtricitabine Interaction not studied.

NRTIs and NNRTIs

NRTIs/Efavirenz Specific interaction studies have Due to the similarity betweennot been performed with lamivudine and emtricitabine, aefavirenz and NRTIs other than component oflamivudine, zidovudine and efavirenz/emtricitabine/tenofovirtenofovir disoproxil. Clinically disoproxil,significant interactions have not efavirenz/emtricitabine/tenofovirbeen found and would not be disoproxil should not be administeredexpected since the NRTIs are concomitantly with lamivudine (seemetabolised via a different route section 4.4).

than efavirenz and would beunlikely to compete for the samemetabolic enzymes andelimination pathways.

NNRTIs/Efavirenz Interaction not studied. Since use of two NNRTIs proved notbeneficial in terms of efficacy andsafety, co-administration ofefavirenz/emtricitabine/tenofovirdisoproxil and another NNRTI is notrecommended.

Didanosine/Tenofovir disoproxil Co-administration of tenofovir Co-administration ofdisoproxil and didanosine results efavirenz/emtricitabine/tenofovirin a 40-60% increase in systemic disoproxil and didanosine is notexposure to didanosine. recommended.

Didanosine/Efavirenz Interaction not studied.

Increased systemic exposure to

Didanosine/Emtricitabine Interaction not studied.

didanosine may increase didanosinerelated adverse reactions. Rarely,pancreatitis and lactic acidosis,sometimes fatal, have been reported.

Co-administration of tenofovirdisoproxil and didanosine at a dose of400 mg daily has been associatedwith a significant decrease in CD4cell count, possibly due to anintracellular interaction increasing

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)phosphorylated (i.e. active)didanosine. A decreased dose of250 mg didanosine co-administeredwith tenofovir disoproxil therapy hasbeen associated with reports of highrates of virological failure withinseveral tested combinations for thetreatment of HIV-1 infection.

Hepatitis C antivirals

Elbasvir/Grazoprevir + Elbasvir: Co administration of

Efavirenz AUC: ↓ 54% efavirenz/emtricitabine/tenofovir

Cmax: ↓ 45% disoproxil with elbasvir/grazoprevir(CYP3A4 or P gp induction - is contraindicated because it may leadeffect on elbasvir) to loss of virologic response toelbasvir/grazoprevir. This loss is due

Grazoprevir: to significant decreases in

AUC: ↓ 83% elbasvir/grazoprevir plasma

Cmax: ↓ 87% concentrations caused by CYP3A4 or(CYP3A4 or P gp induction - P gp induction. Refer to theeffect on grazoprevir) Summary of Product Characteristicsfor elbasvir/grazoprevir for more

Efavirenz: information.

AUC: ↔

Cmax: ↔

Glecaprevir/Pibrentasvir/Efavirenz Expected: Concomitant administration of

Glecaprevir: ↓ glecaprevir/pibrentasvir with

Pibrentasvir: ↓ efavirenz, a component ofefavirenz/emtricitabine/tenofovirdisoproxil, may significantly decreaseplasma concentrations of glecaprevirand pibrentasvir, leading to reducedtherapeutic effect. Coadministrationof glecaprevir/pibrentasvir withefavirenz/emtricitabine/tenofovirdisoproxil is not recommended. Referto the prescribing information forglecaprevir/pibrentasvir for moreinformation.

Ledipasvir/Sofosbuvir Ledipasvir: No dose adjustment is recommended.

(90 mg/400 mg q.d.) + AUC: ↓ 34% (↓ 41 to ↓ 25) The increased exposure of tenofovir

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Efavirenz/Emtricitabine/Tenofovir Cmax: ↓ 34% (↓ 41 to ↑ 25) could potentiate adverse reactionsdisoproxil Cmin: ↓ 34% (↓ 43 to ↑ 24) associated with tenofovir disoproxil,(600 mg/200 mg/245 mg q.d.) Sofosbuvir: including renal disorders. Renal

AUC: ↔ function should be closely monitored

Cmax: ↔ (see section 4.4).

GS-3310071:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98% (↑ 77 to ↑ 123)

Cmax: ↑ 79% (↑ 56 to ↑ 104)

Cmin: ↑ 163% (↑ 137 to ↑ 197)

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

Efavirenz/Emtricitabine/Tenofovir Cmax: ↑ 38% (↑ 14 to ↑ 67) disoproxil and sofosbuvir/velpatasvirdisoproxil GS-3310071: or sofosbuvir/velpatasvir/voxilaprevir(600 mg/200 mg/245 mg q.d.) AUC: ↔ is expected to decrease plasma

Cmax: ↔ concentrations of velpatasvir and

Cmin: ↔ voxilaprevir. Co-administration of

Velpatasvir : efavirenz/emtricitabine/tenofovir

AUC: ↓ 53% (↓ 61 to ↓ 43) disoproxil with sofosbuvir/velpatasvir

Cmax: ↓ 47% (↓ 57 to ↓ 36) or sofosbuvir/velpatasvir/voxilaprevir

Cmin: ↓ 57% (↓ 64 to ↓ 48) is not recommended (see section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81% (↑ 68 to ↑ 94)

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

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: Efavirenz/emtricitabine/tenofovir(400 mg q.d.) + AUC: ↔ disoproxil and sofosbuvir can be co-

Efavirenz/Emtricitabine/Tenofovir Cmax: ↓ 19% (↓ 40 to ↑ 10) administered without dosedisoproxil GS-3310071: adjustment.

(600 mg/200 mg/245 mg q.d.) AUC: ↔

Cmax: ↓ 23% (↓ 30 to ↑ 16)

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 25% (↑ 8 to ↑ 45)

Cmin: ↔

Antibiotics

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

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

Clarithromycin 14- Alternatives to clarithromycin (e.g.

hydroxymetabolite: azithromycin) may be considered.

AUC: ↑ 34% (↑ 18 to ↑ 53) Other macrolide antibiotics, such as

Cmax: ↑ 49% (↑ 32 to ↑ 69) erythromycin, have not been studied

Efavirenz: in combination with

AUC: ↔ efavirenz/emtricitabine/tenofovir

Cmax: ↑ 11% (↑ 3 to ↑ 19) disoproxil.

(CYP3A4 induction)

Rash developed in 46% ofuninfected volunteers receivingefavirenz and clarithromycin.

Clarithromycin/Emtricitabine Interaction not studied.

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Clarithromycin/Tenofovir disoproxil Interaction not studied.

Antimycobacterials

Rifabutin/Efavirenz Rifabutin: The daily dose of rifabutin should be(300 mg q.d./600 mg q.d.) AUC: ↓ 38% (↓ 28 to ↓ 47) increased by 50% when given with

Cmax: ↓ 32% (↓ 15 to ↓ 46) Efavirenz/emtricitabine/tenofovir

Cmin: ↓ 45% (↓ 31 to ↓ 56) disoproxil. Consider doubling the

Efavirenz: rifabutin dose in regimens where

AUC: ↔ rifabutin is given 2 or 3 times a week

Cmax: ↔ in combination with

Cmin: ↓ 12% (↓ 24 to ↑ 1) efavirenz/emtricitabine/tenofovir(CYP3A4 induction) disoproxil. The clinical effect of this

Rifabutin/Emtricitabine Interaction not studied. dose adjustment has not beenadequately evaluated. Individual

Rifabutin/Tenofovir disoproxil Interaction not studied.

tolerability and virological responseshould be considered when makingthe dose adjustment (see section 5.2).

Rifampicin/Efavirenz Efavirenz: When(600 mg q.d./600 mg q.d.) AUC: ↓ 26% (↓ 15 to ↓ 36) efavirenz/emtricitabine/tenofovir

Cmax: ↓ 20% (↓ 11 to ↓ 28) disoproxil is taken with rifampicin in

Cmin: ↓ 32% (↓ 15 to ↓ 46) patients weighing 50 kg or greater, an(CYP3A4 and CYP2B6 additional 200 mg/day (800 mg total)induction) of efavirenz may provide exposure

Rifampicin/Tenofovir disoproxil Rifampicin: similar to a daily efavirenz dose of(600 mg q.d./245 mg q.d.) AUC: ↔ 600 mg when taken without

C : ↔ rifampicin. The clinical effect of thismax

Tenofovir: dose adjustment has not been

AUC: ↔ adequately evaluated. Individual

C : ↔ tolerability and virological responsemaxshould be considered when making

Rifampicin/Emtricitabine Interaction not studied.

the dose adjustment (see section 5.2).

No dose adjustment of rifampicin isrecommended when given withefavirenz/emtricitabine/tenofovirdisoproxil.

Antifungals

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

Cmax: ↓ 37% (↓ 20 to ↓ 51) with efavirenz/emtricitabine/tenofovir

Cmin: ↓ 44% (↓ 27 to ↓ 58)

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)(decrease in itraconazole disoproxil, an alternative antifungalconcentrations: CYP3A4 treatment should be considered.

induction)

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 posaconazole and(-/400 mg q.d.) AUC: ↓ 50% efavirenz/emtricitabine/tenofovir

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

Posaconazole/Emtricitabine Interaction not studied. the risk.

Posaconazole/Tenofovir disoproxil Interaction not studied.

Voriconazole/Efavirenz Voriconazole: Since(200 mg b.i.d./400 mg q.d.) AUC: ↓ 77% efavirenz/emtricitabine/tenofovir

Cmax: ↓ 61% disoproxil is a fixed-dose

Efavirenz: combination product, the dose of

AUC: ↑ 44% efavirenz cannot be altered; therefore,

Cmax: ↑ 38% voriconazole and(competitive inhibition of efavirenz/emtricitabine/tenofoviroxidative metabolism) disoproxil must not be co-

Co-administration of standard administered.

doses of efavirenz andvoriconazole is contraindicated(see section 4.3).

Voriconazole/Emtricitabine Interaction not studied.

Voriconazole/Tenofovir disoproxil Interaction not studied.

Antimalarials

Artemether/Lumefantrine/Efavirenz Artemether: Since decreased concentrations of(20/120 mg tablet, 6 doses of 4 tablets AUC: ↓ 51% artemether, dihydroartemisinin, oreach over 3 days/600 mg q.d.) Cmax: ↓ 21% lumefantrine may result in a decrease

Dihydroartemisinin (active of antimalarial efficacy, caution ismetabolite): recommended when

AUC: ↓ 46% efavirenz/emtricitabine/tenofovir

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Cmax: ↓ 38% disoproxil and

Lumefantrine: artemether/lumefantrine tablets are

AUC: ↓ 21% co-administered.

Cmax: ↔

AUC: ↓ 17%

Cmax: ↔(CYP3A4 induction)

Artemether/Lumefantrine/Emtricitabine Interaction not studied.

Artemether/Lumefantrine/Tenofovir Interaction not studied.

disoproxil

Atovaquone and proguanil Atovaquone: Concomitant administration ofhydrochloride/Efavirenz AUC: ↓ 75% (↓ 62 to ↓ 84) atovaquone/proguanil with(250/100 mg single dose/600 mg q.d.) Cmax: ↓ 44% (↓ 20 to ↓ 61) efavirenz/emtricitabine/tenofovir

Proguanil: disoproxil should be 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 can be(400 mg q.d./600 mg q.d.) AUC: ↓ 27% (↓ 20 to ↓ 33) made for the use of

Cmax: ↓ 20% (↓ 15 to ↓ 24) efavirenz/emtricitabine/tenofovir

Cmin: ↓ 35% (↓ 24 to ↓ 44) disoproxil with carbamazepine. An

Efavirenz: alternative anticonvulsant should be

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

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

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

(decrease in carbamazepineconcentrations: CYP3A4induction; decrease in efavirenzconcentrations: CYP3A4 and

CYP2B6 induction)

Co-administration of higherdoses of either efavirenz orcarbamazepine has not beenstudied.

Carbamazepine/Emtricitabine Interaction not studied.

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Carbamazepine/Tenofovir disoproxil Interaction not studied.

Phenytoin, Phenobarbital, and other Interaction not studied with Whenanticonvulsants that are substrates of efavirenz, emtricitabine, or efavirenz/emtricitabine/tenofovir

CYP isozymes tenofovir disoproxil. There is a disoproxil is co-administered with anpotential for reduction or anticonvulsant that is a substrate ofincrease in the plasma CYP isozymes, periodic monitoringconcentrations of phenytoin, of anticonvulsant levels should bephenobarbital and other conducted.

anticonvulsants that aresubstrates of CYP isozymes withefavirenz.

Valproic acid/Efavirenz No clinically significant effect Efavirenz/emtricitabine/tenofovir(250 mg b.i.d./600 mg q.d.) on efavirenz pharmacokinetics. disoproxil and valproic acid can be

Limited data suggest there is no co-administered without doseclinically significant effect on adjustment. Patients should bevalproic acid pharmacokinetics. monitored for seizure control.

Valproic acid/Emtricitabine Interaction not studied.

Valproic acid/Tenofovir disoproxil Interaction not studied.

Vigabatrin/Efavirenz Interaction not studied. Efavirenz/emtricitabine/tenofovir

Gabapentin/Efavirenz Clinically significant disoproxil and vigabatrin orinteractions are not expected gabapentin can be co-administeredsince vigabatrin and gabapentin without dose adjustment.

are exclusively eliminatedunchanged in the urine and areunlikely to compete for the samemetabolic enzymes andelimination pathways asefavirenz.

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 warfarin or

Acenocoumarol/Efavirenz concentrations and effects of acenocoumarol may be requiredwarfarin or acenocoumarol are when co-administered withpotentially increased or efavirenz/emtricitabine/tenofovirdecreased by efavirenz. disoproxil.

ANTIDEPRESSANTS

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Selective serotonin reuptake inhibitors (SSRIs)

Sertraline/Efavirenz Sertraline: When co-administered with(50 mg q.d./600 mg q.d.) AUC: ↓ 39% (↓ 27 to ↓ 50) efavirenz/emtricitabine/tenofovir

Cmax: ↓ 29% (↓ 15 to ↓ 40) disoproxil, sertraline dose increases

Cmin: ↓ 46% (↓ 31 to ↓ 58) should be guided by clinical

Efavirenz: response.

AUC: ↔

Cmax: ↑ 11% (↑ 6 to ↑ 16)

Cmin: ↔(CYP3A4 induction)

Sertraline/Emtricitabine Interaction not studied.

Sertraline/Tenofovir disoproxil Interaction not studied.

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

Cmax: ↔ administered without dose

Cmin: ↔ adjustment.

AUC: ↔

Cmax: ↔

Cmin: ↔

Paroxetine/Emtricitabine Interaction not studied.

Paroxetine/Tenofovir disoproxil Interaction not studied.

Fluoxetine/Efavirenz Interaction not studied. Since Efavirenz/emtricitabine/tenofovirfluoxetine shares a similar disoproxil and fluoxetine can be co-metabolic profile with administered without doseparoxetine, i.e. a strong CYP2D6 adjustment.

inhibitory effect, a similar lackof 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 dose should[150 mg single dose (sustained AUC: ↓ 55% (↓ 48 to ↓ 62) be guided by clinical response, butrelease)/600 mg q.d.] Cmax: ↓ 34% (↓ 21 to ↓ 47) the maximum recommended dose of

Hydroxybupropion: bupropion should not be exceeded.

AUC: ↔ No dose adjustment is necessary for

Cmax: ↑ 50% (↑ 20 to ↑ 80) efavirenz.

(CYP2B6 induction)

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Bupropion/Emtricitabine Interaction not studied.

Bupropion/Tenofovir disoproxil Interaction not studied.

CARDIOVASCULAR AGENTS

Calcium channel blockers

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

Cmax: ↓ 60% (↓ 50 to ↓ 68) efavirenz/emtricitabine/tenofovir

Cmin: ↓ 63% (↓ 44 to ↓ 75) disoproxil should be guided by

Desacetyl diltiazem: clinical response (refer to the

AUC: ↓ 75% (↓ 59 to ↓ 84) Summary of Product Characteristics

Cmax: ↓ 64% (↓ 57 to ↓ 69) for 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 isnot considered clinicallysignificant.

Diltiazem/Emtricitabine Interaction not studied.

Diltiazem/Tenofovir disoproxil Interaction not studied.

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

Nicardipine efavirenz, emtricitabine, or blockers when co-administered withtenofovir disoproxil. When efavirenz/emtricitabine/tenofovirefavirenz is co-administered disoproxil should be guided bywith a calcium channel blocker clinical response (refer to thethat is a substrate of the Summary of Product Characteristics

CYP3A4 enzyme, there is a for the calcium channel blocker).

potential for reduction in theplasma concentrations of thecalcium channel blocker.

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A reductase inhibitors

Atorvastatin/Efavirenz Atorvastatin:

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)(10 mg q.d./600 mg q.d.) AUC: ↓ 43% (↓ 34 to ↓ 50) Cholesterol levels should be

Cmax: ↓ 12% (↓ 1 to ↓ 26) periodically monitored. Dose2-hydroxy atorvastatin: adjustments of atorvastatin may be

AUC: ↓ 35% (↓ 13 to ↓ 40) required when co-administered with

Cmax: ↓ 13% (↓ 0 to ↓ 23) efavirenz/emtricitabine/tenofovir4-hydroxy atorvastatin: disoproxil (refer to the Summary of

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

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

Total active HMG Co-Areductase inhibitors:

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 be(40 mg q.d./600 mg q.d.) AUC: ↓ 40% (↓ 26 to ↓ 57) periodically monitored. Dose

Cmax: ↓ 18% (↓ 59 to ↑ 12) adjustments of pravastatin may be

Pravastatin/Emtricitabine Interaction not studied. required when co-administered withefavirenz/emtricitabine/tenofovir

Pravastatin/Tenofovir disoproxil Interaction not studied.

disoproxil (refer to the Summary of

Product Characteristics forpravastatin).

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

Cmax: ↓ 76% (↓ 63 to ↓ 79) adjustments of simvastatin may be

Simvastatin acid: required when co-administered with

AUC: ↓ 58% (↓ 39 to ↓ 68) efavirenz/emtricitabine/tenofovir

Cmax: ↓ 51% (↓ 32 to ↓ 58) disoproxil (refer to the Summary of

Total active HMG Co-A Product Characteristics forreductase inhibitors: simvastatin).

AUC: ↓ 60% (↓ 52 to ↓ 68)

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

Co-administration of efavirenzwith atorvastatin, pravastatin, orsimvastatin did not affectefavirenz AUC or Cmax values.

Simvastatin/Emtricitabine Interaction not studied.

Simvastatin/Tenofovir disoproxil Interaction not studied.

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

Rosuvastatin/Efavirenz Interaction not studied. Efavirenz/emtricitabine/tenofovir

Rosuvastatin is largely excreted disoproxil and rosuvastatin can be co-unchanged via the faeces, administered without dosetherefore interaction with adjustment.

efavirenz is not expected.

Rosuvastatin/Emtricitabine Interaction not studied.

Rosuvastatin/Tenofovir disoproxil Interaction not studied.

HORMONAL CONTRACEPTIVES

Oral: Ethinylestradiol: A reliable method of barrier

Ethinylestradiol+Norgestimate/ AUC: ↔ contraception must be used in

Efavirenz Cmax: ↔ addition to hormonal contraceptives(0.035 mg+0.25 mg q.d./600 mg q.d.) Cmin: ↓ 8% (↑ 14 to ↓ 25) (see section 4.6).

Norelgestromin (activemetabolite):

AUC: ↓ 64% (↓ 62 to ↓ 67)

Cmax: ↓ 46% (↓ 39 to ↓ 52)

Cmin: ↓ 82% (↓ 79 to ↓ 85)

Levonorgestrel (activemetabolite):

AUC: ↓ 83% (↓ 79 to ↓ 87)

Cmax: ↓ 80% (↓ 77 to ↓ 83)

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

Efavirenz: no clinicallysignificant interaction.

The clinical significance of theseeffects is not known.

Ethinylestradiol/Tenofovir disoproxil Ethinylestradiol:

(-/245 mg q.d.) AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Norgestimate/Ethinylestradiol/ Interaction not studied.

Injection: In a 3-month medicinal product Because of the limited information

Depomedroxyprogesterone acetate interaction study, no significant available, a reliable method of barrier(DMPA)/Efavirenz differences in MPA contraception must be used in(150 mg IM single dose DMPA) pharmacokinetic parameters addition to hormonal contraceptiveswere found between subjects (see section 4.6).

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)receiving efavirenz-containingantiretroviral therapy andsubjects receiving noantiretroviral therapy. Similarresults were found by otherinvestigators, although the MPAplasma levels were morevariable in the second study. Inboth studies, plasmaprogesterone levels for subjectsreceiving efavirenz and DMPAremained low consistent withsuppression of ovulation.

DMPA/Tenofovir disoproxil Interaction not studied.

DMPA/Emtricitabine Interaction not studied.

Implant: Decreased exposure of A reliable method of barrier

Etonogestrel/Efavirenz etonogestrel may be expected contraception must be used in(CYP3A4 induction). There addition to hormonal contraceptiveshave been occasional post- (see section 4.6).

marketing reports ofcontraceptive failure withetonogestrel in efavirenz-exposed patients.

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 may be required.

sirolimus)/Efavirenz immunosuppressant may be Close monitoring ofexpected (CYP3A4 induction). immunosuppressant concentrations

These immunosuppressants are for at least two weeks (until stablenot anticipated to impact concentrations are reached) isexposure of efavirenz. recommended when starting or

Tacrolimus/Emtricitabine/Tenofovir Tacrolimus: stopping treatment withdisoproxil AUC: ↔ efavirenz/emtricitabine/tenofovir(0.1 mg/kg q.d./200 mg/245 mg q.d.) C : ↔ disoproxil.max

C24h: ↔

AUC: ↔

Cmax: ↔

Effects on medicinal productlevels

Recommendation concerning co-administration with

Mean percent change in AUC,

Medicinal product by therapeutic efavirenz/emtricitabine/tenofovir

Cmax, Cmin with 90%areas disoproxil (efavirenz 600 mg,confidence intervals ifemtricitabine 200 mg, tenofoviravailabledisoproxil 245 mg)(mechanism)

C24h: ↔

Tenofovir disoproxil:

AUC: ↔

Cmax: ↔

C24h: ↔

OPIOIDS

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

Cmax: ↓ 45% (↓ 25 to ↓ 59) disoproxil should be avoided due to(CYP3A4 induction) the risk for QTc prolongation (see

In a study of HIV infected section 4.3).

intravenous drug users, co-administration of efavirenz withmethadone resulted in decreasedplasma levels of methadone andsigns of opiate withdrawal. Themethadone dose was increasedby a mean of 22% to alleviatewithdrawal symptoms.

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.

Buprenorphine/naloxone/Efavirenz Buprenorphine: Despite the decrease in

AUC: ↓ 50% buprenorphine exposure, no patients

Norbuprenorphine: exhibited withdrawal symptoms.

AUC: ↓ 71% Dose adjustment of buprenorphine

Efavirenz: may not be necessary when co-

No clinically significant administered withpharmacokinetic interaction. efavirenz/emtricitabine/tenofovir

Buprenorphine/naloxone/Emtricitabine Interaction not studied. disoproxil.

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 wasadministered with stavudine, zidovudine or famciclovir. There were no clinically significantpharmacokinetic interactions when tenofovir disoproxil was co-administered with emtricitabine, orribavirin.

Women of childbearing potential (see below and section 5.3)

Pregnancy should be avoided in women receiving efavirenz/emtricitabine/tenofovir disoproxil.

Women of childbearing potential should undergo pregnancy testing before initiation ofefavirenz/emtricitabine/tenofovir disoproxil.

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 withefavirenz/emtricitabine/tenofovir disoproxil. Because of the long half-life of efavirenz, use ofadequate contraceptive measures for 12 weeks after discontinuation ofefavirenz/emtricitabine/tenofovir disoproxil 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 (1prospective 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 womenexposed to 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 than1,000 pregnancy 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).

Efavirenz/emtricitabine/tenofovir disoproxil should not be used during pregnancy unless the clinicalcondition of the woman requires treatment 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. Arisk to the infants cannot be excluded. Therefore efavirenz/emtricitabine/tenofovir disoproxil shouldnot be used during breast-feeding.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

No human data on the effect of efavirenz/emtricitabine/tenofovir disoproxil are available. Animalstudies do not indicate harmful effects of 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 efavirenz/emtricitabine/tenofovir disoproxil (study

AI266073) or as the component products (study GS-01-934). Adverse reactions were generallyconsistent with those seen in previous studies of the individual components. The most frequentlyreported adverse reactions considered possibly or probably related to efavirenz/emtricitabine/tenofovirdisoproxil among patients treated up to 48 weeks in study AI266073 were psychiatric disorders(16%), nervous system disorders (13%), and gastrointestinal disorders (7%).

Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; 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 efavirenz/emtricitabine/tenofovir disoproxil (see section 4.4).

Discontinuation of efavirenz/emtricitabine/tenofovir disoproxil therapy in patients co-infected with

HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4).

The administration of efavirenz/emtricitabine/tenofovir disoproxil with food may increase efavirenzexposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 5.2).

The adverse reactions from clinical study and post-marketing experience withefavirenz/emtricitabine/tenofovir disoproxil and the individual components ofefavirenz/emtricitabine/tenofovir disoproxil in antiretroviral combination therapy are listed in Table 2below by body system organ class, frequency and the component(s) ofefavirenz/emtricitabine/tenofovir disoproxil to which the adverse reactions are attributable. Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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 efavirenz/emtricitabine/tenofovir disoproxil:

Treatment-emergent adverse reactions considered possibly or probably related toefavirenz/emtricitabine/tenofovir disoproxil reported in study AI266073 (over 48 weeks; n = 203),which have not been associated with one of the individual components ofefavirenz/emtricitabine/tenofovir disoproxil, include:

Common: - anorexia

Uncommon: - dry mouth

- incoherent speech

- increased appetite

- libido decreased

- myalgia

Table 2: Adverse reactions associated with efavirenz/emtricitabine/tenofovir disoproxil listed bythe component(s) of efavirenz/emtricitabine/tenofovir disoproxil to which the adverse reactionsare attributable

Efavirenz/emtricitabine/tenofovir disoproxil

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

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

Efavirenz/emtricitabine/tenofovir disoproxil

Efavirenz Emtricitabine Tenofovir disoproxil

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

Efavirenz/emtricitabine/tenofovir disoproxil

Efavirenz Emtricitabine Tenofovir disoproxil

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

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

Common bone mineral densitydecreased

Uncommon rhabdomyolysis2,muscular weakness2

Rare osteomalacia(manifested as bonepain and infrequentlycontributing tofractures)2,4, myopathy2

Uncommon increased creatinine,proteinuria, proximalrenal tubulopathy

Efavirenz/emtricitabine/tenofovir disoproxil

Efavirenz Emtricitabine Tenofovir disoproxilincluding 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 patients treatedwith efavirenz in clinical studies (n = 3,969) or exposed to emtricitabine in randomised controlled clinical studies (n = 1,563)or exposed to tenofovir disoproxil in randomised controlled clinical studies and the expanded access programme (n = 7,319).

Rash: In clinical studies 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.

Efavirenz/emtricitabine/tenofovir disoproxil can be reinitiated in patients interrupting therapy becauseof rash. Use of appropriate antihistamines and/or corticosteroids is recommended whenefavirenz/emtricitabine/tenofovir disoproxil 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 efavirenz/emtricitabine/tenofovir disoproxil. In clinical controlled studies of efavirenz,nervous system symptoms of moderate to severe intensity were experienced by 19% (severe 2%) ofpatients, and 2% of patients discontinued therapy due to such symptoms. They usually begin duringthe first one or two days of efavirenz therapy and generally resolve after the first two to four weeks.

They may occur more frequently when efavirenz/emtricitabine/tenofovir disoproxil is takenconcomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosingat 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 efavirenz/emtricitabine/tenofovir disoproxil may cause renal damage,monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safetyprofile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxildiscontinuation. However, in some patients, declines in creatinine clearance did not completelyresolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such aspatients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitantnephrotoxic medicinal products) are at increased risk of experiencing incomplete recovery of renalfunction despite tenofovir disoproxil discontinuation (see section 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 medicinal productsknown to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis duringtenofovir disoproxil 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.

Efavirenz/emtricitabine/tenofovir disoproxil is not recommended in this population (see section 4.2).

Elderly: efavirenz/emtricitabine/tenofovir disoproxil has not been studied in patients over the age of65. Elderly patients are more likely to have decreased hepatic or renal function, therefore cautionshould be exercised when treating elderly patients with efavirenz/emtricitabine/tenofovir disoproxil(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 withefavirenz/emtricitabine/tenofovir disoproxil (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( = 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 HIVinfected 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. Itallows 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 emtricitabinetriphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that bothemtricitabine and tenofovir can be fully phosphorylated when combined together in cells.

Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reversetranscriptase, resulting in DNA chain termination.

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 emtricitabinetogether, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive tosynergistic antiviral 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 differentbinding sites on the target and mechanism of action. The potential for cross-resistance betweenefavirenz and PIs is low because of the different enzyme targets involved.

Resistance to emtricitabine or tenofovir disoproxil has been seen in vitro and in some HIV-1 infectedpatients due to the development of an M184V or M184I substitution in RT with emtricitabine or a

K65R substitution in RT with tenofovir disoproxil. Emtricitabine-resistant viruses with the M184V/Imutation were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine,tenofovir disoproxil and zidovudine. The K65R mutation can also be selected by abacavir ordidanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine andtenofovir disoproxil. Tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the

K65R mutation. Both the K65R and M184V/I mutation remain fully susceptible to efavirenz. Inaddition, a K70E substitution in HIV-1 RT has been selected by tenofovir disoproxil and results inlow-level reduced susceptibility to abacavir, emtricitabine, lamivudine and tenofovir disoproxil.

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 from week 96 to 144), genotyping was performed on plasma HIV-1 isolates fromall patients with confirmed HIV RNA > 400 copies/ml at week 144 or early study medicinal productdiscontinuation (see section on Clinical experience). As of week 144:

* The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in the efavirenz+ emtricitabine + tenofovir disoproxil group and in 10/29 (34.5%) isolates analysed from theefavirenz + lamivudine/zidovudine group (p-value < 0.05, Fisher's Exact test comparing theemtricitabine + tenofovir disoproxil group to the lamivudine/zidovudine group among allsubjects).

* 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/zidovudineemtricitabine+ (N=243)tenofovir disoproxil(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 receivedefavirenz/emtricitabine/tenofovir disoproxil on an empty stomach, 3 additional cases of resistancewere seen. All 3 subjects had received a fixed dose combination of lamivudine and zidovudine andefavirenz for 144 weeks and then switched to efavirenz/emtricitabine/tenofovir disoproxil. Twosubjects with confirmed virologic rebound developed NNRTI resistance-associated substitutions toefavirenz including K103N, V106V/I/M and Y188Y/C reverse transcriptase substitutions at week 240(96 weeks on efavirenz/emtricitabine/tenofovir disoproxil) and week 204 (60 weeks onefavirenz/emtricitabine/tenofovir disoproxil). A third subject had pre-existing NNRTI resistance-associated substitutions to efavirenz and the M184V reverse transcriptase resistance-associatedsubstitution to emtricitabine at entry into the efavirenz/emtricitabine/tenofovir disoproxil 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 efavirenz/emtricitabine/tenofovirdisoproxil).

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-1infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovirdisoproxil or a fixed combination of lamivudine and zidovudine administered twice daily andefavirenz once daily (please refer to the Summary of Product Characteristics for this medicinalproduct). Patients who completed 144 weeks of treatment with either treatment arm in study GS-01-934 were given the option to continue in an open-label extended phase of the study withefavirenz/emtricitabine/tenofovir disoproxil on an empty stomach. Data are available from286 patients who switched to efavirenz/emtricitabine/tenofovir disoproxil: 160 had previouslyreceived efavirenz, emtricitabine and tenofovir disoproxil, and 126 had previously receivedlamivudine/zidovudine and efavirenz. High rates of virologic suppression were maintained bysubjects from both initial treatment groups who then received efavirenz/emtricitabine/tenofovirdisoproxil in the open-label extended phase of the study. After 96 weeks ofefavirenz/emtricitabine/tenofovir disoproxil 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 efavirenz/emtricitabine/tenofovir disoproxil to antiretroviral therapyconsisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) with aprotease inhibitor or non-nucleoside reverse transcriptase inhibitor; however not a regimen containingall efavirenz/emtricitabine/tenofovir disoproxil components (efavirenz, emtricitabine and tenofovirdisoproxil). Efavirenz/emtricitabine/tenofovir disoproxil was administered on an empty stomach (seesection 4.2). Patients had never experienced virological failure on a previous antiretroviral therapy,had no known HIV-1 mutations that confer resistance to any of the three components withinefavirenz/emtricitabine/tenofovir disoproxil, and had been virologically suppressed for at least threemonths at baseline. Patients either changed to efavirenz/emtricitabine/tenofovir disoproxil (N=203) orcontinued on their original antiretroviral treatment regimen (N=97). Forty-eight week data showedthat high levels of virologic suppression, comparable to the original treatment regimen, weremaintained in patients who were randomised to change to efavirenz/emtricitabine/tenofovir disoproxil(see Table 4).

Table 4: 48-week efficacy data from study AI266073 in which efavirenz/emtricitabine/tenofovirdisoproxil was administered to virologically suppressed patients on combination antiretroviraltherapy

Treatment group

Difference between

Stayed on original efavirenz/emtricitabine/t

Efavirenz/emtricitabine/tenofovirtreatment regimen enofovir disoproxil and

Endpoint disoproxil (N=203)(N=97) original treatmentn/N (%)n/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 treatedas failures; 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 efavirenz/emtricitabine/tenofovir disoproxil [92.4%versus 94.0% for the PVR (sensitivity analysis) for efavirenz/emtricitabine/tenofovir disoproxil and

SBR patients respectively; a difference (95%CI) of -1.6% (-10.0%, 6.7%). In the prior-NNRTIstratum, response rates were 98.9% vs 97.4% for efavirenz/emtricitabine/tenofovir disoproxil and

SBR patients respectively; 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 efavirenz/emtricitabine/tenofovir disoproxil according to the type of priorantiretroviral regimen (Kaiser Permanente patient database)

Prior efavirenz/emtricitabine/tenofovir

Prior NNRTI-based regimen Prior PI-based regimendisoproxil components(N=104) (N=34)(N=299)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 efavirenz/emtricitabine/tenofovir disoproxilin treatment-naïve patients or in heavily pretreated patients.

There is no clinical experience with efavirenz/emtricitabine/tenofovir disoproxil 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) (seesection 4.4).

The safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil in children under the age of18 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 efavirenz/emtricitabine/tenofovirdisoproxil film-coated tablet with one efavirenz 600 mg film-coated tablet plus one emtricitabine200 mg hard capsule plus one tenofovir disoproxil 245 mg film-coated tablet (equivalent to 300 mgtenofovir disoproxil) administered together, was established following single dose administration tofasting healthy subjects in 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 Test Reference Test Reference(90%CI) (90%CI) (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 tablet takenunder 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 and steady-state concentrations reached in 6 to 7 days. In 35 patients receiving efavirenz 600 mg once daily,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%)and the AUC was 10.0 ± 3.1 µg*h/ml (31%) over a 24 hour dosing interval.

Following oral administration of a single 245 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%.

Efavirenz/emtricitabine/tenofovir disoproxil 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.

Efavirenz/emtricitabine/tenofovir disoproxil is recommended for administration on an empty stomachsince food may increase efavirenz exposure and may lead to an increase in the frequency of adversereactions (see sections 4.4 and 4.8). It is anticipated that tenofovir exposure (AUC) will beapproximately 30% lower following administration of efavirenz/emtricitabine/tenofovir disoproxil onan empty stomach as compared to the individual component tenofovir disoproxil when taken withfood (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 approximately1.0 and 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-life52 to 76 hours). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a

UGT1A1 substrate) are reduced in the presence of efavirenz (see section 4.5, Table 1). Although invitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictoryreports of both increased and decreased exposures to substrates of these enzymes when co-administered with efavirenz 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 CYPenzymes. Neither emtricitabine nor tenofovir inhibited in vitro medicinal product metabolismmediated by any of the major human CYP isoforms involved in medicinal product biotransformation.

Also, emtricitabine did not inhibit uridine 5'-diphosphoglucuronyl transferase, the enzyme responsiblefor 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 transportsystem with 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 efavirenz/emtricitabine/tenofovir disoproxil ininfants and children under 18 years of age (see section 4.2).

The pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil after co-administration ofthe separate pharmaceutical forms or as efavirenz/emtricitabine/tenofovir disoproxil have not beenstudied in HIV infected patients with renal 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 creatinine clearance >80 ml/min; mild impairment with creatinine clearance=50 to 79 ml/min; moderate impairment withcreatinine 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.

Efavirenz/emtricitabine/tenofovir disoproxil is not recommended for patients with moderate or severerenal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renalimpairment require dose interval adjustment of emtricitabine and tenofovir disoproxil that cannot beachieved with the combination tablet (see sections 4.2 and 4.4).

The pharmacokinetics of efavirenz/emtricitabine/tenofovir disoproxil have not been studied in HIVinfected patients with hepatic impairment. Efavirenz/emtricitabine/tenofovir disoproxil should beadministered with caution to patients with mild hepatic impairment (see sections 4.3 and 4.4).

Efavirenz/emtricitabine/tenofovir disoproxil must not be used in patients with severe hepaticimpairment (see section 4.3) and is not recommended for patients with moderate hepatic impairment.

In a single-dose study of efavirenz, half-life was doubled in the single patient with severe hepaticimpairment (Child-Pugh-Turcotte Class C), indicating a potential for a much greater degree ofaccumulation. A multiple-dose study of efavirenz showed no significant effect on efavirenzpharmacokinetics in patients with mild hepatic impairment (Child-Pugh-Turcotte Class A) comparedwith controls. There were insufficient data to determine whether moderate or severe hepaticimpairment (Child-Pugh-Turcotte Class B or C) affects efavirenz 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 thatno dose adjustment of tenofovir disoproxil is required in these subjects.

Efavirenz: Non-clinical safety pharmacology studies on efavirenz reveal no special hazard forhumans. In repeated-dose toxicity studies, biliary hyperplasia was observed in cynomolgus monkeysgiven efavirenz for ≥ 1 year at a dose resulting in mean AUC values approximately 2-fold greater thanthose in humans given the recommended dose. The biliary hyperplasia regressed upon cessation ofdosing. Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed in somemonkeys receiving efavirenz for ≥ 1 year, at doses yielding plasma AUC values 4- to 13-fold greaterthan those in 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 a urine drug test (UDS) inprimary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleusassay.

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

Hydroxypropylcellulose

Low-substituted hydroxypropylcellulose

Magnesium stearate

Microcrystalline cellulose

Silica, colloidal anhydrous

Sodium metabisulfite (E223)

Lactose monohydrate

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide red (E172)

Macrogol

Poly(vinyl alcohol)

Talc

Titanium dioxide (E171)

Not applicable.

2 years.

Bottle packs of 30 tablets: Use within 60 days after first opening.

Do not store above 25 ºC. Store in the original package in order to protect from light.

HDPE bottle with PP screw cap or PP child-resistant screw cap with aluminium liner wad anddesiccant labelled ‘DO NOT EAT’.

Pack size: 30, 90 film-coated tablets

Multipack size: 90 (3 packs of 30) film-coated tablets

OPA/alu/PE/HDPE/alu blister pack containing 30 and 90 tablets.

OPA/alu/PE/HDPE/alu perforated unit dose blister pack containing 30 x 1, 90 x 1 tablets.

Not all pack sizes may be marketed.

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

Mylan Pharmaceuticals Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/17/1222/001

EU/1/17/1222/002

EU/1/17/1222/003

EU/1/17/1222/004

EU/1/17/1222/005

EU/1/17/1222/006

EU/1/17/1222/007

Date of first authorisation: 05 September 2017

Date of latest renewal: 24 May 2022

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

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