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

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 600 mg/200 mg/245 mg film-coated tablets

Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and tenofovirdisoproxil phosphate equivalent to 245 mg of tenofovir disoproxil.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pink, oval biconvex film-coated tablet of dimensions approx. 20.0 x 10.7 mm.

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 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 Zentiva priorto initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).

The demonstration of the benefit of the combination efavirenz/emtricitabine/tenofovir disoproxil isprimarily based on 48-week data from a clinical study in which patients with stable virologicsuppression on a combination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovirdisoproxil (see section 5.1). No data are currently available from clinical studies with combinationefavirenz/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 Zentiva is one tablet takenorally once daily.

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

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

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

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

It is recommended that Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 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 the combination efavirenz/emtricitabine/tenofovir disoproxil 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 Zentiva 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 Zentiva 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 Zentiva 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 Zentiva should be administered with caution to elderlypatients (see section 4.4).

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 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 disoproxil thatcannot be achieved with the combination tablet (see sections 4.4 and 5.2).

The pharmacokinetics of efavirenz/emtricitabine/tenofovir disoproxil have not been studied in patientswith hepatic impairment. Patients with mild liver disease (Child-Pugh-Turcotte (CPT), Class A) maybe treated with the normal recommended dose of the combination efavirenz/emtricitabine/tenofovirdisoproxil (see sections pct. 4.3, pct. 4.4 and 5.2). Patients should be monitored carefully for adverse reactions,especially nervous system symptoms related to efavirenz (see sections 4.3 and 4.4).

If Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 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 the combination efavirenz/emtricitabine/tenofovir disoproxil in childrenunder the age of 18 years have not been established (see section 5.2).

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 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 Zentiva 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 drugs that are known to prolong the QTc interval (proarrhythmic).

These drugs include:

* antiarrhythmics of classes IA and III,

* neuroleptics, antidepressive agents,

* certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones,imidazole and triazole antifungal agents,

* certain non-sedating antihistamines (terfenadine, astemizole),

* cisapride,

* flecainide,

* certain antimalarials,

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

Co-administration with other medicinal products

As a fixed combination, Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not beadministered concomitantly with other medicinal products containing the same active components,emtricitabine or tenofovir disoproxil.

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva 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 Zentiva should not beadministered concomitantly with other cytidine analogues, such as lamivudine (see section 4.5).

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly withadefovir dipivoxil 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 PI-based antiretroviral regimen

Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switchto efavirenz/emtricitabine/tenofovir disoproxil may lead to a reduction of the response to the therapy(see section 5.1). These patients should be carefully monitored for rises in viral load and, since thesafety 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 Zentiva be taken on anempty stomach, 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 Zentiva 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 Zentiva to patients with mild hepaticimpairment. These patients should be carefully monitored for efavirenz adverse reactions, especiallynervous system symptoms. Laboratory tests should be performed to evaluate their liver disease atperiodic intervals (see section 4.2).

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy (CART) andshould be monitored according to standard practice. If there is evidence of worsening liver disease orpersistent elevations of serum transaminases to greater than 5 times the upper limit of the normalrange, the benefit of continued therapy with 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 clinical experiencesuggests that emtricitabine and tenofovir disoproxil have an anti-HBV activity when used inantiretroviral combination therapy to control HIV infection. Discontinuation ofefavirenz/emtricitabine/tenofovir disoproxil therapy in patients co-infected with HIV and HBV may beassociated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV whodiscontinue efavirenz/emtricitabine/tenofovir disoproxil must be closely monitored with both clinicaland laboratory follow-up for at least four months after stopping treatment withefavirenz/emtricitabine/tenofovir disoproxil. If appropriate, resumption of anti-hepatitis B therapy maybe warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is notrecommended 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 drugs with a known risk for Torsade de

Pointes, consider alternatives to Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva.

Psychiatric symptoms

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with aprior history of psychiatric disorders appear to be at greater risk of serious psychiatric adversereactions. In particular, severe depression was more common in those with a history of depression.

There have also been post-marketing reports of severe depression, death by suicide, delusions,psychosis-like behaviour, and catatonia. Patients should be advised that if they experience symptomssuch as severe depression, psychosis or suicidal ideation, they should contact their doctor immediatelyto assess the possibility that the symptoms may be related to the use of efavirenz, and if so, todetermine whether the risk of continued therapy outweighs the benefits (see section 4.8).

Nervous system symptoms

Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration andabnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mgdaily in clinical studies. Dizziness was also seen in clinical studies with emtricitabine and tenofovirdisoproxil. Headache has been reported in clinical studies with emtricitabine (see section 4.8).

Nervous system symptoms associated with efavirenz usually begin during the first one or two days oftherapy and generally resolve after the first two to four weeks. Patients should be informed that if theydo occur, these common symptoms are likely to improve with continued therapy and are not predictiveof subsequent onset of any of the less frequent psychiatric symptoms.

Convulsions have been observed in patients receiving efavirenz, generally in the presence of a knownmedical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal productsprimarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may requireperiodic monitoring of plasma levels. In a drug 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 Zentiva is not recommended for patients with moderateor severe renal 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 Zentiva should be avoided with concurrent or recent useof a nephrotoxic medicinal product. If concomitant use of efavirenz/emtricitabine/tenofovir disoproxiland nephrotoxic 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 Zentiva is co-administered withan 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 with

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva and renal function (creatinine clearance andserum phosphate) is also monitored after two to four weeks of treatment, after three months oftreatment and every three to six months thereafter in patients without renal risk factors. In patientswith a history of renal dysfunction or in patients who are at risk of renal dysfunction, a more frequentmonitoring of renal function is required.

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min inany patient receiving Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva, renal function must be re-evaluated within one week, including measurements of blood glucose, blood potassium and urineglucose concentrations (see section 4.8, proximal tubulopathy). Since

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is a combination product and the dosing intervalof the individual components cannot be altered, treatment with Efavirenz/Emtricitabine/Tenofovirdisoproxil Zentiva must be interrupted in patients with confirmed creatinine clearance < 50 ml/min ordecreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should also be considered in case of progressivedecline of renal function when no other cause has been identified. Where discontinuation of therapywith one of the components of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is indicated orwhere dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovirdisoproxil 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 of

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. The rash associated with the efavirenzcomponent usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroidsmay improve tolerability and hasten the resolution of rash. Severe rash associated with blistering,moist desquamation or ulceration has been reported in less than 1% of patients treated with efavirenz(see section 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome wasapproximately 0.1%. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva must be discontinued inpatients developing severe rash associated with blistering, desquamation, mucosal involvement orfever. Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTIclass is limited. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is not recommended for patientswho have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking an

NNRTI.

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

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

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirusretinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.

Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

Although the etiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV disease and/or long-term exposure to CART.

Patients should be advised to seek medical advice if they experience joint aches and pain, jointstiffness or difficulty in movement.

Patients with HIV-1 harbouring mutations

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).

The combination of efavirenz/emtricitabine/tenofovir disoproxil has not been studied in patients overthe age of 65. Elderly patients are more likely to have decreased hepatic or renal function, thereforecaution should be exercised when treating elderly patients with Efavirenz/Emtricitabine/Tenofovirdisoproxil Zentiva (see section 4.2).

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

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

As a fixed combination, Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not beadministered concomitantly with other medicinal products containing the components, emtricitabineor tenofovir disoproxil. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not beco-administered with products containing efavirenz unless needed for dose adjustment e.g. withrifampicin (see section 4.2). Due to similarities with emtricitabine, Efavirenz/Emtricitabine/Tenofovirdisoproxil Zentiva should not be administered concomitantly with other cytidine analogues, such aslamivudine. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administeredconcomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates ofthese enzymes may have decreased plasma concentrations when co-administered with efavirenz.

Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observedin vitro and the net effect of co-administration with substrates of these enzymes is not clear (seesection 5.2).

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

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 receiving efavirenz.

Confirmatory testing by a more specific method such as gas chromatography/mass spectrometry isrecommended in such cases.

Contraindications of concomitant use

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva must not be administered concurrently withterfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (forexample, 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 Zentiva with elbasvir/grazoprevir iscontraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir (see section 4.3and Table 1).

Voriconazole

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

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is a fixed-dose combination product, the dose ofefavirenz cannot be altered; therefore, voriconazole and Efavirenz/Emtricitabine/Tenofovir disoproxil

Zentiva must not be co-administered (see section 4.3 and Table 1).

St. John’s wort (Hypericum perforatum)

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva and St. John’s wort orherbal preparations containing St. John’s wort is contraindicated. Plasma levels of efavirenz can bereduced by concomitant use of St. John’s wort due to induction of drug metabolising enzymes and/ortransport proteins by St. John’s wort. If a patient is already taking St. John’s wort, stop St. John’s wort,check viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St.

John’s wort. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation oftreatment (see section 4.3).

QT prolonging drugs

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is contraindicated with concomitant use of drugsthat are known to prolong the QTc interval and could lead to Torsade de Pointes, such as:antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, certain antibioticsincluding some agents of the following classes: macrolides, fluoroquinolones, imidazole, and triazoleantifungal 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 for atazanavir/ritonavir incombination with efavirenz/emtricitabine/tenofovir disoproxil. Therefore co-administration ofatazanavir/ritonavir and Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is not recommended(see Table 1).

Didanosine

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva and didanosine is notrecommended (see Table 1).

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva and sofosbuvir/velpatasviror sofosbuvir/velpatasvir/voxilaprevir is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva with medicinal products that reduce renalfunction or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations ofemtricitabine, tenofovir and/or the co-administered medicinal products.

Use of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should be avoided with concurrent orrecent use of a nephrotoxic medicinal product. Some examples include, but are not limited to,aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir orinterleukin-2 (see section 4.4).

Praziquantel

Concomitant use of praziquantel with efavirenz is not recommended due to significant decrease inplasma concentrations of praziquantel, with risk of treatment failure due to increased hepaticmetabolism by efavirenz. In case the combination is needed, an increased dose of praziquantel couldbe considered.

Interactions between Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva or its individualcomponent(s) and other medicinal products are listed in Table 1 below (increase is indicated as “↑”,decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, once daily as “q.d.” and once every 8 hoursas “q8h”). If available, 90% confidence intervals are shown in parentheses.

Table 1: Interactions between Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva or itsindividual components and other medicinal products

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

ANTI-INFECTIVES

HIV antivirals

Protease inhibitors

Atazanavir/ritonavir/tenofo Atazanavir: Co-administration ofvir disoproxil AUC: ↓ 25% (↓ 42 to ↓ 3) atazanavir/ritonavir and(300 mg q.d./100 mg Cmax: ↓ 28% (↓ 50 to ↑ 5) Efavirenz/Emtricitabine/Tenofoviq.d./245 mg q.d.) Cmin: ↓ 26% (↓ 46 to ↑ 10) r disoproxil Zentiva is notrecommended.

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

Atazanavir/ritonavir/efavire Atazanavir (pm):nz AUC: ↔* (↓ 9% to ↑ 10%)(400 mg q.d./100 mg Cmax: ↑ 17%* (↑ 8 to ↑ 27)q.d./600 mg q.d., all Cmin: ↓ 42%* (↓ 31 to ↓ 51)administered with food)

Atazanavir (pm):

AUC: ↔*/** (↓ 10% to ↑ 26%)

Atazanavir/ritonavir/efavire Cmax: ↔*/** (↓ 5% to ↑ 26%)nz Cmin: ↑ 12%*/** (↓ 16 to ↑ 49)(400 mg q.d./200 mg (CYP3A4 induction).q.d./600 mg q.d., all * When compared to atazanaviradministered with food) 300 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/emtrici Interaction not studied.tabine

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Darunavir/ritonavir/efavire Darunavir: Efavirenz/emtricitabine/tenofovirnz AUC: ↓ 13% disoproxil in combination with(300 mg b.i.d.*/100 mg Cmin: ↓ 31% darunavir/ritonavir 800/100 mgb.i.d./600 mg q.d.) Cmax: ↓ 15% once daily may result in(CYP3A4 induction) suboptimal darunavir Cmin. If

*lower than recommended Efavirenz/Emtricitabine/Tenofovidoses; similar findings are Efavirenz: r disoproxil Zentiva is to be usedexpected with AUC: ↑ 21% in combination withrecommended doses. Cmin: ↑ 17% darunavir/ritonavir, the

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

Darunavir/ritonavir/tenofov Darunavir: used. Darunavir/ritonavir shouldir disoproxil AUC: ↔ be used with caution in(300 mg b.i.d.*/100 mg Cmin: ↔ combination withb.i.d./245 mg q.d.) Efavirenz/Emtricitabine/Tenofovi

Tenofovir: r disoproxil Zentiva. See ritonavir

*lower than recommended AUC: ↑ 22% row below. Monitoring of renaldose Cmin: ↑ 37% function may be indicated,

Darunavir/ritonavir/emtricit Interaction not studied. Based on particularly in patients withabine the different elimination underlying systemic or renalpathways, no interaction is disease, or in patients takingexpected. nephrotoxic agents.

Fosamprenavir/ritonavir/efa No clinically significant Efavirenz/Emtricitabine/Tenofovivirenz pharmacokinetic interaction. r disoproxil Zentiva and(700 mg b.i.d./100 mg fosamprenavir/ritonavir can be co-b.i.d./600 mg q.d.) administered without dose

Fosamprenavir/ritonavir/em Interaction not studied. adjustment. See ritonavir rowtricitabine below.

Fosamprenavir/ritonavir/ten Interaction not studied.ofovir disoproxil

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

Cmax: ↔ for indinavir when dosed with the

Cmin: ↔ combination ofefavirenz/emtricitabine/tenofovir

Indinavir: disoproxil. While the clinical

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

Cmin: ↓ 40% indinavir concentrations has notbeen established, the magnitude of

A similar reduction in indinavir the observed pharmacokineticexposures was observed when interaction should be taken intoindinavir 1,000 mg q8h was consideration when choosing agiven with efavirenz 600 mg regimen containing bothq.d. efavirenz, a component of(CYP3A4 induction) Efavirenz/Emtricitabine/Tenofovi

For co-administration of r disoproxil Zentiva, andefavirenz with low-dose indinavir.ritonavir in combination with aprotease inhibitor, see section onritonavir below.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Indinavir/emtricitabine Indinavir:(800 mg q8h/200 mg q.d.) AUC: ↔

Cmax: ↔

AUC: ↔

Cmax: ↔

Indinavir/tenofovir Indinavir:disoproxil AUC: ↔(800 mg q8h/245 mg q.d.) Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Lopinavir/ritonavir/tenofov Lopinavir/ritonavir: Insufficient data are available toir disoproxil AUC: ↔ make a dosing recommendation(400 mg b.i.d./100 mg Cmax: ↔ for lopinavir/ritonavir when dosedb.i.d./245 mg q.d.) Cmin: ↔ with the combination ofefavirenz/emtricitabine/tenofovir

Tenofovir: disoproxil. Co-administration of

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

Cmax: ↔ Efavirenz/Emtricitabine/Tenofovi

Cmin: ↑ 51% (↑ 37 to ↑ 66) r disoproxil Zentiva is notrecommended.

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

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Lopinavir/ritonavir soft Substantial decrease in lopinavircapsules or oral exposure, necessitating dosagesolution/efavirenz adjustment oflopinavir/ritonavir. When usedin combination with efavirenzand two NRTIs, 533/133 mglopinavir/ritonavir (softcapsules) twice daily yieldedsimilar lopinavir plasmaconcentrations as compared tolopinavir/ritonavir (softcapsules) 400/100 mg twicedaily without efavirenz(historical data).

Lopinavir/ritonavir Lopinavir concentrations: ↓ 30-tablets/efavirenz 40%(400/100 mg b.i.d./600 mgq.d.)(500/125 mg b.i.d./600 mg Lopinavir concentrations:q.d.) similar to lopinavir/ritonavir400/100 mg twice daily withoutefavirenz. Dosage adjustment oflopinavir/ritonavir is necessarywhen given with efavirenz. Forco-administration of efavirenzwith low-dose ritonavir incombination with a proteaseinhibitor, see section onritonavir below.

Lopinavir/ritonavir/emtricit Interaction not studied.abine

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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 and33) Efavirenz/Emtricitabine/Tenofovi

Evening AUC: ↔ r disoproxil Zentiva is not

Morning Cmax: ↑ 24% (↑ 12 to ↑ recommended. When using38) Efavirenz/Emtricitabine/Tenofovi

Evening Cmax: ↔ r disoproxil Zentiva with low-

Morning Cmin: ↑ 42% (↑ 9 to ↑ dose ritonavir, the possibility of86) an increase in the incidence of

Evening Cmin: ↑ 24% (↑ 3 to ↑ efavirenz-associated adverse50) events should be considered, dueto 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.

Ritonavir/emtricitabine Interaction not studied.

Ritonavir/tenofovir Interaction not studied.disoproxil

Saquinavir/ritonavir/efavire Interaction not studied. For Insufficient data are available tonz co-administration of efavirenz make a dosing recommendationwith low-dose ritonavir in for saquinavir/ritonavir whencombination with a protease dosed with the combination ofinhibitor, see section on efavirenz/emtricitabine/tenofovirritonavir above. disoproxil.

Saquinavir/ritonavir/tenofo There were no clinically Co-administration ofvir disoproxil significant pharmacokinetic saquinavir/ritonavir andinteractions when tenofovir Efavirenz/Emtricitabine/Tenofovidisoproxil was co-administered r disoproxil Zentiva is notwith ritonavir boosted recommended. Use ofsaquinavir. Efavirenz/Emtricitabine/Tenofovi

Saquinavir/ritonavir/emtrici Interaction not studied. r disoproxil Zentiva intabine combination with saquinavir asthe sole protease inhibitor is notrecommended.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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 Maraviroc:disoproxil AUC12h: ↔(300 mg b.i.d./245 mg q.d.) Cmax: ↔

Tenofovir concentrations notmeasured, no effect is expected.

Maraviroc/emtricitabine Interaction not studied.

Integrase strand transfer inhibitor

Raltegravir/efavirenz Raltegravir: Efavirenz/Emtricitabine/Tenofovi(400 mg single dose/-) AUC: ↓ 36% r disoproxil Zentiva and

C12h: ↓ 21% raltegravir can be co-administered

Cmax: ↓ 36% without dose adjustment.(UGT1A1 induction)

Raltegravir/tenofovir Raltegravir:disoproxil AUC: ↑ 49%(400 mg b.i.d./-) C12h: ↑ 3%

Cmax: ↑ 64%(mechanism of interactionunknown)

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/Tenofovitenofovir disoproxil. Clinically r disoproxil Zentiva,significant interactions have not Efavirenz/Emtricitabine/Tenofovibeen found and would not be r disoproxil Zentiva should not beexpected since the NRTIs are administered concomitantly withmetabolised via a different route lamivudine (see section 4.4).than efavirenz and would beunlikely to compete for the samemetabolic enzymes andelimination pathways.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

NNRTIs/efavirenz Interaction not studied. Since use of two NNRTIs provednot beneficial in terms of efficacyand safety, co-administration of

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva and another

NNRTI is not recommended.

Didanosine/tenofovir Co-administration of tenofovir Co-administration ofdisoproxil disoproxil and didanosine results Efavirenz/Emtricitabine/Tenofoviin a 40-60% increase in systemic r disoproxil Zentiva andexposure to didanosine. didanosine is not recommended.

Didanosine/efavirenz Interaction not studied. Increased systemic exposure to

Didanosine/emtricitabine Interaction not studied. didanosine may increasedidanosine related adversereactions. Rarely, pancreatitis andlactic acidosis, sometimes fatal,have been reported. Co-administration of tenofovirdisoproxil and didanosine at adose of 400 mg daily has beenassociated with a significantdecrease in CD4 cell count,possibly due to an intracellularinteraction increasingphosphorylated (i.e. active)didanosine. A decreased dosage of250 mg didanosine co-administered with tenofovirdisoproxil therapy has beenassociated with reports of highrates of virological failure withinseveral tested combinations forthe treatment of HIV-1 infection.

Hepatitis C antivirals

Elbasvir/Grazoprevir + Elbasvir: Co-administration of

Efavirenz AUC: ↓ 54% Efavirenz/Emtricitabine/Tenofovi

Cmax: ↓ 45% r disoproxil Zentiva with(CYP3A4 or P-gp induction - elbasvir/grazoprevir iseffect on elbasvir) contraindicated because it maylead to loss of virologic response

Grazoprevir: to elbasvir/grazoprevir. This loss

AUC: ↓ 83% is due to significant decreases in

Cmax: ↓ 87% elbasvir/grazoprevir plasma(CYP3A4 or P-gp induction - concentrations caused byeffect on grazoprevir) CYP3A4 or P-gp induction. Referto the Summary of Product

Efavirenz: Characteristics for

AUC: ↔ elbasvir/grazoprevir for more

Cmax: ↔ information.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Glecaprevir/Pibrentasvir/Ef Expected: Concomitant administration ofavirenz Glecaprevir: ↓ glecaprevir/pibrentasvir with

Pibrentasvir: ↓ efavirenz, a component of

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva maysignificantly decrease plasmaconcentrations of glecaprevir andpibrentasvir, leading to reducedtherapeutic effect. Co-administration ofglecaprevir/pibrentasvir with

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is notrecommended. Refer to theprescribing information forglecaprevir/pibrentasvir for moreinformation.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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

Efavirenz/emtricitabine/ten Cmax: ↓ 34% (↓ 41 to ↑ 25) exposure of tenofovir couldofovir disoproxil Cmin: ↓ 34% (↓ 43 to ↑ 24) potentiate adverse reactions(600 mg/200 mg/245 mg associated with tenofovirq.d.) Sofosbuvir: disoproxil, including renal

AUC: ↔ disorders. Renal function should

Cmax: ↔ be closely monitored (see section4.4).

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)

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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

Efavirenz/emtricitabine/ten Cmax: ↑ 38% (↑ 14 to ↑ 67) disoproxil andofovir disoproxil sofosbuvir/velpatasvir or(600 mg/200 mg/245 mg GS-3310071: sofosbuvir/velpatasvir/q.d.) AUC: ↔ voxilaprevir is expected to

Cmax: ↔ decrease plasma concentrations of

Cmin: ↔ velpatasvir and voxilaprevir.

Co-administration of

Velpatasvir: Efavirenz/Emtricitabine/Tenofovi

AUC: ↓ 53% (↓ 61 to ↓ 43) r disoproxil Zentiva with

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

Cmin: ↓ 57% (↓ 64 to ↓ 48) sofosbuvir/velpatasvir/voxilaprevir is not recommended

Efavirenz: (see section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81% (↑ 68 to ↑ 94)

Cmax: ↑ 77% (↑ 53 to ↑ 104)

Cmin: ↑ 121% (↑ 100 to ↑ 143)

Sofosbuvir/velpatasvir/voxi Interaction only studied withlaprevir sofosbuvir/velpatasvir.(400 mg/100 mg/100 mgq.d.) + Expected:efavirenz/emtricitabine/ten Voxilaprevir: ↓ofovir disoproxil(600 mg/200 mg/245 mgq.d.)

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Sofosbuvir (400 mg q.d.) + Sofosbuvir: Efavirenz/Emtricitabine/Tenofovi

Efavirenz/emtricitabine/ten AUC: ↔ r disoproxil Zentiva andofovir disoproxil Cmax: ↓ 19% (↓ 40 to ↑ 10) sofosbuvir can be co-administered(600 mg/200 mg/245 mg without dose adjustment.q.d.) GS-3310071:

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. Alternativesto clarithromycin (e.g.

Clarithromycin azithromycin) may be considered.14-hydroxymetabolite: Other macrolide antibiotics, such

AUC: ↑ 34% (↑ 18 to ↑ 53) as erythromycin, have not been

Cmax: ↑ 49% (↑ 32 to ↑ 69) studied in combination withefavirenz/emtricitabine/tenofovir

Efavirenz: disoproxil.

AUC: ↔

Cmax: ↑ 11% (↑ 3 to ↑ 19)(CYP3A4 induction)

Rash developed in 46% ofuninfected volunteers receivingefavirenz and clarithromycin.

Clarithromycin/emtricitabin Interaction not studied.e

Clarithromycin/tenofovir Interaction not studied.disoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Antimycobacterials

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

Cmax: ↓ 32% (↓ 15 to ↓ 46) with

Cmin: ↓ 45% (↓ 31 to ↓ 56) Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. Consider

Efavirenz: doubling the rifabutin dose in

AUC: ↔ regimens where rifabutin is given

Cmax: ↔ 2 or 3 times a week in

Cmin: ↓ 12% (↓ 24 to ↑ 1) combination with(CYP3A4 induction) Efavirenz/Emtricitabine/Tenofovi

Rifabutin/emtricitabine Interaction not studied. r disoproxil Zentiva. The clinical

Rifabutin/tenofovir Interaction not studied. effect of this dose adjustment hasdisoproxil not been adequately evaluated.

Individual tolerability andvirological response should beconsidered when making the doseadjustment (see section 5.2).

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

Cmax: ↓ 20% (↓ 11 to ↓ 28) r disoproxil Zentiva is taken with

Cmin: ↓ 32% (↓ 15 to ↓ 46) rifampicin in patients weighing(CYP3A4 and CYP2B6 50 kg or greater, an additionalinduction) 200 mg/day (800 mg total) of

Rifampicin/tenofovir Rifampicin: efavirenz may provide exposuredisoproxil AUC: ↔ similar to a daily efavirenz dose(600 mg q.d./245 mg q.d.) Cmax: ↔ of 600 mg when taken withoutrifampicin. The clinical effect of

Tenofovir: this dose adjustment has not been

AUC: ↔ adequately evaluated. Individual

Cmax: ↔ tolerability and virological

Rifampicin/emtricitabine Interaction not studied. response should be consideredwhen making the dose adjustment(see section 5.2). No doseadjustment of rifampicin isrecommended when given with

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Antifungals

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

Cmax: ↓ 37% (↓ 20 to ↓ 51) when used with

Cmin: ↓ 44% (↓ 27 to ↓ 58) Efavirenz/Emtricitabine/Tenofovi(decrease in itraconazole r disoproxil Zentiva, an alternativeconcentrations: CYP3A4 antifungal treatment should beinduction) considered.

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 Interaction not studied.disoproxil

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

Cmax: ↓ 45% Efavirenz/Emtricitabine/Tenofovi(UDP-G induction) r disoproxil Zentiva should be

Posaconazole/emtricitabine Interaction not studied. avoided unless the benefit to the

Posaconazole/tenofovir Interaction not studied. patient outweighs the risk.disoproxil

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

Cmax: ↓ 61% r disoproxil Zentiva is a fixed-dose combination product, the

Efavirenz: dose of efavirenz cannot be

AUC: ↑ 44% altered; therefore, voriconazole

Cmax: ↑ 38% and(competitive inhibition of Efavirenz/Emtricitabine/Tenofovioxidative metabolism) r disoproxil Zentiva must not beco-administered.

Co-administration of standarddoses of efavirenz andvoriconazole is contraindicated(see section 4.3).

Voriconazole/emtricitabine Interaction not studied.

Voriconazole/tenofovir Interaction not studied.disoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Antimalarials

Artemether/lumefantrine/ef Artemether: Since decreased concentrations ofavirenz AUC: ↓ 51% artemether, dihydroartemisinin, or(20/120 mg tablet, 6 doses Cmax: ↓ 21% lumefantrine may result in aof 4 tablets each over 3 decrease of antimalarial efficacy,days/600 mg q.d.) Dihydroartemisinin (active caution is recommended whenmetabolite): Efavirenz/Emtricitabine/Tenofovi

AUC: ↓ 46% r disoproxil Zentiva and

Cmax: ↓ 38% artemether/lumefantrine tabletsare co-administered.

Lumefantrine:

AUC: ↓ 21%

Cmax: ↔

AUC: ↓ 17%

Cmax: ↔(CYP3A4 induction)

Artemether/lumefantrine/e Interaction not studied.mtricitabine

Artemether/lumefantrine/te Interaction not studied.nofovir disoproxil

Atovaquone and proguanil Atovaquone: Concomitant administration ofhydrochloride/efavirenz AUC: ↓ 75% (↓ 62 to ↓ 84) atovaquone/proguanil with(250/100 mg single Cmax: ↓ 44% (↓ 20 to ↓ 61) Efavirenz/Emtricitabine/Tenofovidose/600 mg q.d.) r disoproxil Zentiva should be

Proguanil: avoided.

AUC: ↓ 43% (↓ 7 to ↓ 65)

Cmax: ↔

Atovaquone and proguanil Interaction not studied.hydrochloride/emtricitabine

Atovaquone and proguanil Interaction not studied.hydrochloride/tenofovirdisoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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/Tenofovi

Cmin: ↓ 35% (↓ 24 to ↓ 44) r disoproxil Zentiva withcarbamazepine. An alternative

Efavirenz: anticonvulsant should be

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

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

Cmin: ↓ 47% (↓ 41 to ↓ 53) monitored periodically.(decrease in carbamazepineconcentrations: CYP3A4induction; decrease in efavirenzconcentrations: CYP3A4 and

CYP2B6 induction)

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

Carbamazepine/emtricitabi Interaction not studied.ne

Carbamazepine/tenofovir Interaction not studied.disoproxil

Phenytoin, phenobarbital, Interaction not studied with Whenand other anticonvulsants efavirenz, emtricitabine, or Efavirenz/Emtricitabine/Tenofovithat are substrates of CYP tenofovir disoproxil. There is a r disoproxil Zentiva is co-isozymes potential for reduction or administered with anincrease in the plasma anticonvulsant that is a substrateconcentrations of phenytoin, of CYP isozymes, periodicphenobarbital and other monitoring of anticonvulsantanticonvulsants that are levels should be conducted.substrates of CYP isozymeswith efavirenz.

Valproic acid/efavirenz No clinically significant effect Efavirenz/Emtricitabine/Tenofovi(250 mg b.i.d./600 mg q.d.) on efavirenz pharmacokinetics. r disoproxil Zentiva and valproic

Limited data suggest there is no acid can be co-administeredclinically significant effect on without dose adjustment. Patientsvalproic acid pharmacokinetics. should be monitored for seizure

Valproic acid/emtricitabine Interaction not studied. control.

Valproic acid/tenofovir Interaction not studied.disoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Vigabatrin/efavirenz Interaction not studied. Efavirenz/Emtricitabine/Tenofovi

Gabapentin/efavirenz Clinically significant r disoproxil Zentiva andinteractions are not expected vigabatrin or gabapentin can besince vigabatrin and gabapentin co-administered without doseare exclusively eliminated adjustment.unchanged in the urine and areunlikely to compete for the samemetabolic enzymes andelimination pathways asefavirenz.

Vigabatrin/emtricitabine Interaction not studied.

Gabapentin/emtricitabine

Vigabatrin/tenofovir Interaction not studied.disoproxil

Gabapentin/tenofovirdisoproxil

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/Tenofovidecreased by efavirenz. r disoproxil Zentiva.

ANTIDEPRESSANTS

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/Tenofovi

Cmax: ↓ 29% (↓ 15 to ↓ 40) r disoproxil Zentiva, sertraline

Cmin: ↓ 46% (↓ 31 to ↓ 58) dose increases should be guidedby clinical response.

AUC: ↔

Cmax: ↑ 11% (↑ 6 to ↑ 16)

Cmin: ↔(CYP3A4 induction)

Sertraline/emtricitabine Interaction not studied.

Sertraline/tenofovir Interaction not studied.disoproxil

Paroxetine/efavirenz Paroxetine: Efavirenz/Emtricitabine/Tenofovi(20 mg q.d./600 mg q.d.) AUC: ↔ r disoproxil Zentiva and

Cmax: ↔ paroxetine can be co-administered

Cmin: ↔ without dose adjustment.

AUC: ↔

Cmax: ↔

Cmin: ↔

Paroxetine/emtricitabine Interaction not studied.

Paroxetine/tenofovir Interaction not studied.disoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Fluoxetine/efavirenz Interaction not studied. Since Efavirenz/Emtricitabine/Tenofovifluoxetine shares a similar r disoproxil Zentiva andmetabolic profile with fluoxetine can be co-administeredparoxetine, i.e. a strong without dose adjustment.

CYP2D6 inhibitory effect, asimilar lack of interaction wouldbe expected for fluoxetine.

Fluoxetine/emtricitabine Interaction not studied.

Fluoxetine/tenofovir Interaction not studied.disoproxil

Norepinephrine and dopamine reuptake inhibitor

Bupropion/efavirenz Bupropion: Increases in bupropion dosage[150 mg single dose AUC: ↓ 55% (↓ 48 to ↓ 62) should be guided by clinical(sustained release)/600 mg Cmax: ↓ 34% (↓ 21 to ↓ 47) response, but the maximumq.d.] recommended dose of bupropion

Hydroxybupropion: should not be exceeded. No dose

AUC: ↔ adjustment is necessary for

Cmax: ↑ 50% (↑ 20 to ↑ 80) efavirenz.(CYP2B6 induction)

Bupropion/emtricitabine Interaction not studied.

Bupropion/tenofovir Interaction not studied.disoproxil

CARDIOVASCULAR AGENTS

Calcium Channel Blockers

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

Cmax: ↓ 60% (↓ 50 to ↓ 68) Efavirenz/Emtricitabine/Tenofovi

Cmin: ↓ 63% (↓ 44 to ↓ 75) r disoproxil Zentiva should beguided by clinical response (refer

Desacetyl diltiazem: to the Summary of Product

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

Cmax: ↓ 64% (↓ 57 to ↓ 69)

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 Interaction not studied.disoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

Verapamil, felodipine, Interaction not studied with Dose adjustments of calciumnifedipine and Nicardipine efavirenz, emtricitabine, or channel blockers when co-tenofovir disoproxil. When administered withefavirenz is co- administered Efavirenz/Emtricitabine/Tenofoviwith a calcium channel blocker r disoproxil Zentiva should bethat is a substrate of the guided by clinical response (refer

CYP3A4 enzyme, there is a to the Summary of Productpotential for reduction in the Characteristics for the calciumplasma concentrations of the channel blocker).calcium channel blocker.

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A Reductase Inhibitors

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

Cmax: ↓ 12% (↓ 1 to ↓ 26) adjustments of atorvastatin maybe required when co-administered2-hydroxy atorvastatin: with

AUC: ↓ 35% (↓ 13 to ↓ 40) Efavirenz/Emtricitabine/Tenofovi

Cmax: ↓ 13% (↓ 0 to ↓ 23) r disoproxil Zentiva (refer to the

Summary of Product4-hydroxy atorvastatin: Characteristics for atorvastatin).

AUC: ↓ 4% (↓ 0 to ↓ 31)

Cmax: ↓ 47% (↓ 9 to ↓ 51)

Total active HMG Co-Areductaseinhibitors:

AUC: ↓ 34% (↓ 21 to ↓ 41)

Cmax: ↓ 20% (↓ 2 to ↓ 26)

Atorvastatin/emtricitabine Interaction not studied.

Atorvastatin/tenofovir Interaction not studied.disoproxil

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

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

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

Pravastatin/tenofovir Interaction not studied. withdisoproxil Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva (refer to the

Summary of Product

Characteristics for pravastatin).

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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

Cmax: ↓ 76% (↓ 63 to ↓ 79) adjustments of simvastatin may berequired when co-administered

Simvastatin acid: with

AUC: ↓ 58% (↓ 39 to ↓ 68) Efavirenz/Emtricitabine/Tenofovi

Cmax: ↓ 51% (↓ 32 to ↓ 58) r disoproxil Zentiva (refer to the

Summary of Product

Total active HMG Co-A Characteristics for simvastatin).reductase inhibitors:

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 Interaction not studied.disoproxil

Rosuvastatin/efavirenz Interaction not studied. Efavirenz/Emtricitabine/Tenofovi

Rosuvastatin is largely excreted r disoproxil Zentiva andunchanged via the faeces, rosuvastatin can be co-therefore interaction with administered without doseefavirenz is not expected. adjustment.

Rosuvastatin/emtricitabine Interaction not studied.

Rosuvastatin/tenofovir Interaction not studied.disoproxil

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

HORMONAL CONTRACEPTIVES

Oral: Ethinyloestradiol: A reliable method of barrier

Ethinyloestradiol+norgesti AUC: ↔ contraception must be used inmate/ Cmax: ↔ addition to hormonalefavirenz Cmin: ↓ 8% (↑ 14 to ↓ 25) contraceptives (see section 4.6).(0.035 mg+0.25 mgq.d./600 mg q.d.) 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 ofthese effects is not known.

Ethinyloestradiol/tenofovir Ethinyloestradiol:disoproxil AUC: ↔(-/245 mg q.d.) Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Norgestimate/ethinyloestra Interaction not studied.diol/ emtricitabine

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

Depomedroxyprogesterone study, no significant differences information available, a reliableacetate (DMPA)/efavirenz in MPA pharmacokinetic method of barrier contraception(150 mg IM single dose parameters were found between must be used in addition to

DMPA) subjects receiving efavirenz- hormonal contraceptives (seecontaining antiretroviral therapy section 4.6).and subjects 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.

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

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 hormonalhave been occasional post- contraceptives (see section 4.6).marketing reports ofcontraceptive failure withetonogestrel in efavirenz-exposed patients.

Etonogestrel/tenofovir Interaction not studied.disoproxil

Etonogestrel/emtricitabine Interaction not studied.

IMMUNOSUPPRESSANTS

Immunosuppressants Interaction not studied. Dose adjustments of themetabolised by CYP3A4 ↓ exposure of the immunosuppressant may be(e.g. cyclosporine, immunosuppressant may be required. Close monitoring oftacrolimus, expected (CYP3A4 induction). immunosuppressantsirolimus)/efavirenz These immunosuppressants are concentrations for at least twonot anticipated to impact weeks (until stable concentrationsexposure of efavirenz. are reached) is recommended

Tacrolimus/emtricitabine/te Tacrolimus: when starting or stoppingnofovir disoproxil AUC: ↔ treatment with(0.1 mg/kg Cmax: ↔ Efavirenz/Emtricitabine/Tenofoviq.d./200 mg/245 mg q.d.) C24h: ↔ r disoproxil Zentiva.

AUC: ↔

Cmax: ↔

C24h: ↔

Tenofovir disoproxil:

AUC: ↔

Cmax: ↔

C24h: ↔

Medicinal product by Effects on drug levels Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with

Cmax, Cmin with 90% Efavirenz/Emtricitabine/Tenofoconfidence intervals if vir disoproxil Zentiva (efavirenzavailable (mechanism) 600 mg, emtricitabine 200 mg,tenofovir disoproxil 245 mg)

OPIOIDS

Methadone/efavirenz Methadone: Concomitant administration with(35-100 mg q.d./600 mg AUC: ↓ 52% (↓ 33 to ↓ 66) Efavirenz/Emtricitabine/Tenofoviq.d.) Cmax: ↓ 45% (↓ 25 to ↓ 59) r disoproxil Zentiva should be(CYP3A4 induction) avoided due to the risk for QTcprolongation (see section 4.3).

In a study of HIV infectedintravenous 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 Methadone:disoproxil AUC: ↔(40-110 mg q.d./245 mg Cmax: ↔q.d.) Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Methadone/emtricitabine Interaction not studied.

Buprenorphine/naloxone/ef Buprenorphine: Despite the decrease inavirenz AUC: ↓ 50% buprenorphine exposure, nopatients exhibited withdrawal

Norbuprenorphine: symptoms. Dose adjustment of

AUC: ↓ 71% buprenorphine may not benecessary when co-administered

Efavirenz: with

No clinically significant Efavirenz/Emtricitabine/Tenofovipharmacokinetic interaction. r disoproxil Zentiva.

Buprenorphine/naloxone/e Interaction not studied.mtricitabine

Buprenorphine/naloxone/te Interaction not studied.nofovir disoproxil1 The predominant circulating metabolite of sofosbuvir.

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

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

Women of childbearing potential (see below and section 5.3)

Pregnancy should be avoided in women receiving Efavirenz/Emtricitabine/Tenofovir disoproxil

Zentiva. Women of childbearing potential should undergo pregnancy testing before initiation of

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva.

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

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva.

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks afterdiscontinuation of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is recommended.

There have been seven retrospective reports of findings consistent with neural tube defects, includingmeningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospectiveand 1 retrospective) including events consistent with neural tube defects have been reported with thefixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil. A causalrelationship of these events to the use of efavirenz has not been established, and the denominator isunknown. As neural tube defects occur within the first 4 weeks of foetal development (at which timeneural tubes are sealed), this potential risk would concern women exposed to efavirenz during the firsttrimester of pregnancy.

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live births.

One child was reported to have a neural tube defect, and the frequency and pattern of other birthdefects were similar to those seen in children exposed to non-efavirenz-containing regimens, as wellas those in HIV negative controls. The incidence of neural tube defects in the general populationranges from 0.5-1 case per 1,000 live births.

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

Emtricitabine and tenofovir disoproxil

A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates nomalformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil.

Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity (seesection 5.3).

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be used during pregnancy unless theclinical condition 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.

A risk to the infants cannot be excluded. Therefore Efavirenz/Emtricitabine/Tenofovir disoproxil

Zentiva should not 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 to the infant.

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 containing 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 patients receivingefavirenz/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 with the combinationefavirenz/emtricitabine/tenofovir disoproxil and the individual components of the combinationefavirenz/emtricitabine/tenofovir disoproxil in antiretroviral combination therapy are listed in Table 2below by body system organ class, frequency and the component(s) efavirenz/emtricitabine/tenofovirdisoproxil to which the adverse reactions are attributable. Within each frequency grouping,undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as verycommon (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000to < 1/1,000).

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

Common: - anorexia

Uncommon: - dry mouth

- incoherent speech

- increased appetite

- libido decreased

- myalgia

Table 2: Adverse reactions associated with the combination of efavirenz/emtricitabine/tenofovirdisoproxil listed by the component(s) to which the adverse reactions are attributable

Efavirenz Emtricitabine Tenofovir disoproxil

Common neutropenia

Uncommon anaemia1

I mmune system disorders:

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

Uncommon suicide attempt3,suicide ideation3,psychosis3, mania3,paranoia3,hallucination3,euphoric mood3, affectlability3, confusionalstate3, 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, thinkingabnormal3, ataxia3,coordination abnormal3,agitation3, tremor

Uncommon vision blurred

Ear and labyrinth disorders:

Uncommon tinnitus, vertigo

Efavirenz Emtricitabine Tenofovir disoproxil

Uncommon flushing

Very common diarrhoea, nausea diarrhoea, vomiting,nausea

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

Uncommon pancreatitis pancreatitis

Common elevated aspartate elevated serum AST increasedaminotransferase and/or elevated serum transaminases(AST), elevated alanine ALT,aminotransferase hyperbilirubinaemia(ALT), elevatedgamma-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

Efavirenz Emtricitabine Tenofovir disoproxil

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

Uncommon increased creatinine,proteinuria, proximalrenal tubulopathyincluding Fanconisyndrome

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

Uncommon gynaecomastia

Very common asthenia

Common fatigue pain, asthenia1 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine wasadministered to paediatric patients.

2 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causallyassociated with tenofovir disoproxil in the absence of this condition.

3 See section 4.8 Description of selected adverse reactions for more details.4 This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovirdisoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients treatedwith efavirenz in clinical trials (n = 3,969) or exposed to emtricitabine in randomised controlled clinical trials (n = 1,563)or exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access programme (n = 7,319).

In clinical trials of efavirenz, rashes were usually mild-to-moderate maculopapular skin eruptions thatoccurred within the first two weeks of initiating therapy with efavirenz. In most patients rash resolvedwith continuing therapy with efavirenz within one month. The combinationefavirenz/emtricitabine/tenofovir disoproxil can be reinitiated in patients interrupting therapy becauseof rash. Use of appropriate antihistamines and/or corticosteroids is recommended when thecombination efavirenz/emtricitabine/tenofovir disoproxil is restarted.

Psychiatric symptoms

Patients with a history of psychiatric disorders appear to be at greater risk of serious psychiatricadverse reactions listed in the efavirenz column of Table 2.

Nervous system symptoms

Nervous system symptoms are common with efavirenz, one of the components of

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. 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 the combination of efavirenz/emtricitabine/tenofovir disoproxilis taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2).

Dosing at bedtime seems to improve the tolerability of these symptoms (see section 4.2).

Hepatic failure with efavirenz

Hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiablerisk factors, as reported post-marketing, were sometimes characterised by a fulminant course,progressing in some cases to transplantation or death.

As the combination of efavirenz/emtricitabine/tenofovir disoproxil may cause renal damage,monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile).

Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation.

However, in some patients, declines in creatinine clearance did not completely resolve despitetenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients withbaseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxicmedications) are at increased risk of experiencing incomplete recovery of renal function despitetenofovir disoproxil discontinuation (see section 4.4).

Lactic acidosis:

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination withother antiretrovirals. Patients with predisposing factors such as severe hepatic impairment (CPT, Class

C) (see section 4.3), or patients receiving concomitant medications known to induce lactic acidosis areat increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, includingfatal outcomes.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4).

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (seesection 4.4).

Insufficient safety data are available for children below 18 years of age.

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is not recommended in this population (seesection 4.2).

The combination of efavirenz/emtricitabine/tenofovir disoproxil has not been studied in patients overthe age of 65. Elderly patients are more likely to have decreased hepatic or renal function, thereforecaution should be exercised when treating elderly patients with Efavirenz/Emtricitabine/Tenofovirdisoproxil Zentiva (see section 4.2).

Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommendedin any patient with mild renal impairment treated with Efavirenz/Emtricitabine/Tenofovir disoproxil

Zentiva (see sections 4.2, pct. 4.4 and 5.2).

HIV/HBV or HCV co-infected patients

Only a limited number of patients were co-infected with HBV (n = 13) or HCV (n = 26) in study

GS-01-934. The adverse reaction profile of efavirenz, emtricitabine and tenofovir disoproxil inpatients co-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with

HIV without co-infection. However, as would be expected in this patient population, elevations in

AST and ALT occurred more frequently than in the general HIV infected population.

Exacerbations of hepatitis after discontinuation of treatment

In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis mayoccur 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: Antivirals for systemic use, antivirals for treatment of HIV infections,combinations, ATC code: J05AR06

Mechanism of action and pharmacodynamic effects

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

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

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

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

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

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

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

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

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

K103N substitution confers loss of susceptibility to all three NNRTIs.

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

PIs is low because of the different enzyme targets involved.

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

M184V/I mutation remain fully susceptible to efavirenz. In addition, a K70E substitution in HIV-1 RThas been selected by tenofovir and results in low-level reduced susceptibility to abacavir,emtricitabine, lamivudine and tenofovir.

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

In vivo resistance (antiretroviral-naïve patients)

In a 144-week open-label randomised clinical study (GS-01-934) in antiretroviral-naïve patients,where efavirenz, emtricitabine and tenofovir disoproxil were used as individual formulations (or asefavirenz and the fixed combination of emtricitabine and tenofovir disoproxil from week 96 to 144),genotyping was performed on plasma HIV-1 isolates from all patients with confirmed HIV RNA> 400 copies/ml at week 144 or early study drug discontinuation (see section on Clinical experience).

As of week 144:

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

* No virus analysed contained the K65R or K70E mutation.

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

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

Efavirenz + Efavirenz + lamivudine /emtricitabine + zidovudine (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.

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

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

In the open-label extended phase of study GS-01-934, where patients received the combination ofefavirenz/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 combination of efavirenz/emtricitabine/tenofovirdisoproxil. Two subjects with confirmed virologic rebound developed NNRTI resistance-associatedsubstitutions to efavirenz including K103N, V106V/I/M and Y188Y/C reverse transcriptasesubstitutions at week 240 (96 weeks on combination of efavirenz/emtricitabine/tenofovir disoproxil)and week 204 (60 weeks on combination of efavirenz/emtricitabine/tenofovir disoproxil). A thirdsubject had pre-existing NNRTI resistance-associated substitutions to efavirenz and the M184Vreverse transcriptase resistance-associated substitution to emtricitabine at entry into the combination ofefavirenz/emtricitabine/tenofovir disoproxil extension phase and experienced a suboptimal virologicresponse, and developed K65K/R, S68N and K70K/E NRTI resistance-associated substitutions atweek 180 (36 weeks on combination of efavirenz/emtricitabine/tenofovir disoproxil).

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

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

HIV-1 infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovirdisoproxil or a fixed combination of lamivudine and zidovudine administered twice daily andefavirenz once daily. Patients who completed 144 weeks of treatment with either treatment arm instudy GS-01-934 were given the option to continue in an open-label extended phase of the study withcombination of efavirenz/emtricitabine/tenofovir disoproxil on an empty stomach. Data are availablefrom 286 patients who switched to combination of efavirenz/emtricitabine/tenofovir disoproxil: 160had previously received efavirenz, emtricitabine and tenofovir disoproxil, and 126 had previouslyreceived lamivudine and zidovudine and efavirenz. High rates of virologic suppression weremaintained by subjects from both initial treatment groups who then received combination ofefavirenz/emtricitabine/tenofovir disoproxil in the open-label extended phase of the study. After 96weeks of the combination of efavirenz/emtricitabine/tenofovir disoproxil treatment, HIV-1 RNAplasma concentrations remained < 50 copies/ml in 82% of patients and < 400 copies/ml in 85% ofpatients (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 the combination of efavirenz/emtricitabine/tenofovir disoproxil toantiretroviral therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors(NRTIs) with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor; however not aregimen containing all components efavirenz, emtricitabine and tenofovir disoproxil. The combinationof efavirenz/emtricitabine/tenofovir disoproxil was administered on an empty stomach (see section4.2). Patients had never experienced virological failure on a previous antiretroviral therapy, had noknown HIV-1 mutations that confer resistance to any of the three components(efavirenz/emtricitabine/tenofovir disoproxil), and had been virologically suppressed for at least threemonths at baseline. Patients either changed to combination of efavirenz/emtricitabine/tenofovirdisoproxil (N=203) or continued on their original antiretroviral treatment regimen (N=97). Forty-eightweek data showed that high levels of virologic suppression, comparable to the original treatmentregimen, were maintained in patients who were randomised to change to combination ofefavirenz/emtricitabine/tenofovir disoproxil (see Table 4).

Table 4: 48-week efficacy data from study AI266073 in which the combination ofefavirenz/emtricitabine/tenofovir disoproxil was administered to virologically suppressedpatients on combination antiretroviral therapy

Treatment group

Endpoint Combination of Stayed on original Difference betweenefavirenz/treatment regimen combination of efavirenz /

Emtricitabine/(N=97) emtricitabine /tenofovir disoproxil n/N (%) tenofovir disoproxil and(N=203) original treatment regimenn/N (%) (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 eventswere treated as 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 combination of efavirenz/emtricitabine/tenofovirdisoproxil [92.4% versus 94.0% for the PVR (sensitivity analysis) for combination ofefavirenz/emtricitabine/tenofovir disoproxil and SBR patients respectively; a difference (95%CI) of -1.6% (-10.0%, 6.7%). In the prior-NNRTI stratum, response rates were 98.9% vs 97.4% forcombination of efavirenz/emtricitabine/tenofovir disoproxil and SBR patients respectively; adifference (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 combination of efavirenz/emtricitabine/tenofovir disoproxil according to thetype of prior antiretroviral regimen (Kaiser Permanente patient database)

Prior combination Prior NNRTI-based regimen Prior PI-based regimen(efavirenz/emtricitabine/(N=104) (N=34)tenofovir disoproxil)components(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 combination ofefavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve patients or in heavily pretreatedpatients. There is no clinical experience with combination of efavirenz/emtricitabine/tenofovirdisoproxil in patients who are experiencing virological failure in a first-line antiretroviral treatmentregimen or in combination with other 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 combination of efavirenz/emtricitabine/tenofovir disoproxil in childrenunder the age of 18 years have not been established.

The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil were used todetermine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil, administeredseparately in HIV infected patients. The bioequivalence of one film coated tablet containing thecombination of efavirenz/emtricitabine/tenofovir disoproxil with one efavirenz 600 mg film coatedtablet plus one emtricitabine 200 mg hard capsule plus one tenofovir disoproxil 245 mg film coatedtablet (equivalent to 300 mg tenofovir disoproxil fumarate) administered together, was establishedfollowing single dose administration to fasting healthy subjects in study GS US 177 0105 (see Table6).

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

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

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

Parameters Test Reference (90%CI) Test Reference (90%CI) Test Reference (90%CI)

Cmax 2,264.3 2,308.6 98.79(92.28, 2,130.6 2,384.4 88.84 325.1 352.9 91.46(ng/ml) (26.8) (30.3) 105.76) (25.3) (20.4) (84.02, (84.64,93.94) (34.2) (29.6) 98.83)

AUC 95.84 97.98 99.290-last 125,623.6 132,795.7(ng∙h/ml) (25.7) (27.0) (90.73, 10,682.6 10,874.4 1,948.8 1,969.0101.23) (18.1) (14.9) (94.90,101.16) (32.9) (32.8) (91.02,108.32)

AUCinf 146,074.9 155,518.6 95.87(89.63, 10,854.9 11,054.3 97.96(94.86, 2,314.0 2,319.4 100.45(ng∙h/ml) (33.1) (34.6) 102.55) (17.9) (14.9) 101.16) (29.2) (30.3) (93.22,108.23)

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 245 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 was 184 ±73 µM*h (40%).

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

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

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

Following oral administration of a single 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%.

The combination of efavirenz/emtricitabine/tenofovir disoproxil has not been evaluated in thepresence 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.

The combination of efavirenz/emtricitabine/tenofovir disoproxil is recommended for administration onan empty stomach since food may increase efavirenz exposure and may lead to an increase in thefrequency of adverse reactions (see sections 4.4 and 4.8). It is anticipated that tenofovir exposure(AUC) will be approximately 30% lower following administration of the combination ofefavirenz/emtricitabine/tenofovir disoproxil on an empty stomach as compared to the individualcomponent tenofovir disoproxil when taken with food (see section 5.1).

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

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

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

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

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

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

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

There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includesoxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) andconjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitrostudies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYPenzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any ofthe major human CYP isoforms involved in drug biotransformation. Also, emtricitabine did not inhibituridine 5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.

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

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

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

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

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

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

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

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

Pharmacokinetic studies have not been performed with the combination ofefavirenz/emtricitabine/tenofovir disoproxil in infants and children under 18 years of age (see section4.2).

The pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil after co-administration ofthe separate pharmaceutical forms or as combination of efavirenz/emtricitabine/tenofovir disoproxilhave not been studied 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 creatinine clearance=10 to29 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 over 48hours 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.

The combination of efavirenz/emtricitabine/tenofovir disoproxil is not recommended for patients withmoderate or severe renal impairment (creatinine clearance < 50 ml/min). Patients with moderate orsevere renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxil thatcannot be achieved with the combination tablet (see sections 4.2 and 4.4).

The pharmacokinetics of combination of efavirenz/emtricitabine/tenofovir disoproxil have not beenstudied in HIV infected patients with hepatic impairment. The combination ofefavirenz/emtricitabine/tenofovir disoproxil should be administered with caution to patients with mildhepatic impairment (see sections 4.3 and 4.4).

The combination of efavirenz/emtricitabine/tenofovir disoproxil must not be used in patients withsevere hepatic impairment (see section 4.3) and is not recommended for patients with moderatehepatic impairment. In a single-dose study of efavirenz, half-life was doubled in the single patient withsevere hepatic impairment (Child-Pugh-Turcotte Class C), indicating a potential for a much greaterdegree of accumulation. 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 that nodose adjustment of tenofovir disoproxil is required in these subjects.

Non-clinical safety pharmacology studies on efavirenz reveal no special hazard for humans. Inrepeated-dose toxicity studies, biliary hyperplasia was observed in cynomolgus monkeys givenefavirenz for ≥ 1 year at a dose resulting in mean AUC values approximately 2-fold greater than thosein humans given the recommended dose. The biliary hyperplasia regressed upon cessation of dosing.

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

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

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

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studiesof safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction and development.

Tenofovir disoproxil

Non-clinical safety pharmacology studies on tenofovir disoproxil reveal no special hazard for humans.

Findings in repeated-dose toxicity studies in rats, dogs and monkeys at exposure levels greater than orequal to clinical exposure levels and with possible relevance to clinical use include renal and bonetoxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed asosteomalacia (monkeys) and reduced BMD (rats and dogs). The bone toxicity in young adult rats anddogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurredin juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold theexposure in patients). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.

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

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

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

Combination of emtricitabine and tenofovir disoproxil

Genotoxicity and repeated-dose toxicity studies of one month or less with the combination of thesetwo components found no exacerbation of toxicological effects compared to studies with the separatecomponents.

Microcrystalline cellulose

Croscarmellose sodium

Hydroxypropylcellulose

Sodium laurilsulfate

Magnesium stearate

Colloidal anhydrous silica

Talc

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide, red (E172)

Iron oxide, yellow (E172)

Iron oxide, black (E172)

Not applicable.

2 years

Shelf-life after first opening is 30 days.

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from moisture. Keep the bottle tightly closed.

High density polyethylene (HDPE) bottle with a polypropylene child-resistant screw cap and inductionheat sealing (with aluminium foil).

The bottle contains 30 film coated tablets and a silica gel desiccant (in a canister).

The following pack sizes are available:

Outer carton containing 1 bottle of 30 film-coated tablets and outer carton containing 90 (3 bottles of30) film-coated tablets.

Not all pack sizes may be marketed.

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

Bottles should be opened by pressing the child-resistant cap down and turning it counter-clock wise.

Zentiva, k.s.

U Kabelovny 130102 37 Prague 10

Czech Republic

EU/1/17/1210/001

EU/1/17/1210/002

Date of first authorisation: 17 July 2017

Date of latest renewal: 17 May 2022

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

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