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

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

Each film-coated tablet contains 600 mg of efavirenz (efavirenzum), 200 mg of emtricitabine(emtricitabinum) and 245 mg of tenofovir disoproxil (tenofovirum disoproxilum) (assuccinate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Tablets are light orange pink, oval, biconvex, film-coated tablets with beveled edges. Tabletdimension: 20 x 11 mm.

Efavirenz/Emtricitabine/Tenofovir disoproxil Krka 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 RNA levels 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 Krka prior toinitiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).

The demonstration of the benefit of efavirenz/emtricitabine/tenofovir disoproxil is primarily based on48-week data from a clinical study in which patients with stable virologic suppression on acombination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovir disoproxil (see section5.1). No data are currently available from clinical studies with efavirenz/emtricitabine/tenofovirdisoproxil 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 Krka is one tablet takenorally once daily.

If a patient misses a dose of Efavirenz/Emtricitabine/Tenofovir disoproxil Krka within 12 hours of thetime it is usually taken, the patient should take Efavirenz/Emtricitabine/Tenofovir disoproxil Krka assoon as possible and resume the normal dosing schedule. If a patient misses a dose of

Efavirenz/Emtricitabine/Tenofovir disoproxil Krka by more than 12 hours and it is almost time for thenext dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

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

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

It is recommended that Efavirenz/Emtricitabine/Tenofovir disoproxil Krka 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 adverse reactions on the nervous system, bedtime dosing is recommended (see section 4.8).

It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower followingadministration of efavirenz/emtricitabine/tenofovir disoproxil on an empty stomach as compared to theindividual component tenofovir disoproxil when taken with food (see section 5.2). Data on the clinicaltranslation of the decrease in pharmacokinetic exposure are not available. In virologically suppressedpatients, 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 is indicated or where dose modification is necessary, separate preparations of efavirenz,emtricitabine and tenofovir disoproxil are available. Please refer to the Summary of Product

Characteristics for these medicinal products.

If therapy with efavirenz/emtricitabine/tenofovir disoproxil is discontinued, consideration should begiven 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.

Dose adjustment: If efavirenz/emtricitabine/tenofovir disoproxil is co-administered with rifampicin topatients weighing 50 kg or more, an additional 200 mg/day (800 mg total) of efavirenz may beconsidered (see section 4.5).

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

Efavirenz/emtricitabine/tenofovir disoproxil is not recommended for patients with moderate or severerenal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renalimpairment require dose interval adjustment of emtricitabine and tenofovir disoproxil that cannot beachieved with the combination tablet (see sections 4.4 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 efavirenz/emtricitabine/tenofovir disoproxil (seesections pct. 4.3, pct. 4.4 and 5.2). Patients should be monitored carefully for adverse reactions, especiallynervous system symptoms related to efavirenz (see sections 4.3 and 4.4).

If efavirenz/emtricitabine/tenofovir disoproxil is discontinued in patients co-infected with HIV andhepatitis B virus (HBV), these patients should be closely monitored for evidence of exacerbation ofhepatitis (see section 4.4).

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

Efavirenz/Emtricitabine/Tenofovir disoproxil Krka 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. Sinceefavirenz/emtricitabine/tenofovir disoproxil is a fixed dose combination product, the dose of efavirenzcannot be altered (see section 4.5).

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

Administration to patients with:

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

- a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or withcongestive cardiac failure accompanied by reduced left ventricle ejection fraction.

- severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.

Co administration with medicinal products that are known to prolong the QTc interval(proarrhythmic).

These medicinal products include:

- antiarrhythmics of classes IA and III,

- neuroleptics, antidepressive agents,

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

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

- cisapride,

- flecainide,

- certain antimalarials,

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

Co-administration with other medicinal products

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

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

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

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

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

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

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

Switching from a protease inhibitor (PI)-based antiretroviral regimen

Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen 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 be taken on an emptystomach, preferably at bedtime.

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

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

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

These patients should be carefully monitored for efavirenz adverse reactions, especially nervoussystem symptoms. Laboratory tests should be performed to evaluate their liver disease at periodicintervals (see section 4.2).

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy (CART) andshould be monitored according to standard practice. If there is evidence of worsening liver disease orpersistent elevations of serum transaminases to greater than 5 times the upper limit of the normalrange, the benefit of continued therapy with efavirenz/emtricitabine/tenofovir disoproxil needs to beweighed against the potential risks of significant liver toxicity. In such patients, interruption ordiscontinuation of treatment must be considered (see section 4.8).

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

Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic diseaseor other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be considered forall patients independent of pre-existing hepatic dysfunction or other risk factors.

Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection

Patients with chronic hepatitis B or C and treated with CART are at an increased risk for severe andpotentially fatal hepatic adverse reactions.

Physicians should refer to current HIV treatment guidelines for the optimal management of HIVinfection in patients co-infected with HBV.

In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summaryof Product Characteristics for these medicinal products.

The safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil have not been studied for thetreatment of chronic HBV infection. Emtricitabine and tenofovir individually and in combination haveshown activity against HBV in pharmacodynamic studies (see section 5.1). Limited 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 medicinal products with a known risk for

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

Psychiatric symptoms

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

There have also been post-marketing reports of severe depression, death by suicide, delusionspsychosis-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 adverse reactions 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 medicinal product interaction study, carbamazepine plasmaconcentrations were decreased when carbamazepine was co-administered with efavirenz (see section4.5). Caution must be taken in any patient with a history of seizures.

Efavirenz/emtricitabine/tenofovir disoproxil is not recommended for patients with moderate or severerenal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renalimpairment require a dose adjustment of emtricitabine and tenofovir disoproxil that cannot beachieved with the combination tablet (see sections 4.2 and 5.2). Use ofefavirenz/emtricitabine/tenofovir disoproxil should be avoided with concurrent or recent use of anephrotoxic medicinal product. If concomitant use of efavirenz/emtricitabine/tenofovir disoproxil andnephrotoxic agents (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine,vancomycin, cidofovir, interleukin-2) is unavoidable, renal function must be monitored weekly (seesection 4.5).

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatorydrugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factorsfor renal dysfunction. If efavirenz/emtricitabine/tenofovir disoproxil is co-administered with an

NSAID, renal function should be monitored adequately.

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinicalpractice (see section 4.8).

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy withefavirenz/emtricitabine/tenofovir disoproxil and renal function (creatinine clearance and serumphosphate) is also monitored after two to four weeks of treatment, after three months of treatment andevery three to six months thereafter in patients without renal risk factors. In patients with a history ofrenal dysfunction or in patients who are at risk of renal dysfunction, a more frequent monitoring ofrenal function is required.

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min inany patient receiving efavirenz/emtricitabine/tenofovir disoproxil, renal function must be re-evaluatedwithin one week, including measurements of blood glucose, blood potassium and urine glucoseconcentrations (see section 4.8, proximal tubulopathy). Since efavirenz/emtricitabine/tenofovirdisoproxil is a combination product and the dosing interval of the individual components cannot bealtered, treatment with efavirenz/emtricitabine/tenofovir disoproxil must be interrupted in patientswith confirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl(0.32 mmol/l). Interrupting treatment with efavirenz/emtricitabine/tenofovir disoproxil should also beconsidered in case of progressive decline of renal function when no other cause has been identified.

Where discontinuation of therapy with one of the components of efavirenz/emtricitabine/tenofovirdisoproxil is indicated or where dose modification is necessary, separate preparations of efavirenz,emtricitabine and tenofovir disoproxil are available.

Bone effects

In a 144-week controlled clinical study (GS-99-903) that compared tenofovir disoproxil withstavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, smalldecreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups.

Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greaterin the tenofovir disoproxil treatment group at 144 weeks. Decreases in BMD of the hip weresignificantly greater in this group until 96 weeks. However, there was no increased risk of fractures orevidence for clinically relevant bone abnormalities over 144 weeks in this study.

In other studies (prospective and crosssectional), the most pronounced decreases in BMD were seen inpatients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor.

Overall in view of the bone abnormalities associated with tenofovir disoproxil and the limitations oflong term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternativetreatment regimens should be considered for patients with osteoporosis that are at a high risk forfractures.

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

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).

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

Mild-to-moderate rash has been reported with the individual components ofefavirenz/emtricitabine/tenofovir disoproxil. The rash associated with the efavirenz component usuallyresolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improvetolerability and hasten the resolution of rash. Severe rash associated with blistering, moistdesquamation or ulceration has been reported in less than 1% of patients treated with efavirenz (seesection 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately0.1%. Efavirenz/emtricitabine/tenofovir disoproxil must be discontinued in patients developing severerash associated with blistering, desquamation, mucosal involvement or fever. Experience withefavirenz in patients who discontinued other antiretroviral agents of the non-nucleoside reversetranscriptase inhibitor (NNRTI) class is limited. Efavirenz/emtricitabine/tenofovir disoproxil is notrecommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnsonsyndrome) while taking an NNRTI.

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

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; 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, particulary 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).

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

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

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

As efavirenz/emtricitabine/tenofovir disoproxil contains efavirenz, emtricitabine and tenofovirdisoproxil, any interactions that have been identified with these agents individually may occur withefavirenz/emtricitabine/tenofovir disoproxil. Interaction studies with these agents have only beenperformed in adults.

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

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 must not be administered concurrently with terfenadine,astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example,ergotamine, dihydroergotamine, ergonovine, and methylergonovine), since inhibition of theirmetabolism may lead to serious, life-threatening events (see section 4.3).

Elbasvir/grazoprevir

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil with elbasvir/grazoprevir iscontraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir(see section 4.3 and Table 1).

Voriconazole

Co-administration of standard doses of efavirenz and voriconazole is contraindicated. Sinceefavirenz/emtricitabine/tenofovir disoproxil is a fixed-dose combination product, the dose of efavirenzcannot be altered; therefore, voriconazole and efavirenz/emtricitabine/tenofovir disoproxil must not beco-administered (see section 4.3 and Table 1).

St. John’s wort (Hypericum perforatum)

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and St. John’s wort or herbalpreparations containing St. John’s wort is contraindicated. Plasma levels of efavirenz can be reducedby concomitant use of St. John’s wort due to induction of active substance metabolising enzymesand/or transport proteins by St. John’s wort. If a patient is already taking St. John’s wort, stop St.

John’s wort, check viral levels and if possible efavirenz levels. Efavirenz levels may increase onstopping St. John’s wort. The inducing effect of St. John’s wort may persist for at least 2 weeks aftercessation of treatment (see section 4.3).

Metamizole

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 active substance levels should be monitored asappropriate.

QT Prolonging medicinal products

Efavirenz/emtricitabine/tenofovir disoproxil is contraindicated with concomitant use of medicinalproducts that are known to prolong the QTc interval and could lead to Torsade de Pointes, such as:antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, certain 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 is not recommended (see Table1).

Didanosine

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and didanosine is not recommended(see Table 1).

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and sofosbuvir/velpatasvir orsofosbuvir/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 ofefavirenz/emtricitabine/tenofovir disoproxil with medicinal products that reduce renal function orcompete for active tubular secretion (e.g. cidofovir) may increase serum concentrations ofemtricitabine, tenofovir and/or the co-administered medicinal products.

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

Praziquantel

Concomitant use with praziquantel is not recommended due to significant decrease in plasmaconcentrations of praziquantel, with risk of treatment failure due to increased hepatic metabolism byefavirenz. In case the combination is needed, an increased dose of praziquantel could be considered.

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

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

Medicinal product by therapeutic Effects on active substances levels Recommendation concerningareas Mean percent change in AUC, Cmax, co-administration with

Cmin with 90% confidence intervals if efavirenz/emtricitabine/tenofovavailable (mechanism) ir disoproxil (efavirenz 600 mg,emtricitabine 200 mg, tenofovirdisoproxil 245 mg)

ANTI-INFECTIVES

HIV antivirals

Protease inhibitors

Atazanavir/ritonavir/Tenofovir Atazanavir: Co-administration ofdisoproxil AUC: ↓ 25% (↓ 42 to ↓ 3) atazanavir/ritonavir and(300 mg q.d./100 mg q.d./245 mg Cmax: ↓ 28% (↓ 50 to ↑ 5) efavirenz/emtricitabine/tenofovirq.d.) Cmin: ↓ 26% (↓ 46 to ↑ 10) disoproxil a is not recommended.

Co-administration of atazanavir/ritonavirwith tenofovir resulted in increased exposureto tenofovir. Higher tenofovir concentrationscould potentiate tenofovir-associatedadverse events, including renal disorders.

Atazanavir/ritonavir/Efavirenz Atazanavir (pm):

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

Cmin: ↓ 42%* (↓ 31 to ↓ 51)

Atazanavir/ritonavir/Efavirenz Atazanavir (pm):

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

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

* When compared to atazanavir300 mg/ritonavir 100 mg q.d. in the eveningwithout efavirenz. This decrease inatazanavir Cmin might negatively impact theefficacy of atazanavir.

** based on historical comparison.

Co-administration of efavirenz withatazanavir/ritonavir is not recommended.

Atazanavir/ritonavir/Emtricitabine Interaction not studied.

Darunavir/ritonavir/Efavirenz Darunavir: Efavirenz/emtricitabine/tenofovir(300 mg b.i.d.*/100 mg AUC: ↓ 13% disoproxil in combination with

C : ↓ 31%b.i.d./600 mg q.d.) min darunavir/ritonavir 800/100 mg

Cmax: ↓ 15%(CYP3A4 induction) once daily may result in

*lower than recommended doses; suboptimal darunavir Cmin. Ifsimilar findings are expected with Efavirenz: efavirenz/emtricitabine/tenofovirrecommended doses. AUC: ↑ 21% disoproxil is to be used in

Cmin: ↑ 17% combination with

Cmax: ↑ 15%darunavir/ritonavir, the(CYP3A4 inhibition)darunavir/ritonavir 600/100 mg

Darunavir/ritonavir/Tenofovir Darunavir:

twice daily regimen should bedisoproxil AUC: ↔used. Darunavir/ritonavir should(300 mg b.i.d.*/100 mg Cmin: ↔b.i.d./245 mg q.d.) be used with caution in

Tenofovir: combination with

*lower than recommended dose AUC: ↑ 22% efavirenz/emtricitabine/tenofovir

Cmin: ↑ 37% disoproxil. See ritonavir row

Darunavir/ritonavir/Emtricitabine Interaction not studied. Based on the below. Monitoring of renaldifferent elimination pathways, no function may be indicated,interaction is expected. particularly in patients withunderlying systemic or renaldisease, or in patients takingnephrotoxic agents.

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

Fosamprenavir/ritonavir/Emtricitab Interaction not studied. co-administered without doseine adjustment.

Fosamprenavir/ritonavir/Tenofovir Interaction not studied. See ritonavir row below.

disoproxil

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

Cmax: ↔ for indinavir when dosed with

Cmin: ↔ efavirenz/emtricitabine/tenofovirdisoproxil. While the clinical

Indinavir: significance of decreased

AUC: ↓ 31% (↓ 8 to ↓ 47) indinavir concentrations has not

Cmin: ↓ 40% been established, the magnitudeof the observed pharmacokinetic

A similar reduction in indinavir interaction should be taken intoexposures was observed when consideration when choosing aindinavir 1 000 mg q8h was given with regimen containing bothefavirenz 600 mg q.d. (CYP3A4 induction) efavirenz, a component of

For co-administration of efavirenz with low- efavirenz/emtricitabine/tenofovirdose ritonavir in combination with a disoproxil, and indinavir.

protease inhibitor, see section on ritonavirbelow.

Indinavir/Emtricitabine Indinavir:

(800 mg q8h/200 mg q.d.) AUC: ↔

Cmax: ↔

AUC: ↔

Cmax: ↔

Indinavir/Tenofovir disoproxil Indinavir:

(800 mg q8h/245 mg q.d.) AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Lopinavir/ritonavir/Tenofovir Lopinavir/Ritonavir: Insufficient data are available todisoproxil AUC: ↔ make a dosing recommendation(400 mg b.i.d./100 mg Cmax: ↔ for lopinavir/ritonavir whenb.i.d./245 mg q.d.) Cmin: ↔ dosed withefavirenz/emtricitabine/tenofovir

Tenofovir: disoproxil. Co-administration of

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

Cmax: ↔ efavirenz/emtricitabine/tenofovir

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

Higher tenofovir concentrations couldpotentiate tenofovir-associated adverseevents, including renal disorders.

Lopinavir/ritonavir soft capsules or Substantial decrease in lopinavir exposure,oral necessitating dose adjustment ofsolution/Efavirenz lopinavir/ritonavir. When used incombination with efavirenz and twonucleoside reverse transcriptase inhibitors(NRTIs), 533/133 mg lopinavir/ritonavir(soft capsules) twice daily yielded similarlopinavir plasma concentrations as comparedto lopinavir/ritonavir (soft capsules)400/100 mg twice daily without efavirenz(historical data).

Lopinavir/ritonavirtablets/Efavirenz Lopinavir concentrations: ↓ 30-40%(400/100 mg b.i.d./600 mg q.d.)

Lopinavir concentrations: similar to(500/125 mg b.i.d./600 mg q.d.) lopinavir/ritonavir 400/100 mg twice dailywithout efavirenz. Dose adjustment oflopinavir/ritonavir is necessary when givenwith efavirenz.

For co-administration of efavirenz with low-dose ritonavir in combination with aprotease inhibitor, see section on ritonavirbelow.

Lopinavir/ritonavir/Emtricitabine Interaction not studied.

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

Evening AUC: ↔ efavirenz/emtricitabine/tenofovir

Morning Cmax: ↑ 24% (↑ 12 to ↑ 38) disoproxil is not recommended.

Evening Cmax: ↔ When using

Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) efavirenz/emtricitabine/tenofovir

Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) disoproxil with low-doseritonavir, the possibility of an

Efavirenz: increase in the incidence of

AUC: ↑ 21% (↑ 10 to ↑ 34) efavirenz-associated adverse

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

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

metabolism)

When efavirenz was given with ritonavir500 mg or 600 mg twice daily, thecombination was not well tolerated (forexample, dizziness, nausea, paraesthesia andelevated liver enzymes occurred). Sufficientdata on the tolerability of efavirenz withlow-dose ritonavir (100 mg, once or twicedaily) are not available.

Ritonavir/Emtricitabine Interaction not studied.

Ritonavir/Tenofovir disoproxil Interaction not studied.

Saquinavir/ritonavir/Efavirenz Interaction not studied. For co- Insufficient data are available toadministration of efavirenz with low-dose make a dosing recommendationritonavir in combination with a protease for saquinavir/ritonavir wheninhibitor, see section on ritonavir above. dosed with

Saquinavir/ritonavir/Tenofovir There were no clinically significant efavirenz/emtricitabine/tenofovirdisoproxil pharmacokinetic interactions when tenofovir disoproxil. Co-administration ofdisoproxil was co-administered with saquinavir/ritonavir andritonavir boosted saquinavir. efavirenz/emtricitabine/tenofovir

Saquinavir/ritonavir/Emtricitabine Interaction not studied. disoproxil is not recommended.

Use ofefavirenz/emtricitabine/tenofovirdisoproxil in combination withsaquinavir as the sole proteaseinhibitor is not recommended.

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 not measured, noeffect is expected.

Maraviroc/Tenofovir disoproxil Maraviroc:

(300 mg b.i.d./245 mg q.d.) AUC12h: ↔

Cmax: ↔

Tenofovir concentrations not measured, noeffect is expected.

Maraviroc/Emtricitabine Interaction not studied.

Integrase strand transfer inhibitor

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

C12h: ↓ 21% co-administered without dose

Cmax: ↓ 36% adjustment.

(UGT1A1 induction)

Raltegravir/Tenofovir disoproxil Raltegravir:

(400 mg b.i.d./-) AUC: ↑ 49%

C12h: ↑ 3%

Cmax: ↑ 64%(mechanism of interaction unknown)

Tenofovir:

AUC: ↓ 10%

C12h: ↓ 13%

Cmax: ↓ 23%

Raltegravir/Emtricitabine Interaction not studied.

NRTIs and NNRTIs

NRTIs/Efavirenz Specific interaction studies have not been Due to the similarity betweenperformed with efavirenz and NRTIs other lamivudine and emtricitabine, athan lamivudine, zidovudine and tenofovir component ofdisoproxil. Clinically significant interactions efavirenz/emtricitabine/tenofovirhave not been found and would not be disoproxil,expected since the NRTIs are metabolised efavirenz/emtricitabine/tenofovirvia a different route than efavirenz and disoproxil should not bewould be unlikely to compete for the same administered concomitantly withmetabolic enzymes and elimination lamivudine (see section 4.4).

pathways.

NNRTIs/Efavirenz Interaction not studied. Since use of two NNRTIs provednot beneficial in terms of efficacyand safety, co-administration ofefavirenz/emtricitabine/tenofovirdisoproxil and another NNRTI isnot recommended.

Didanosine/Tenofovir disoproxil Co-administration of tenofovir disoproxil Co-administration ofand didanosine results in a 40-60% increase efavirenz/emtricitabine/tenofovirin systemic exposure to didanosine. disoproxil and didanosine is not

Didanosine/Efavirenz Interaction not studied recommended.

Didanosine/Emtricitabine Interaction not studied

Increased systemic exposure todidanosine 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 dose of250 mg didanosine co-administered with tenofovirdisoproxil therapy has beenassociated with reports of highrates of virologic failure withinseveral tested combinations forthe treatment of HIV-1 infection.

Hepatitis C antivirals

Elbasvir/Grazoprevir + Elbasvir: Co-administration of

Efavirenz AUC: ↓ 54% efavirenz/emtricitabine/tenofovir

Cmax: ↓ 45% disoproxil with(CYP3A4 or P-gp induction - effect on elbasvir/grazoprevir iselbasvir) 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 - effect on concentrations caused bygrazoprevir) CYP3A4 or P-gp induction.

Refer to the Summary of Product

Efavirenz: Characteristics for

AUC: ↔ elbasvir/grazoprevir for more

Cmax: ↔ information.

Glecaprevir/Pibrentasvir/Efavirenz Expected: Concomitant administration of

Glecaprevir: ↓ glecaprevir/pibrentasvir with

Pibrentasvir: ↓ efavirenz, a component ofefavirenz/emtricitabine/tenofovirdisoproxil, may significantlydecrease plasma concentrationsof glecaprevir and pibrentasvir,leading to reduced therapeuticeffect. Co-administration ofglecaprevir/pibrentasvir withefavirenz/emtricitabine/tenofovirdisoproxil is not recommended.

Refer to the prescribinginformation forglecaprevir/pibrentasvir for moreinformation.

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

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

Sofosbuvir: disoproxil, including renal

AUC: ↔ disorders. Renal function should

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

GS3310071:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98% (↑ 77 to ↑ 123)

Cmax: ↑ 79% (↑ 56 to ↑ 104)

Cmin: ↑ 163% (↑ 137 to ↑ 197)

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

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

AUC: ↔ voxilaprevir is expected to

Cmax: ↔ decrease plasma concentrations

Cmin: ↔ of velpatasvir and voxilaprevir.

Co-administration of

Velpatasvir: efavirenz/emtricitabine/tenofovir

AUC: ↓ 53% (↓ 61 to ↓ 43) disoproxil 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/Voxilaprevi Interaction only studied withr sofosbuvir/velpatasvir.

(400 mg/100 mg/100 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir Expected:

disoproxil Voxilaprevir:↓(600 mg/200 mg/245 mg q.d.)

Sofosbuvir (400 mg q.d.) + Sofosbuvir: Efavirenz/emtricitabine/tenofovir

Efavirenz/Emtricitabine/Tenofovir AUC: ↔ disoproxil and sofosbuvir can bedisoproxil Cmax: ↓ 19% (↓ 40 to ↑ 10) coadministered without dose(600 mg/200 mg/245 mg q.d.) adjustment

GS3310071:

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% of uninfectedvolunteers receiving efavirenz andclarithromycin.

Clarithromycin/Emtricitabine Interaction not studied.

Clarithromycin/Tenofovir Interaction not studied.

disoproxil

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/tenofovirdisoproxil. Consider doubling the

Efavirenz: rifabutin dose in regimens where

AUC: ↔ rifabutin is given 2 or 3 times a

Cmax: ↔ week in combination with

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

Rifabutin/Emtricitabine Interaction not studied. this dose adjustment has not been

Rifabutin/Tenofovir disoproxil Interaction not studied. adequately evaluated. Individualtolerability and virologicalresponse should be consideredwhen making the dose adjustment(see section 5.2).

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

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

Cmin: ↓ 32% (↓ 15 to ↓ 46) rifampicin in patients weighing(CYP3A4 and CYP2B6 induction) 50 kg or greater, an additional

Rifampicin/Tenofovir disoproxil Rifampicin: 200 mg/day (800 mg total) of(600 mg q.d./245 mg q.d.) AUC: ↔ efavirenz may provide exposure

Cmax: ↔ similar to a daily efavirenz doseof 600 mg when taken without

Tenofovir: rifampicin. The clinical effect of

AUC: ↔ this dose adjustment has not been

Cmax: ↔ adequately evaluated. Individual

Rifampicin/Emtricitabine Interaction not studied. tolerability and virologicalresponse should be consideredwhen making the dose adjustment(see section 5.2). No doseadjustment of rifampicin isrecommended when given withefavirenz/emtricitabine/tenofovirdisoproxil.

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/tenofovir(decrease in itraconazole disoproxil, an alternativeconcentrations: CYP3A4 induction) antifungal treatment should beconsidered.

Hydroxyitraconazole:

AUC: ↓ 37% (↓ 14 to ↓ 55)

Cmax: ↓ 35% (↓ 12 to ↓ 52)

Cmin: ↓ 43% (↓ 18 to ↓ 60)

AUC: ↔

Cmax: ↔

Cmin: ↔

Itraconazole/Emtricitabine Interaction not studied.

Itraconazole/Tenofovir disoproxil Interaction not studied.

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

Cmax: ↓ 45% efavirenz/emtricitabine/tenofovir(UDP-G induction) disoproxil should be avoided

Posaconazole/Emtricitabine Interaction not studied. unless the benefit to the patient

Posaconazole/Tenofovir disoproxil Interaction not studied. outweighs the risk.

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

Cmax: ↓ 61% disoproxil is a fixeddose

Combination product, the dose of

Efavirenz: efavirenz cannot be altered;

AUC: ↑ 44% therefore, voriconazole and

Cmax: ↑ 38% efavirenz/emtricitabine/tenofovir(competitive inhibition of oxidative disoproxil must not be co-metabolism) administered.

Co-administration of standard doses ofefavirenz and voriconazole iscontraindicated (see section 4.3).

Voriconazole/Emtricitabine Interaction not studied.

Voriconazole/Tenofovir disoproxil Interaction not studied.

Antimalarials

Artemether/Lumefantrine/Efaviren Artemether: Since decreased concentrations ofz AUC: ↓ 51% artemether, dihydroartemisinin,(20/120 mg tablet, 6 doses of Cmax: ↓ 21% or lumefantrine may result in a4 tablets each over 3 days/600 mg decrease of antimalarial efficacy,q.d.) Dihydroartemisinin (active caution is recommended whenmetabolite): efavirenz/emtricitabine/tenofovir

AUC: ↓ 46% disoproxil and

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

Lumefantrine:

AUC: ↓ 21%

Cmax: ↔

AUC: ↓ 17%

Cmax: ↔(CYP3A4 induction)

Artemether/Lumefantrine/Emtricita Interaction not studied.

bine

Artemether/Lumefantrine/Tenofovi Interaction not studied.

r disoproxil

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

Proguanil:

AUC: ↓ 43% (↓ 7 to ↓ 65)

Cmax: ↔

Atovaquone and proguanil Interaction not studied.

hydrochloride/Emtricitabine

Atovaquone and proguanil Interaction not studied.

hydrochloride/Tenofovir disoproxil

ANTICONVULSANTS

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

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

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

An alternative anticonvulsant

Efavirenz: should be considered.

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

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

Cmin: ↓ 47% (↓ 41 to ↓ 53)(decrease in carbamazepine concentrations:

CYP3A4 induction; decrease in efavirenzconcentrations: CYP3A4 and CYP2B6induction)

Co-administration of higher doses of eitherefavirenz or carbamazepine has not beenstudied.

Carbamazepine/Emtricitabine Interaction not studied.

Carbamazepine/Tenofovir Interaction not studied.

disoproxil

Phenytoin, Phenobarbital, and Interaction not studied with efavirenz, Whenother anticonvulsants that are emtricitabine, or tenofovir disoproxil. There efavirenz/emtricitabine/tenofovirsubstrates of CYP isozymes is a potential for reduction or increase in the disoproxil is coadministered withplasma concentrations of phenytoin, an anticonvulsant that is aphenobarbital and other anticonvulsants that substrate of CYP isozymes,are substrates of CYP isozymes with periodic monitoring ofefavirenz. anticonvulsant levels should beconducted.

Valproic acid/Efavirenz No clinically significant effect on efavirenz Efavirenz/emtricitabine/tenofovir(250 mg b.i.d./600 mg q.d.) pharmacokinetics. Limited data suggest disoproxil and valproic acid canthere is no clinically significant effect on be co-administered without dosevalproic acid pharmacokinetics. adjustment. Patients should be

Valproic acid/Emtricitabine Interaction not studied. monitored for seizure control.

Valproic acid/Tenofovir disoproxil Interaction not studied.

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

Gabapentin/Efavirenz interactions are not expected since disoproxil and vigabatrin orvigabatrin and gabapentin are exclusively gabapentin can be coadministeredeliminated unchanged in the urine and are without dose adjustment.

unlikely to compete for the same metabolicenzymes and elimination pathways asefavirenz.

Vigabatrin/Emtricitabine Interaction not studied.

Gabapentin/Emtricitabine

Vigabatrin/Tenofovir disoproxil Interaction not studied.

Gabapentin/Tenofovir disoproxil

ANTICOAGULANTS

Warfarin/Efavirenz Interaction not studied. Plasma Dose adjustment of warfarin or

Acenocoumarol/Efavirenz concentrations and effects of warfarin or acenocoumarol may be requiredacenocoumarol are potentially increased or when co-administered withdecreased by efavirenz. efavirenz/emtricitabine/tenofovirdisoproxil.

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/tenofovir

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

Cmin: ↓ 46% (↓ 31 to ↓ 58) increases should be guided byclinical response.

AUC: ↔

Cmax: ↑ 11% (↑ 6 to ↑ 16)

Cmin: ↔(CYP3A4 induction)

Sertraline/Emtricitabine Interaction not studied.

Sertraline/Tenofovir disoproxil Interaction not studied.

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

Cmax: ↔ co-administered without dose

Cmin: ↔ adjustment.

AUC: ↔

Cmax: ↔

Cmin: ↔

Paroxetine/Emtricitabine Interaction not studied.

Paroxetine/Tenofovir disoproxil Interaction not studied.

Fluoxetine/Efavirenz Interaction not studied. Since fluoxetine Efavirenz/emtricitabine/tenofovirshares a similar metabolic profile with disoproxil and fluoxetine can beparoxetine, i.e. a strong CYP2D6 inhibitory co-administered without doseeffect, a similar lack of interaction would be adjustment.

expected for fluoxetine.

Fluoxetine/Emtricitabine Interaction not studied.

Fluoxetine/Tenofovir disoproxil Interaction not studied.

Norepinephrine and dopamine reuptake inhibitor

Bupropion/Efavirenz Bupropion: Increases in bupropion dose[150 mg single dose (sustained AUC: ↓ 55% (↓ 48 to ↓ 62) should be guided by clinicalrelease)/600 mg q.d.] Cmax: ↓ 34% (↓ 21 to ↓ 47) response, but the maximumrecommended 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 disoproxil Interaction not studied.

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 coadministered with

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

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

Desacetyl diltiazem: 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 efavirenz pharmacokineticparameters is not considered clinicallysignificant.

Diltiazem/Emtricitabine Interaction not studied.

Diltiazem/Tenofovir disoproxil Interaction not studied.

Verapamil, Felodipine, Nifedipine Interaction not studied with efavirenz, Dose adjustments of calciumand emtricitabine, or tenofovir disoproxil. When channel blockers when co-

Nicardipine efavirenz is coadministered with a calcium administered withchannel blocker that is a substrate of the efavirenz/emtricitabine/tenofovir

CYP3A4 enzyme, there is a potential for disoproxil should be guided byreduction in the plasma concentrations of the clinical response (refer to thecalcium channel blocker. Summary of Product

Characteristics for the calciumchannel 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. Dose

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

AUC: ↓ 35% (↓ 13 to ↓ 40) efavirenz/emtricitabine/tenofovir

Cmax: ↓ 13% (↓ 0 to ↓ 23) disoproxil (refer to the Summaryof Product Characteristics for4-hydroxy atorvastatin: atorvastatin).

AUC: ↓ 4% (↓ 0 to ↓ 31)

Cmax: ↓ 47% (↓ 9 to ↓ 51)

Total active HMG Co-A reductaseinhibitors:

AUC: ↓ 34% (↓ 21 to ↓ 41)

Cmax: ↓ 20% (↓ 2 to ↓ 26)

Atorvastatin/Emtricitabine Interaction not studied.

Atorvastatin/Tenofovir disoproxil Interaction not studied.

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

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

Pravastatin/Emtricitabine Interaction not studied. be required when co-administered

Pravastatin/Tenofovir disoproxil Interaction not studied. withefavirenz/emtricitabine/tenofovirdisoproxil (refer to the Summaryof Product Characteristics forpravastatin).

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

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

Simvastatin acid: with

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

Cmax: ↓ 51% (↓ 32 to ↓ 58) disoproxil (refer to the Summaryof Product Characteristics for

Total active HMG Co-A reductase simvastatin).

inhibitors:

AUC: ↓ 60% (↓ 52 to ↓ 68)

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

Co-administration of efavirenz withatorvastatin, pravastatin, or simvastatin didnot affect efavirenz AUC or Cmax values.

Simvastatin/Emtricitabine Interaction not studied.

Simvastatin/Tenofovir disoproxil Interaction not studied.

Rosuvastatin/Efavirenz Interaction not studied. Rosuvastatin Efavirenz/emtricitabine/tenofoviris largely excreted unchanged via the disoproxil and rosuvastatin canfaeces, therefore interaction with be co-administered without doseefavirenz is not expected. adjustment.

Rosuvastatin/Emtricitabine Interaction not studied.

Rosuvastatin/Tenofovir disoproxil Interaction not studied.

HORMONAL CONTRACEPTIVES

Oral: Ethinyloestradiol: A reliable method of barrier

Ethinyloestradiol+Norgestimate/Ef AUC: ↔ contraception must be used inavirenz Cmax: ↔ addition to hormonal(0.035 mg+0.25 mg q.d./600 mg Cmin: ↓ 8% (↑ 14 to ↓ 25) contraceptives (see section 4.6).

q.d.)

Norelgestromin (active metabolite):

AUC: ↓ 64% (↓ 62 to ↓ 67)

Cmax: ↓ 46% (↓ 39 to ↓ 52)

Cmin: ↓ 82% (↓ 79 to ↓ 85)

Levonorgestrel (active metabolite):

AUC: ↓ 83% (↓ 79 to ↓ 87)

Cmax: ↓ 80% (↓ 77 to ↓ 83)

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

Efavirenz: no clinically significantinteraction.

The clinical significance of these effects isnot known.

Ethinyloestradiol/Tenofovir Ethinyloestradiol:

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

Tenofovir:

AUC: ↔

Cmax: ↔

Norgestimate/Ethinyloestradiol/ Interaction not studied.

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

Depomedroxyprogesterone acetate study, no significant differences in MPA information available, a reliable(DMPA)/Efavirenz pharmacokinetic parameters were found method of barrier contraception(150 mg IM single dose DMPA) between subjects receiving efavirenz- must be used in addition tocontaining antiretroviral therapy and hormonal contraceptives (seesubjects receiving no antiretroviral therapy. section 4.6).

Similar results were found by otherinvestigators, although the MPA plasmalevels were more variable in the secondstudy. In both studies, plasma progesteronelevels for subjects receiving efavirenz and

DMPA remained low consistent withsuppression of ovulation.

DMPA/Tenofovir disoproxil Interaction not studied.

DMPA/Emtricitabine Interaction not studied.

Implant: Decreased exposure of etonogestrel may be A reliable method of barrier

Etonogestrel/Efavirenz expected (CYP3A4 induction). There have contraception must be used inbeen occasional post-marketing reports of addition to hormonalcontraceptive failure with etonogestrel in contraceptives (see section 4.6).

efavirenz-exposed patients.

Etonogestrel/Tenofovir disoproxil Interaction not studied.

Etonogestrel/Emtricitabine Interaction not studied.

IMMUNOSUPPRESSANTS

Immunosuppressants metabolised Interaction not studied. Dose adjustments of theby CYP3A4 (e.g. cyclosporine, ↓ exposure of the immunosuppressant may immunosuppressant may betacrolimus, sirolimus)/Efavirenz be expected (CYP3A4 induction). required. Close monitoring of

These immunosuppressants are not immunosuppressantanticipated to impact exposure of efavirenz. concentrations for at least two

Tacrolimus/Emtricitabine/Tenofovi Tacrolimus: weeks (until stable concentrationsr disoproxil AUC: ↔ are reached) is recommended(0.1 mg/kg q.d./200 mg/245 mg Cmax: ↔ when starting or stoppingq.d.) C24h: ↔ treatment withefavirenz/emtricitabine/tenofovir

Emtricitabine: disoproxil.

AUC: ↔

Cmax: ↔

C24h: ↔

Tenofovir disoproxil:

AUC: ↔

Cmax: ↔

C24h: ↔

OPIOIDS

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

Cmax: ↓ 45% (↓ 25 to ↓ 59) disoproxil should be avoided due(CYP3A4 induction) to the risk for QTc prolongation(see section 4.3).

In a study of HIV infected intravenousmedicinal product users, co-administrationof efavirenz with methadone resulted indecreased plasma levels of methadone andsigns of opiate withdrawal. The methadonedose was increased by a mean of 22% toalleviate withdrawal symptoms.

Methadone/Tenofovir disoproxil Methadone:

(40-110 mg q.d./245 mg q.d.) AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Methadone/Emtricitabine Interaction not studied.

Buprenorphine/naloxone/Efavirenz Buprenorphine: Despite the decrease in

AUC: ↓ 50% buprenorphine exposure, nopatients exhibited withdrawal

Norbuprenorphine: symptoms.

AUC: ↓ 71% Dose adjustment ofbuprenorphine may not be

Efavirenz: necessary when co-administered

No clinically significant pharmacokinetic withinteraction. efavirenz/emtricitabine/tenofovir

Buprenorphine/naloxone/Emtricita Interaction not studied. disoproxil.

bine

Buprenorphine/naloxone/Tenofovir Interaction not studied.

disoproxil1 The predominant circulating metabolite of sofosbuvir.

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

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

Women of childbearing potential (see below and section 5.3)

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

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

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

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks afterdiscontinuation of efavirenz/emtricitabine/tenofovir disoproxil 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 of904 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 livebirths. One child was reported to have a neural tube defect, and the frequency and pattern of otherbirth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, aswell as those in HIV negative controls. The incidence of neural tube defects in the general populationranges from 0.5-1 case per 1 000 live births.

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

Emtricitabine and tenofovir disoproxil

A large amount of data on pregnant women (more than 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 should not be used during pregnancy unless the clinicalcondition of the woman requires treatment with efavirenz/emtricitabine/tenofovir disoproxil.

Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There isinsufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants.

A risk to the infants cannot be excluded. Therefore efavirenz/emtricitabine/tenofovir disoproxil shouldnot be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

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

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

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

The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patientseither as the fixed-dose combination tablet efavirenz/emtricitabine/tenofovir disoproxil (study

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

Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatricadverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures);severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported.

Rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy(including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing tofractures) have also been reported. Monitoring of renal function is recommended for 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 withefavirenz/emtricitabine/tenofovir disoproxil and the individual components ofefavirenz/emtricitabine/tenofovir disoproxil in antiretroviral combination therapy are listed in Table 2below by body system organ class, frequency and the component(s) ofefavirenz/emtricitabine/tenofovir disoproxil to which the adverse reactions are attributable. Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000to < 1/100) or rare (≥ 1/10 000 to < 1/1 000).

Adverse reactions associated with the use of efavirenz/emtricitabine/tenofovir disoproxil

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

Common:

- anorexia

Uncommon:

- dry mouth

- incoherent speech

- increased appetite

- libido decreased

- myalgia

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

Efavirenz Emtricitabine Tenofovir disoproxil

Common neutropenia

Uncommon anaemia1

Common allergic reaction

Uncommon hypersensitivity

Efavirenz Emtricitabine Tenofovir disoproxil

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

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

Very common headache dizziness

Common cerebellar coordination dizziness headacheand balance disturbances3,somnolence (2.0%)3,headache (5.7%)3,disturbance in attention(3.6%)3, dizziness (8.5%)3

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

Uncommon vision blurred

Ear and labyrinth disorders:

Uncommon tinnitus, vertigo

Uncommon flushing

Very common diarrhoea, nausea diarrhoea, vomiting,nausea

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

Uncommon pancreatitis pancreatitis

Common elevated aspartate elevated serum AST Increased transaminasesaminotransferase (AST), and/or elevated serumelevated alanine ALT,

Aminotransferase (ALT), hyperbilirubinaemiaelevated gamma-glutamyltransferase(GGT)

Efavirenz Emtricitabine Tenofovir disoproxil

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, skindiscolouration (increasedpigmentation)1

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

Rare photoallergic dermatitis angioedema

Very common elevated creatine kinase

Uncommon rhabdomyolysis2,muscular weakness2

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

Uncommon increased creatinine,proteinuria, proximalrenal tubulopathyincluding Fanconisyndrome

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

Uncommon gynaecomastia

Very common asthenia

Common fatigue pain, asthenia1 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine wasadministered to paediatric patients.2 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causallyassociated with tenofovir disoproxil in the absence of this condition.3 See section 4.8 Description of selected adverse reactions for more details.4 This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovirdisoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients treatedwith efavirenz in clinical studies (n = 3 969) or exposed to emtricitabine in randomised controlled clinical studies (n = 1 563)or exposed to tenofovir disoproxil in randomised controlled clinical studies and the expanded access programme (n = 7 319).

In clinical studies of efavirenz, rashes were usually mild-to-moderate maculopapular skin eruptionsthat occurred within the first two weeks of initiating therapy with efavirenz. In most patients rashresolved with continuing therapy with efavirenz within one month. Efavirenz/emtricitabine/tenofovirdisoproxil can be reinitiated in patients interrupting therapy because of rash. Use of appropriateantihistamines and/or corticosteroids is recommended when efavirenz/emtricitabine/tenofovirdisoproxil 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 ofefavirenz/emtricitabine/tenofovir disoproxil. In clinical controlled studies of efavirenz, nervous systemsymptoms of moderate to severe intensity were experienced by 19% (severe 2%) of patients, and 2%of patients discontinued therapy due to such symptoms. They usually begin during the first one or twodays of efavirenz therapy and generally resolve after the first two to four weeks. They may occur morefrequently when efavirenz/emtricitabine/tenofovir disoproxil is taken concomitantly with mealspossibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems toimprove 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 efavirenz/emtricitabine/tenofovir disoproxil may cause renal damage, monitoring of renal functionis recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathygenerally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients,declines in creatinine clearance did not completely resolve despite tenofovir disoproxildiscontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors,advanced HIV disease, or patients receiving concomitant nephrotoxic medicinal products) are atincreased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxildiscontinuation (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 medicinal products known to induce lacticacidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxiltreatment, including fatal 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 is not recommended in this population (see section 4.2).

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

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

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(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 in patientsco-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIVwithout 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: Antiviral for systemic use, antivirals for treatment of HIV infections,combinations, ATC code: J05AR06.

Mechanism of action and pharmacodynamic effects

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

Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphateand tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine andtenofovir can be fully phosphorylated when combined together in cells. Emtricitabine 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. Crossresistance profiles for efavirenz, nevirapine and delavirdine in vitro demonstrated that the K103Nsubstitution 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 medicinal product discontinuation (see sectionon 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+ emtricitabine+ tenofovir Efavirenz+lamivudine/disoproxil zidovudine (N=243)(N=244)

Resistance analysis by week 144 19 31

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

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

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

K101E 3 (16%) 3 (10%)

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

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

V108I 1 (5%) 1 (3%)

P225H 0 2 (7%)

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

K65R 0 0

K70E 0 0

TAMs2 0 2 (7%)

* p-value < 0.05, Fisher’s Exact test comparing efavirenz + emtricitabine + tenofovir disoproxil group to efavirenz +lamivudine/zidovudine group among all patients.1 Other efavirenz resistance mutations included A98G (n=1), K103E (n=1), V179D (n=1), and M230L (n=1).2 Thymidine analogue associated mutations included D67N (n=1) and K70R (n=1).

In the open-label extended phase of study GS-01-934, where patients receivedefavirenz/emtricitabine/tenofovir disoproxil on an empty stomach, 3 additional cases of resistancewere seen. All 3 subjects had received a fixed dose combination of lamivudine and zidovudine andefavirenz for 144 weeks and then switched to efavirenz/emtricitabine/tenofovir disoproxil. Twosubjects with confirmed virologic rebound developed NNRTI resistance-associated substitutions toefavirenz including K103N, V106V/I/M and Y188Y/C reverse transcriptase substitutions at week 240(96 weeks on efavirenz/emtricitabine/tenofovir disoproxil) and week 204 (60 weeks onefavirenz/emtricitabine/tenofovir disoproxil). A third subject had pre-existing NNRTI resistance-associated substitutions to efavirenz and the M184V reverse transcriptase resistance-associatedsubstitution to emtricitabine at entry into the efavirenz/emtricitabine/tenofovir disoproxil extensionphase and experienced a suboptimal virologic response, and developed K65K/R, S68N and K70K/E

NRTI resistance-associated substitutions at week 180 (36 weeks on efavirenz/emtricitabine/tenofovirdisoproxil).

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

In a 144-week open-label randomised clinical study (GS-01-934) antiretroviral treatment-naïve HIV-1infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovirdisoproxil or a fixed combination of lamivudine and zidovudine administered twice daily andefavirenz once daily (please refer to the Summary of Product Characteristics foremtricitabine/tenofovir disoproxil). Patients who completed 144 weeks of treatment with eithertreatment arm in study GS-01-934 were given the option to continue in an open-label extended phaseof the study with efavirenz/emtricitabine/tenofovir disoproxil on an empty stomach. Data are availablefrom 286 patients who switched to efavirenz/emtricitabine/tenofovir disoproxil: 160 had previouslyreceived efavirenz, emtricitabine and tenofovir disoproxil, and 126 had previously receivedlamivudine/zidovudine and efavirenz. High rates of virologic suppression were maintained by subjectsfrom both initial treatment groups who then received efavirenz/emtricitabine/tenofovir disoproxil inthe open-label extended phase of the study. After 96 weeks of efavirenz/emtricitabine/tenofovirdisoproxil treatment, HIV-1 RNA plasma concentrations remained < 50 copies/ml in 82% of patientsand < 400 copies/ml in 85% of patients (intention to treat analysis (ITT), missing=failure).

Study AI266073 was a 48-week open-label randomised clinical study in HIV infected patientscomparing the efficacy of efavirenz/emtricitabine/tenofovir disoproxil to antiretroviral therapyconsisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) with aprotease inhibitor or non-nucleoside reverse transcriptase inhibitor; however not a regimen containingall efavirenz/emtricitabine/tenofovir disoproxil components (efavirenz, emtricitabine and tenofovirdisoproxil). Efavirenz/emtricitabine/tenofovir disoproxil was administered on an empty stomach (seesection 4.2). Patients had never experienced virological failure on a previous antiretroviral therapy,had no known HIV-1 mutations that confer resistance to any of the three components withinefavirenz/emtricitabine/tenofovir disoproxil, and had been virologically suppressed for at least threemonths at baseline. Patients either changed to efavirenz/emtricitabine/tenofovir disoproxil (N=203) orcontinued on their original antiretroviral treatment regimen (N=97). Forty-eight week data showed thathigh levels of virologic suppression, comparable to the original treatment regimen, were maintained inpatients who were randomised to change to efavirenz/emtricitabine/tenofovir disoproxil (see Table 4).

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

Treatment group

Endpoint Efavirenz/emtricitabine/tenofovir Stayed on Difference betweendisoproxil (N=203) original efavirenz/emtricitabine/tenofovir disoproxiln/N (%) treatment and original treatment regimen (95%CI)regimen(N=97)n/N (%)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 190/203 (93.6%) 94/97 (96.9%) -3.3 (-8.3% to 2.7%)

LOCFpatients with HIV-1 RNA < 200 copies/ml

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

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

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

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

M: Missing

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

When the two strata were analysed separately, response rates in the stratum with prior PI-treatmentwere numerically lower for patients switched to efavirenz/emtricitabine/tenofovir disoproxil [92.4%versus 94.0% for the PVR (sensitivity analysis) for efavirenz/emtricitabine/tenofovir disoproxil and

SBR patients respectively; a difference (95%CI) of -1.6% (-10.0%, 6.7%). In the prior-NNRTIstratum, response rates were 98.9% vs 97.4% for efavirenz/emtricitabine/tenofovir disoproxil and SBRpatients respectively; a difference (95%CI) of 1.4% (-4.0%, 6.9%)].

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

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

Table 5).

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

Prior efavirenz/emtricitabine/tenofovir disoproxil Prior NNRTI-based Prior PI-basedcomponents regimen regimen(N=299) (N=104) (N=34)98.9% (0.6%) 98.0% (1.4%) 93.4% (4.5%)[96.8%, 99.7%] [92.3%, 99.5%] [76.2%, 98.3%]

No data are currently available from clinical studies with efavirenz/emtricitabine/tenofovir disoproxilin treatment-naïve patients or in heavily pretreated patients. There is no clinical experience withefavirenz/emtricitabine/tenofovir disoproxil in patients who are experiencing virological failure in afirst-line antiretroviral treatment regimen 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)(see section 4.4).

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

The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil were used todetermine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil, administeredseparately in HIV infected patients. The bioequivalence of one efavirenz/emtricitabine/tenofovirdisoproxil film-coated tablet with one efavirenz 600 mg film-coated tablet plus one emtricitabine200 mg hard capsule plus one tenofovir disoproxil 245 mg film-coated tablet administered together,was established following single dose administration to fasting healthy subjects in study GS-US-177-0105 (see Table 6).

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

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

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

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

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

AUC0-last 95.84 97.98 99.29(ng∙h/ml) 125 623.6 132 795.7 10 682.6 10 874.4 1 948.8 1 969.0(90.73, (94.90, (91.02,(25.7) (27.0) (18.1) (14.9) (32.9) (32.8)101.23) 101.16) 108.32)

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

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

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 tablettaken under fasted conditions.

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

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

In HIV infected patients, peak efavirenz plasma concentrations were attained by 5 hours 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%.

Efavirenz/emtricitabine/tenofovir disoproxil has not been evaluated in the presence of food.

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

Efavirenz/emtricitabine/tenofovir disoproxil is recommended for administration on an empty stomachsince food may increase efavirenz exposure and may lead to an increase in the frequency of adversereactions (see sections 4.4 and 4.8). It is anticipated that tenofovir exposure (AUC) will beapproximately 30% lower following administration of efavirenz/emtricitabine/tenofovir disoproxil onan empty stomach as compared to the individual component tenofovir disoproxil when taken 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 active substance metabolism mediatedby any of the major human CYP isoforms involved in active substance biotransformation. Also,emtricitabine did not inhibit uridine 5' diphosphoglucuronyl transferase, the enzyme responsible forglucuronidation.

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 efavirenz/emtricitabine/tenofovir disoproxil ininfants and children under 18 years of age (see section 4.2).

The pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil after co-administration ofthe separate pharmaceutical forms or as efavirenz/emtricitabine/tenofovir disoproxil have not beenstudied in HIV infected patients with renal impairment.

Pharmacokinetic parameters were determined following administration of single doses of theindividual preparations of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infectedpatients with varying degrees of renal impairment. The degree of renal impairment was definedaccording to baseline creatinine clearance (normal renal function when creatinine clearance >80 ml/min; mild impairment with creatinine clearance=50 to 79 ml/min; moderate impairment withcreatinine clearance=30 to 49 ml/min and severe impairment with 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 activesubstance exposures substantially increased over 72 hours to 53 µg*h/ml (19%) of emtricitabine, andover 48 hours to 42 857 ng*h/ml (29%) of tenofovir.

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

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

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

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

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

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

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected patients withvarying degrees of hepatic impairment defined according to CPT classification. Tenofovirpharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting 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 bone mineral density (BMD) (rats and dogs). The bone toxicityin young adult rats and dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adultpatients; bone toxicity occurred in juvenile infected monkeys at very high exposures followingsubcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat and monkey studiesindicated that there was a substance-related decrease in intestinal absorption of phosphate withpotential 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 unscheduled DNAsynthesis (UDS) test in primary rat hepatocytes. However, it was negative in an in vivo mouse bonemarrow 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 in peripostnatal 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

Hydroxypropylcellulose

Sodium laurilsulfate

Croscarmellose sodium

Ferric oxide red (E172)

Magnesium stearate

Sodium stearyl fumarate

Poly(vinyl alcohol)

Macrogol 3350

Titanium dioxide (E171)

Talc

Ferric oxide red (E172)

Ferric oxide yellow (E172)

Not applicable.

3 years

Shelf life after first opening is 2 months when stored in original packaging at a temperature not above25°C.

Do not store above 30°C.

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

For storage conditions after first opening of the medicinal product, see section 6.3.

High density polyethylene (HDPE) bottle with a child-resistant tamper evident polypropylene closurewith integrated a silica gel desiccant.

Pack sizes: 30 film-coated tablets and 90 (3x30) film-coated tablets (3 bottles of 30 tablets).

Not all pack sizes may be marketed.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

EU/1/17/1263/001 30 film-coated tablets

EU/1/17/1263/002 90 (3 x 30) film-coated tablets

Date of first authorisation: 8 February 2018

Date of latest renewal: 7 November 2022

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

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