STOCRIN 600mg tablets medication leaflet

STOCRIN 600 mg film-coated tablets

STOCRIN 50 mg film-coated tablets

STOCRIN 200 mg film-coated tablets

STOCRIN 600 mg film-coated tablets

Each film-coated tablet contains 600 mg of efavirenz.

Each film-coated tablet contains 249.6 mg of lactose (as monohydrate).

STOCRIN 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of efavirenz.

Each film-coated tablet contains 20.8 mg of lactose (as monohydrate).

STOCRIN 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of efavirenz.

Each film-coated tablet contains 83.2 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet

STOCRIN 600 mg film-coated tablets

Dark yellow, capsule-shaped, debossed with “225” on one side.

STOCRIN 50 mg film-coated tablets

Yellow, round, debossed with “113” on one side.

STOCRIN 200 mg film-coated tablets

Yellow, round, debossed with “223” on one side.

STOCRIN is indicated in antiviral combination treatment of human immunodeficiency virus-1(HIV-1) infected adults, adolescents and children 3 years of age and older.

STOCRIN has not been adequately studied in patients with advanced HIV disease, namely in patientswith CD4 counts < 50 cells/mm3, or after failure of protease inhibitor (PI) containing regimens.

Although cross-resistance of efavirenz with PIs has not been documented, there are at presentinsufficient data on the efficacy of subsequent use of PI based combination therapy after failure ofregimens containing STOCRIN.

For a summary of clinical and pharmacodynamic information, see section 5.1.

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

Efavirenz must be given in combination with other antiretroviral medicines (see section 4.5).

In order to improve the tolerability of nervous system adverse reactions, bedtime dosing isrecommended (see section 4.8).

The recommended dose of efavirenz in combination with nucleoside analogue reverse transcriptaseinhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily.

If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose must beincreased to 400 mg every 12 hours and the efavirenz dose must be reduced by 50 %, i.e., to 300 mgonce daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should berestored (see section 4.5).

If efavirenz is coadministered with rifampicin to patients weighing 50 kg or more, an increase in thedose of efavirenz to 800 mg/day may be considered (see section 4.5).

Children and adolescents (3 to 17 years)

The recommended dose of efavirenz in combination with a PI and/or NRTIs for patients between 3and 17 years of age is described in Table 1. Efavirenz tablets must only be administered to childrenwho are able to reliably swallow tablets.

Table 1: Paediatric dose to be administered once daily*

Body Weight Efavirenzkg Dose (mg)13 to < 15 20015 to < 20 25020 to < 25 30025 to < 32.5 35032.5 to < 40 400≥ 40 600 Efavirenz 50 mg, 200 mg and 600 mg film-coated tablets are available.

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however,less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the impact of renalimpairment on efavirenz elimination should be minimal (see section 4.4).

Patients with mild liver disease may be treated with their normally recommended dose of efavirenz.

Patients should be monitored carefully for dose-related adverse reactions, especially nervous systemsymptoms (see sections 4.3 and 4.4).

The safety and efficacy of efavirenz in children below the age of 3 years or weighing less than 13 kghave not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2, butno recommendation on a posology can be made.

It is recommended that STOCRIN be taken on an empty stomach. The increased efavirenzconcentrations observed following administration of STOCRIN with food may lead to an increase infrequency of adverse reactions (see sections 4.4 and 5.2).

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

Patients with severe hepatic impairment (Child Pugh 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)because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create thepotential for serious and/or life-threatening adverse reactions [for example, cardiac arrhythmias,prolonged sedation or respiratory depression] (see section 4.5).

Herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of decreasedplasma concentrations and reduced clinical effects of efavirenz (see section 4.5).

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 arrythmias or with clinically relevant bradycardia or withcongestive cardiac failure accompanied by reduced left ventricle ejection fraction.

- severe disturbances of electrolyte balance e.g., hypokalaemia or hypomagnesaemia.

Patients taking drugs that are known to prolong the QTc interval (proarrhythmic).

These drugs include:

- antiarrhythmics of classes IA and III,

- neuroleptics, antidepressive agents,

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

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

- cisapride,

- flecainide,

- certain antimalarials,

- methadone.

Co-administration with elbasvir/grazoprevir due to the expected significant decreases in elbasvir andgrazoprevir plasma concentrations (see section 4.5). This effect is due to an induction of CYP3A4 or

P-gp by efavirenz and is expected to result in the loss of virologic response of elbasvir/grazoprevir.

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failingregimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choiceof new antiretroviral agent(s) to be used in combination with efavirenz should take into considerationthe potential for viral cross-resistance (see section 5.1).

Co-administration of efavirenz with a fixed combination tablet containing efavirenz, emtricitabine,and tenofovir disoproxil, is not recommended unless needed for dose adjustment (for example, withrifampicin).

Co-administration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasmaconcentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect.

Co-administration of glecaprevir/pibrentasvir with efavirenz is not recommended (see section 4.5).

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

When prescribing medicinal products concomitantly with efavirenz, physicians should refer to thecorresponding Summary of Product Characteristics.

If any antiretroviral medicinal product in a combination regimen is interrupted because of suspectedintolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviralmedicinal products. The antiretroviral medicinal products should be restarted at the same time uponresolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction ofantiretroviral agents is not advisable because of the increased potential for selection of resistant virus.

Mild-to-moderate rash has been reported in clinical studies with efavirenz and usually resolves withcontinued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability andhasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulcerationhas been reported in less than 1 % of patients treated with efavirenz. The incidence of erythemamultiforme or Stevens-Johnson syndrome was approximately 0.1 %. Efavirenz must be discontinuedin patients developing severe rash associated with blistering, desquamation, mucosal involvement orfever. If therapy with efavirenz is discontinued, consideration should also be given to interruptingtherapy with other antiretroviral agents to avoid development of resistant virus (see section 4.8).

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI classis limited (see section 4.8). Efavirenz is not recommended for patients who have had a life-threateningcutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI.

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 these serious psychiatric adversereactions. In particular, severe depression was more common in those with a history of depression.

There have also been post-marketing reports of severe depression, death by suicide, delusions,psychosis-like behaviour and catatonia. Patients should be advised that if they experience symptomssuch as severe depression, psychosis or suicidal ideation, they should contact their doctor immediatelyto assess the possibility that the symptoms may be related to the use of efavirenz, and if so, todetermine whether the risks of continued therapy outweigh 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 (see section 4.8). Nervous system symptoms usually begin during the first oneor two days of therapy and generally resolve after the first 2 - 4 weeks. Patients should be informedthat if they do occur, these common symptoms are likely to improve with continued therapy and arenot predictive of subsequent onset of any of the less frequent psychiatric symptoms.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion,psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenztherapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 geneticpolymorphisms, which are associated with increased efavirenz levels despite standard dosing of

STOCRIN. Patients presenting with signs and symptoms of serious neurologic adverse experiencesshould be evaluated promptly to assess the possibility that these events may be related to efavirenzuse, and whether discontinuation of STOCRIN is warranted.

Convulsions have been observed in patients receiving efavirenz, generally in the presence of knownmedical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal productsprimarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may requireperiodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasmaconcentrations were decreased when carbamazepine was co-administered with efavirenz (seesection 4.5). Caution must be taken in any patient with a history of seizures.

A few of the post-marketing reports of hepatic failure occurred in patients with no pre-existing hepaticdisease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should beconsidered for patients without pre-existing hepatic dysfunction or other risk factors.

QTc Prolongation

QTc prolongation has been observed with the use of efavirenz (see sections 4.5 and 5.1).

Consider alternatives to efavirenz for co-administration with a drug with a known risk of Torsade de

Pointes or when to be administered to patients at higher risk of Torsade de Pointes.

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

In HIV infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,such reactions have been observed within the first few weeks or months of initiation of CART.

Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Anyinflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in thesetting of immune reactivation; however, the reported time to onset is more variable and these eventscan occur many months after initiation of treatment.

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.

Although the aetiology 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 combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint aches and pain, joint stiffness or difficulty in movement.

Efavirenz is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2) andnot recommended in patients with moderate hepatic impairment because of insufficient data todetermine whether dose adjustment is necessary. Because of the extensive cytochrome P450-mediatedmetabolism of efavirenz and limited clinical experience in patients with chronic liver disease, cautionmust be exercised in administering efavirenz to patients with mild hepatic impairment. Patients shouldbe monitored carefully for dose-related adverse reactions, especially nervous system symptoms.

Laboratory tests should be performed to evaluate their liver disease at periodic intervals(see section 4.2).

The safety and efficacy of efavirenz has not been established in patients with significant underlyingliver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviraltherapy are at increased risk for severe and potentially fatal hepatic adverse reactions. Patients withpre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liverfunction abnormalities during combination antiretroviral therapy and should be monitored accordingto standard practice. If there is evidence of worsening liver disease or persistent elevations of serumtransaminases to greater than 5 times the upper limit of the normal range, the benefit of continuedtherapy with efavirenz needs to be weighed against the potential risks of significant liver toxicity. Insuch patients, interruption or discontinuation 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. In case of concomitant antiviral therapy for hepatitis B or C, pleaserefer also to the relevant product information for these medicinal products.

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however,less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the impact of renalimpairment on efavirenz elimination should be minimal (see section 4.2). There is no experience inpatients with severe renal failure and close safety monitoring is recommended in this population.

Insufficient numbers of older patients have been evaluated in clinical studies to determine whetherthey respond differently than younger patients.

Efavirenz has not been evaluated in children below 3 years of age or who weigh less than 13 kg.

Therefore, efavirenz should not be given to children less than 3 years of age.

Rash was reported in 26 of 57 children (46 %) treated with efavirenz during a 48-week period and wassevere in three patients. Prophylaxis with appropriate antihistamines prior to initiating therapy withefavirenz in children may be considered.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product. Individuals with theseconditions may take efavirenz oral solution, which is free from lactose.

These medicinal products contain less than 1 mmol sodium (23 mg) per film-coated tablet, that is tosay essentially ‘sodium free’.

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. Invitro efavirenz is also an inhibitor of CYP3A4. Theoretically, efavirenz may therefore initiallyincrease the exposure to CYP3A4 substrates and caution is warranted for CYP3A4 substrates withnarrow therapeutic index (see section 4.3). Efavirenz may be an inducer of CYP2C19 and CYP2C9;however inhibition has also been observed in vitro and the net effect of co-administration withsubstrates of these enzymes is not clear (see section 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 herbal preparations (for example Ginkgo biloba extracts and St. John’s wort) whichinduce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant useof St. John’s wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts isnot recommended (see section 4.4).

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

QT Prolonging Drugs

Efavirenz is contraindicated with concomitant use of drugs (they may cause prolonged QTc intervaland Torsade de Pointes) such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressantagents, certain antibiotics including some agents of the following classes: macrolides,fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics(terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3).

Interaction studies have only been performed in adults.

Contraindications of concomitant use

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

Efavirenz must not be administered with elbasvir/grazoprevir due to the expected significant decreasesin elbasvir and grazoprevir plasma concentrations caused by induction of drug metabolising enzymesand/or transport proteins and which are expected to result in the loss of virologic response ofelbasvir/grazoprevir (see section 4.5).

St. John’s wort (Hypericum perforatum)

Co-administration of efavirenz and St. John’s wort or herbal preparations containing St. John’s wort iscontraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John's wort dueto induction of drug metabolising enzymes and/or transport proteins by St. John's wort. If a patient isalready taking St. John’s wort, stop St. John’s wort, check viral levels and if possible efavirenz levels.

Efavirenz levels may increase on stopping St. John’s wort and the dose of efavirenz may needadjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation oftreatment (see section 4.3).

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 and protease inhibitors, antiretroviral agents other than proteaseinhibitors and other non-antiretroviral medicinal products are listed in Table 2 below (increase isindicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hours as “q8h” or“q12h”). If available, 90 % or 95 % confidence intervals are shown in parentheses. Studies wereconducted in healthy subjects unless otherwise noted.

Table 2: Interactions between efavirenz and other medicinal products in adults

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

ANTI-INFECTIVES

HIV antivirals

Protease inhibitors (PI)

Atazanavir/ ritonavir/Efavirenz Atazanavir (pm): Co-administration of efavirenz(400 mg once daily/100 mg once AUC: ↔* (↓ 9 to ↑ 10) with atazanavir/ritonavir is notdaily/600 mg once daily, all Cmax: ↑ 17 %* (↑ 8 to ↑ 27) recommended. If theadministered with food) Cmin: ↓ 42 %* (↓ 31 to ↓ 51) co-administration of atazanavirwith an NNRTI is required, an

Atazanavir/ritonavir/Efavirenz Atazanavir (pm): increase in the dose of both(400 mg once daily/200 mg once AUC: ↔*/** (↓ 10 to ↑ 26) atazanavir and ritonavir to 400 mgdaily/600 mg once daily, all Cmax: ↔*/** (↓ 5 to ↑ 26) and 200 mg, respectively, inadministered with food) Cmin: ↑ 12 %*/** (↓ 16 to ↑ 49) combination with efavirenz could(CYP3A4 induction). be considered with close clinical

* When compared to atazanavir monitoring.300 mg/ritonavir 100 mg oncedaily in the evening withoutefavirenz. This decrease inatazanavir Cmin might negativelyimpact the efficacy of atazanavir.

** based on historical comparison

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Darunavir/ritonavir/Efavirenz Darunavir: Efavirenz in combination with(300 mg twice daily*/100 mg twice AUC : ↓ 13 % darunavir/ritonavir 800/100 mgdaily/600 mg once daily) Cmin : ↓ 31 % once daily may result in

Cmax: ↓ 15% suboptimal darunavir Cmin. If

*lower than recommended doses, (CYP3A4 induction) efavirenz is to be used insimilar findings are expected with Efavirenz: combination withrecommended doses. AUC : ↑ 21 % darunavir/ritonavir, the

Cmin: ↑ 17 % darunavir/ritonavir 600/100 mg

Cmax: ↑ 15% twice daily regimen should be(CYP3A4 inhibition) used. This combination should beused with caution.

See also ritonavir row below.

Fosamprenavir/ritonavir/Efavirenz No clinically significant No dose adjustment is necessary(700 mg twice daily/100 mg twice pharmacokinetic interaction. for any of these medicinaldaily/600 mg once daily) products.

See also ritonavir row below.

Fosamprenavir/Nelfinavir/Efavirenz Interaction not studied No dose adjustment is necessaryfor any of these medicinalproducts.

Fosamprenavir/Saquinavir/Efavirenz Interaction not studied Not recommended, as theexposure to both PIs is expected tobe significantly decreased.

Indinavir/Efavirenz Indinavir: While the clinical significance of(800 mg q8h/200 mg once daily) AUC: ↓ 31 % (↓ 8 to ↓ 47) decreased indinavir concentrations

Cmin: ↓ 40 % has not been established, the

A similar reduction in indinavir magnitude of the observedexposures was observed when pharmacokinetic interactionindinavir 1,000 mg q8h was given should be taken into considerationwith efavirenz 600 mg daily. when choosing a regimen(CYP3A4 induction) containing both efavirenz and

Efavirenz: indinavir.

No clinically significantpharmacokinetic interaction No dose adjustment is necessaryfor efavirenz when given with

Indinavir/ritonavir/Efavirenz Indinavir: indinavir or indinavir/ritonavir.(800 mg twice daily/100 mg twice AUC: ↓ 25 % (↓ 16 to ↓ 32) bdaily/600 mg once daily) Cmax: ↓ 17 % (↓ 6 to ↓ 26)b

Cmin: ↓ 50 % (↓ 40 to ↓ 59)b See also ritonavir row below.

No clinically significantpharmacokinetic interaction

The geometric mean Cmin forindinavir (0.33 mg/l) when givenwith ritonavir and efavirenz washigher than the mean historical

Cmin (0.15 mg/l) when indinavirwas given alone at 800 mg q8h. In

HIV-1 infected patients (n = 6),the pharmacokinetics of indinavirand efavirenz were generallycomparable to these uninfectedvolunteer data.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Lopinavir/ritonavir soft capsules or Substantial decrease in lopinavir With efavirenz, an increase of theoral solution/Efavirenz exposure. lopinavir/ritonavir soft capsule ororal solution doses by 33 % shouldbe considered (4 capsules/~6.5 mL

Lopinavir/ritonavir tablets/ Efavirenz twice daily instead of3 capsules/5 mL twice daily).

Caution is warranted since this(400/100 mg twice daily/600 mg once Lopinavir concentrations: dose adjustment might bedaily) ↓ 30-40 % insufficient in some patients. Thedose of lopinavir/ritonavir tablets(500/125 mg twice daily/600 mg once Lopinavir concentrations: similar should be increased to 500/125 mgdaily) to lopinavir/ritonavir 400/100 mg twice daily when co-administeredtwice daily without efavirenz with efavirenz 600 mg once daily.

See also ritonavir row below.

Nelfinavir/Efavirenz Nelfinavir: No dose adjustment is necessary(750 mg q8h/600 mg once daily) AUC: ↑ 20 % (↑ 8 to ↑ 34) for either medicinal product.

Cmax: ↑ 21 % (↑ 10 to ↑ 33)

The combination was generallywell tolerated.

Ritonavir/Efavirenz Ritonavir: When using efavirenz with(500 mg twice daily/600 mg once Morning AUC: ↑ 18 % (↑ 6 to low-dose ritonavir, the possibilitydaily) ↑ 33) of an increase in the incidence of

Evening AUC: ↔ efavirenz-associated adverse

Morning Cmax: ↑ 24 % (↑ 12 to events should be considered, due↑ 38) to possible pharmacodynamic

Evening Cmax: ↔ interaction.

Morning Cmin: ↑ 42 % (↑ 9 to↑ 86)b

Evening Cmin: ↑ 24 % (↑ 3 to↑ 50)b

AUC: ↑ 21 % (↑ 10 to ↑ 34)

Cmax: ↑ 14 % (↑ 4 to ↑ 26)

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

When efavirenz was given withritonavir 500 mg or 600 mg twicedaily, the combination was notwell tolerated (for example,dizziness, nausea, paraesthesiaand elevated liver enzymesoccurred). Sufficient data on thetolerability of efavirenz withlow-dose ritonavir (100 mg, onceor twice daily) are not available.

Saquinavir/ritonavir/Efavirenz Interaction not studied. No data are available to make adose recommendation. See alsoritonavir row above. Use ofefavirenz in combination withsaquinavir as the sole proteaseinhibitor is not recommended.

CCR5 antagonist

Maraviroc/Efavirenz Maraviroc: Refer to the Summary of Product(100 mg twice daily/600 mg once AUC12: ↓ 45 % (↓ 38 to ↓ 51) Characteristics for the medicinaldaily) Cmax: ↓ 51 % (↓ 37 to ↓ 62) product containing maraviroc.

Efavirenz concentrations notmeasured, no effect is expected.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Integrase strand transfer inhibitor

Raltegravir/Efavirenz Raltegravir: No dose adjustment is necessary(400 mg single dose/ - ) AUC: ↓ 36 % for raltegravir.

C12: ↓ 21 %

Cmax: ↓ 36 %(UGT1A1 induction)

NRTIs and NNRTIs

NRTIs/Efavirenz Specific interaction studies have No dose adjustment is necessarynot been performed with efavirenz for either medicinal product.and NRTIs other than lamivudine,zidovudine, and tenofovirdisoproxil. Clinically significantinteractions are not expected sincethe NRTIs are metabolised via adifferent route than efavirenz andwould be unlikely to compete forthe same metabolic enzymes andelimination pathways.

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

Hepatitis C antivirals

Boceprevir/Efavirenz Boceprevir: Plasma trough concentrations of(800 mg 3 times daily/600 mg once AUC: ↔ 19%* boceprevir were decreased whendaily) Cmax: ↔ 8% administered with efavirenz. The

Cmin: ↓ 44% clinical outcome of this observed

Efavirenz: reduction of boceprevir trough

AUC: ↔ 20% concentrations has not been

Cmax: ↔ 11% directly assessed.(CYP3A induction - effect onboceprevir)

*0-8 hours

No effect (↔) equals a decreasein mean ratio estimate of ≤20% orincrease in mean ratio estimate of≤25%

Telaprevir/Efavirenz Telaprevir (relative to 750 mg If efavirenz and telaprevir are co-(1,125 mg q8h/600 mg once daily) q8h): administered, telaprevir 1,125 mg

AUC: ↓ 18% (↓ 8 to ↓ 27) every 8 hours should be used.

Cmax: ↓ 14% (↓ 3 to ↓ 24)

Cmin: ↓ 25% (↓ 14 to ↓ 34)%

AUC: ↓ 18% (↓ 10 to ↓ 26)

Cmax: ↓ 24% (↓ 15 to ↓ 32)

Cmin: ↓ 10% (↑ 1 to ↓ 19)%(CYP3A induction by efavirenz)

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Simeprevir/Efavirenz Simeprevir: Concomitant administration of(150 mg once daily /600 mg once AUC: ↓ 71% (↓ 67 to ↓ 74) simeprevir with efavirenz resulteddaily) Cmax: ↓ 51% (↓ 46 to ↓ 56) in significantly decreased plasma

Cmin: ↓ 91% (↓ 88 to ↓ 92) concentrations of simeprevir due

Efavirenz: to CYP3A induction by efavirenz,

AUC: ↔ which may result in loss of

Cmax: ↔ therapeutic effect of simeprevir.

Cmin: ↔ Co-administration of simeprevir

No effect (↔) equals a decrease with efavirenz is notin mean ratio estimate of ≤20% or recommended.)increase in mean ratio estimate of≤25%(CYP3A4 enzyme induction)

Elbasvir/grazoprevir Elbasvir: Concomitant administration of

AUC: ↓54% STOCRIN with

Cmax: ↓45% elbasvir/grazoprevir iscontraindicated (see section 4.3)

Grazoprevir: because it may lead to loss of

AUC: ↓83% virologic response to

Cmax: ↓87% elbasvir/grazoprevir. This loss isdue to significant decreases inelbasvir and grazoprevir plasmaconcentrations caused by CYP3A4or P-gp induction (refer to the

Summary of Product

Characteristics forelbasvir/grazoprevir for additionalinformation).

Sofosbuvir/velpatasvir Sofosbuvir: Co-administration ofsofosbuvir/velpatasvir/voxilaprevir Cmax ↑38% efavirenz/emtricitabine/tenofovirdisoproxil with

Velpatasvir sofosbuvir/velpatasvir has been

AUC ↓53% shown to significantly decrease

Cmax ↓47% plasma concentrations of

Cmin ↓57% velpatasvir due to CYP3Ainduction by efavirenz, which mayresult in loss of therapeutic effect

Expected: of velpatasvir. Although not↓Voxilaprevir studied, a similar decrease invoxilaprevir exposure isanticipated. Co-administration of

STOCRIN withsofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilapreviris not recommended (refer to the

Summary of Product

Characteristics forsofosbuvir/velpatasvir andsofosbuvir/velpatasvir/voxilaprevirfor additional information).

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Glecaprevir/pibrentasvir ↓glecaprevir Concomitant administration of↓pibrentasvir glecaprevir/pibrentasvir withefavirenz may significantlydecrease plasma concentrations ofglecaprevir and pibrentasvir,leading to reduced therapeuticeffect.

Co-administration ofglecaprevir/pibrentasvir withefavirenz is not recommended.

Refer to the prescribinginformation forglecaprevir/pibrentasvir for moreinformation.

Antibiotics

Azithromycin/Efavirenz No clinically significant No dose adjustment is necessary(600 mg single dose/400 mg once pharmacokinetic interaction. for either medicinal product.daily)

Clarithromycin/Efavirenz Clarithromycin: The clinical significance of these(500 mg q12h/400 mg once daily) AUC: ↓ 39 % (↓ 30 to ↓ 46) changes in clarithromycin plasma

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

Clarithromycin to clarithromycin (e.g.,14-hydroxymetabolite: azithromycin) may be considered.

AUC: ↑ 34 % (↑ 18 to ↑ 53) No dose adjustment is necessary

Cmax: ↑ 49 % (↑ 32 to ↑ 69) for efavirenz.

AUC: ↔

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

Rash developed in 46 % ofuninfected volunteers receivingefavirenz and clarithromycin.

Other macrolide antibiotics (e.g., Interaction not studied. No data are available to make aerythromycin)/Efavirenz dose recommendation.

Antimycobacterials

Rifabutin/Efavirenz Rifabutin: The daily dose of rifabutin should(300 mg once daily/600 mg once AUC: ↓ 38 % (↓ 28 to ↓ 47) be increased by 50 % whendaily) Cmax: ↓ 32 % (↓ 15 to ↓ 46) administered with efavirenz.

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

Efavirenz: dose in regimens where rifabutin

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

Cmax: ↔ combination with efavirenz. The

Cmin: ↓ 12 % (↓ 24 to ↑ 1) clinical effect of this dose(CYP3A4 induction) adjustment has not beenadequately evaluated. Individualtolerability and virologicalresponse should be consideredwhen making the dose adjustment(see section 5.2).

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Rifampicin/Efavirenz Efavirenz: When taken with rifampicin in(600 mg once daily/600 mg once AUC: ↓ 26 % (↓ 15 to ↓ 36) patients weighing 50 kg or greater,daily) Cmax: ↓ 20 % (↓ 11 to ↓ 28) increasing efavirenz daily dose to

Cmin: ↓ 32 % (↓ 15 to ↓ 46) 800 mg may provide exposure(CYP3A4 and CYP2B6 similar to a daily dose of 600 mg,induction) when taken without rifampicin.

The clinical effect of this doseadjustment has not beenadequately evaluated. Individualtolerability and virologicalresponse should be consideredwhen making the dose adjustment(see section 5.2). No doseadjustment is necessary forrifampicin, including 600 mg.

Antifungals

Itraconazole/Efavirenz Itraconazole: Since no dose recommendation for(200 mg q12h/600 mg once daily) AUC: ↓ 39 % (↓ 21 to ↓ 53) itraconazole can be made,

Cmax: ↓ 37 % (↓ 20 to ↓ 51) alternative antifungal treatment

Cmin: ↓ 44 % (↓ 27 to ↓ 58) should be considered.(decrease in itraconazoleconcentrations: CYP3A4induction)

Hydroxyitraconazole:

AUC: ↓ 37 % (↓ 14 to ↓ 55)

Cmax: ↓ 35 % (↓ 12 to ↓ 52)

Cmin: ↓ 43 % (↓ 18 to ↓ 60)

No clinically significantpharmacokinetic change.

Posaconazole/Efavirenz Posaconazole: Concomitant use of posaconazole

- -/400 mg once daily AUC: ↓ 50 % and efavirenz should be avoided

Cmax: ↓ 45 % unless the benefit to the patient(UDP-G induction) outweighs the risk.

Voriconazole/Efavirenz Voriconazole: When efavirenz is co-administered(200 mg twice daily/400 mg once AUC: ↓ 77 % with voriconazole, thedaily) Cmax: ↓ 61 % voriconazole maintenance dose

Efavirenz: must be increased to 400 mg twice

AUC: ↑ 44 % daily and the efavirenz dose must

Cmax: ↑ 38 % be reduced by 50 %, i.e., to

Voriconazole/Efavirenz Voriconazole: 300 mg once daily. When(400 mg twice daily/300 mg once AUC: ↓ 7 % (↓ 23 to ↑ 13) * treatment with voriconazole isdaily) Cmax: ↑ 23 % (↓ 1 to ↑ 53) * stopped, the initial dose of

Efavirenz: efavirenz should be restored.

AUC: ↑ 17 % (↑ 6 to ↑ 29) **

Cmax: ↔**

*compared to 200 mg twice dailyalone

** compared to 600 mg oncedaily alone(competitive inhibition ofoxidative metabolism)

Fluconazole/Efavirenz No clinically significant No dose adjustment is necessary(200 mg once daily/400 mg once pharmacokinetic interaction for either medicinal product.daily)

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Ketoconazole and other imidazole Interaction not studied No data are available to make aantifungals dose recommendation.

Antimalarials

Artemether/lumefantrine/ Artemether: Since decreased concentrations of

Efavirenz AUC: ↓ 51% artemether, dihydroartemisinin, or(20/120 mg tablet, 6 doses of 4 Cmax: ↓ 21% lumefantrine may result in atablets each over 3 days/600 mg once Dihydroartemisinin: decrease of antimalarial efficacy,daily) AUC: ↓ 46% caution is recommended when

Cmax: ↓ 38% efavirenz and

Lumefantrine: artemether/lumefantrine tablets are

AUC: ↓ 21% coadministered.

Cmax: ↔

AUC: ↓ 17%

Cmax: ↔(CYP3A4 induction)

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 should be avoided.once daily)

Proguanil:

AUC: ↓ 43% (↓ 7 to ↓ 65)

Cmax: ↔

ACID REDUCING AGENTS

Aluminium hydroxide-magnesium Neither aluminium/magnesium Co-administration of efavirenzhydroxide-simethicone hydroxide antacids nor famotidine with medicinal products that alterantacid/Efavirenz altered the absorption of gastric pH would not be expected(30 mL single dose/400 mg single efavirenz. to affect efavirenz absorption.dose)

Famotidine/Efavirenz(40 mg single dose/400 mg singledose)

ANTIANXIETY AGENTS

Lorazepam/Efavirenz Lorazepam: No dose adjustment is necessary(2 mg single dose/600 mg once daily) AUC: ↑ 7 % (↑ 1 to ↑ 14) for either medicinal product.

Cmax: ↑ 16 % (↑ 2 to ↑ 32)

These changes are not consideredclinically significant.

ANTICOAGULANTS

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

Acenocoumarol/Efavirenz concentrations and effects of acenocoumarol may be required.

warfarin or acenocoumarol arepotentially increased or decreasedby efavirenz.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

ANTICONVULSANTS

Carbamazepine/Efavirenz Carbamazepine: No dose recommendation can be(400 mg once daily/600 mg once AUC: ↓ 27 % (↓ 20 to ↓ 33) made. An alternativedaily) Cmax: ↓ 20 % (↓ 15 to ↓ 24) anticonvulsant should be

Cmin: ↓ 35 % (↓ 24 to ↓ 44) considered. Carbamazepine

Efavirenz: plasma levels should be monitored

AUC: ↓ 36 % (↓ 32 to ↓ 40) periodically.

Cmax: ↓ 21 % (↓ 15 to ↓ 26)

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

CYP2B6 induction)

The steady-state AUC, Cmax and

Cmin of the active carbamazepineepoxide metabolite remainedunchanged. Co-administration ofhigher doses of either efavirenz orcarbamazepine has not beenstudied.

Phenytoin, Phenobarbital, and other Interaction not studied. There is a When efavirenz is co-administeredanticonvulsants that are substrates of potential for reduction or increase with an anticonvulsant that is a

CYP450 isoenzymes in the plasma concentrations of substrate of CYP450 isoenzymes,phenytoin, phenobarbital and periodic monitoring ofother anticonvulsants that are anticonvulsant levels should besubstrates of CYP450 isoenzymes conducted.when co-administered withefavirenz.

Valproic acid/Efavirenz No clinically significant effect on No dose adjustment is necessary(250 mg twice daily/600 mg once efavirenz pharmacokinetics. for efavirenz. Patients should bedaily) Limited data suggest there is no monitored for seizure control.

clinically significant effect onvalproic acid pharmacokinetics.

Vigabatrin/Efavirenz Interaction not studied. Clinically No dose adjustment is necessary

Gabapentin/Efavirenz significant interactions are not for any of these medicinalexpected since vigabatrin and products.gabapentin are exclusivelyeliminated unchanged in the urineand are unlikely to compete forthe same metabolic enzymes andelimination pathways asefavirenz.

ANTIDEPRESSANTS

Selective Serotonin Reuptake Inhibitors (SSRIs)

Sertraline/Efavirenz Sertraline: Sertraline dose increases should be(50 mg once daily/600 mg once daily) AUC: ↓ 39 % (↓ 27 to ↓ 50) guided by clinical response.

Cmax: ↓ 29 % (↓ 15 to ↓ 40) No dose adjustment is necessary

Cmin: ↓ 46 % (↓ 31 to ↓ 58) for efavirenz.

AUC: ↔

Cmax: ↑ 11 % (↑ 6 to ↑ 16)

Cmin: ↔(CYP3A4 induction)

Paroxetine/Efavirenz No clinically significant No dose adjustment is necessary(20 mg once daily/600 mg once daily) pharmacokinetic interaction for either medicinal product.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

Fluoxetine/Efavirenz Interaction not studied. Since No dose adjustment is necessaryfluoxetine shares a similar for either medicinal product.metabolic profile with paroxetine,i.e., a strong CYP2D6 inhibitoryeffect, a similar lack of interactionwould be expected for fluoxetine.

Norepinephrine and dopamine reuptake inhibitor

Bupropion/Efavirenz Bupropion: Increases in bupropion dosage[150 mg single dose (sustained AUC: ↓ 55% (↓ 48 to ↓ 62) should be guided by clinicalrelease)/600 mg once daily] Cmax: ↓ 34% (↓ 21 to ↓ 47) response, but the maximum

Hydroxybupropion: recommended dose of bupropion

AUC: ↔ should not be exceeded. No dose

C : ↑ 50% (↑ 20 to ↑ 80) adjustment is necessary formax(CYP2B6 induction) efavirenz.

ANTIHISTAMINES

Cetirizine/Efavirenz Cetirizine: No dose adjustment is necessary(10 mg single dose/600 mg once AUC: ↔ for either medicinal product.daily) Cmax: ↓ 24 % (↓ 18 to ↓ 30)

These changes are not consideredclinically significant.

No clinically significantpharmacokinetic interaction.

CARDIOVASCULAR AGENTS

Calcium Channel Blockers

Diltiazem/Efavirenz Diltiazem: Dose adjustments of diltiazem(240 mg once daily/600 mg once AUC: ↓ 69 % (↓ 55 to ↓ 79) should be guided by clinicaldaily) Cmax: ↓ 60 % (↓ 50 to ↓ 68) response (refer to the Summary of

Cmin: ↓ 63 % (↓ 44 to ↓ 75) Product Characteristics for

Desacetyl diltiazem: diltiazem). No dose adjustment is

AUC: ↓ 75 % (↓ 59 to ↓ 84) necessary for efavirenz.

Cmax: ↓ 64 % (↓ 57 to ↓ 69)

Cmin: ↓ 62 % (↓ 44 to ↓ 75)

N-monodesmethyl diltiazem:

AUC: ↓ 37 % (↓ 17 to ↓ 52)

Cmax: ↓ 28 % (↓ 7 to ↓ 44)

Cmin: ↓ 37 % (↓ 17 to ↓ 52)

AUC: ↑ 11 % (↑ 5 to ↑ 18)

Cmax: ↑ 16 % (↑ 6 to ↑ 26)

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

The increase in efavirenzpharmacokinetic parameters isnot considered clinicallysignificant.

Verapamil, Felodipine, Nifedipine Interaction not studied. When Dose adjustments of calciumand Nicardipine efavirenz is co-administered with channel blockers should be guideda calcium channel blocker that is a by clinical response (refer to thesubstrate of the CYP3A4 enzyme, Summary of Productthere is a potential for reduction in Characteristics for the calciumthe plasma concentrations of the channel blocker).calcium channel blocker.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A Reductase Inhibitors

Atorvastatin/Efavirenz Atorvastatin: Cholesterol levels should be(10 mg once daily/600 mg once daily) AUC: ↓ 43 % (↓ 34 to ↓ 50) periodically monitored. Dose

Cmax: ↓ 12 % (↓ 1 to ↓ 26) adjustments of atorvastatin may be2-hydroxy atorvastatin: required (refer to the Summary of

AUC: ↓ 35 % (↓ 13 to ↓ 40) Product Characteristics for the

Cmax: ↓ 13 % (↓ 0 to ↓ 23) atorvastatin). No dose adjustment4-hydroxy atorvastatin: is necessary for efavirenz.

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)

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

Cmax: ↓ 18 % (↓ 59 to ↑ 12) adjustments of pravastatin may berequired (refer to the Summary of

Product Characteristics forpravastatin). No dose adjustmentis necessary for efavirenz.

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

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

Simvastatin acid: required (refer to the Summary of

AUC: ↓ 58 % (↓ 39 to ↓ 68) Product Characteristics for

Cmax: ↓ 51 % (↓ 32 to ↓ 58) simvastatin). No dose adjustment

Total active HMG Co-A reductase is necessary for efavirenz.inhibitors:

AUC: ↓ 60 % (↓ 52 to ↓ 68)

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

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

Rosuvastatin/Efavirenz Interaction not studied. No dose adjustment is necessary

Rosuvastatin is largely excreted for either medicinal product.unchanged via the faeces,therefore interaction withefavirenz is not expected.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

HORMONAL CONTRACEPTIVES

Oral: Ethinyloestradiol: A reliable method of barrier

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

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

AUC: ↓ 64 % (↓ 62 to ↓ 67)

Cmax: ↓ 46 % (↓ 39 to ↓ 52)

Cmin: ↓ 82 % (↓ 79 to ↓ 85)

Levonorgestrel (activemetabolite):

AUC: ↓ 83 % (↓ 79 to ↓ 87)

Cmax: ↓ 80 % (↓ 77 to ↓ 83)

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

Efavirenz: no clinicallysignificant interaction.

The clinical significance of theseeffects is not known.

Injection: Depo-medroxyprogesterone In a 3-month drug interaction Because of the limited informationacetate (DMPA)/Efavirenz study, no significant differences available, a reliable method of(150 mg IM single dose DMPA) in MPA pharmacokinetic barrier contraception must be usedparameters were found between in addition to hormonalsubjects receiving efavirenz- contraceptives (see section 4.6).containing antiretroviral therapyand subjects receiving noantiretroviral therapy. Similarresults were found by otherinvestigators, although the MPAplasma levels were more variablein the second study. In bothstudies, plasma progesteronelevels for subjects receivingefavirenz and DMPA remainedlow consistent with suppressionof ovulation.

Implant: Etonogestrel/Efavirenz Decreased exposure of A reliable method of barrieretonogestrel may be expected contraception must be used in(CYP3A4 induction). There have addition to hormonalbeen occasional post-marketing contraceptives (see section 4.6).reports of contraceptive failurewith etonogestrel in efavirenz-exposed patients.

IMMUNOSUPPRESSANTS

Immunosuppressants metabolised by Interaction not studied. Decreased Dose adjustments of the

CYP3A4 (e.g., cyclosporine, exposure of the immunosuppressant may betacrolimus, sirolimus)/Efavirenz immunosuppressant may be required. Close monitoring ofexpected (CYP3A4 induction). immunosuppressant

These immunosuppressants are concentrations for at least 2 weeksnot anticipated to affect exposure (until stable concentrations areof efavirenz. reached) is recommended whenstarting or stopping treatment withefavirenz.

Medicinal product by therapeutic Effects on drug levels Recommendation concerningareas Mean percent change in AUC, co-administration with efavirenz(dose) Cmax, Cmin with confidenceintervals if availablea(mechanism)

OPIOIDS

Methadone/Efavirenz Methadone: Concomitant administration with(stable maintenance, 35-100 mg once AUC: ↓ 52 % (↓ 33 to ↓ 66) efavirenz should be avoided due todaily/600 mg once daily) Cmax: ↓ 45 % (↓ 25 to ↓ 59) the risk for QTc prolongation (see(CYP3A4 induction) section 4.3).

In a study of HIV infectedintravenous drug users,co-administration of efavirenzwith methadone resulted indecreased plasma levels ofmethadone and signs of opiatewithdrawal. The methadone dosewas increased by a mean of 22 %to alleviate withdrawal symptoms.

Buprenorphine/naloxone/Efavirenz Buprenorphine: Despite the decrease in

AUC: ↓ 50 % buprenorphine exposure, no

Norbuprenorphine: patients exhibited withdrawal

AUC: ↓ 71 % symptoms. Dose adjustment of

Efavirenz: buprenorphine or efavirenz may

No clinically significant not be necessary whenpharmacokinetic interaction co-administered.

a 90 % confidence intervals unless otherwise noted.b 95 % confidence intervals.

Other interactions: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoidtest results have been reported with some screening assays in uninfected and HIV-infected subjectsreceiving efavirenz. Confirmatory testing by a more specific method such as gaschromatography/mass spectrometry is recommended in such cases.

Barrier contraception should always be used in combination with other methods of contraception (forexample, oral or other hormonal contraceptives, see section 4.5). Because of the long half-life ofefavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz isrecommended.

Efavirenz should not be used during pregnancy, unless the patient’s clinical condition requires suchtreatment. Women of childbearing potential should undergo pregnancy testing before initiation ofefavirenz (see section 5.3).

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

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

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

Efavirenz has been shown to be excreted in human milk. There is insufficient information on theeffects of efavirenz in newborns/infants. Risk to the infant cannot be excluded. Breast-feeding shouldbe discontinued during treatment with efavirenz. It is recommended that women living with HIV donot breast-feed their infants in order to avoid transmission of HIV.

The effect of efavirenz on male and female fertility in rats has only been evaluated at doses thatachieved systemic drug exposures equivalent to or below those achieved in humans givenrecommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility of maleor female rats (doses up to 100 mg/kg/bid), and did not affect sperm or offspring of treated male rats(doses up to 200 mg/bid). The reproductive performance of offspring born to female rats givenefavirenz was not affected.

Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should beinstructed that if they experience these symptoms they should avoid potentially hazardous tasks suchas driving or operating machinery.

Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the mostfrequently reported adverse reactions of at least moderate severity reported in at least 5 % of patientswere rash (11.6 %), dizziness (8.5 %), nausea (8.0 %), headache (5.7 %) and fatigue (5.5 %). The mostnotable adverse reactions associated with efavirenz are rash and nervous system symptoms. Nervoussystem symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatricadverse reactions including severe depression, death by suicide, and psychosis like behaviour; andseizures have been reported in patients treated with efavirenz. The administration of efavirenz withfood may increase efavirenz exposure and may lead to an increase in the frequency of adversereactions (see section 4.4).

The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006)in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine +lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was notassociated with any new safety concerns.

Adverse reactions of moderate or greater severity with at least possible relationship to treatmentregimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommendeddose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactionsobserved post-marketing in association with efavirenz-containing antiretroviral treatment regimens.

Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100,< 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); or notknown (cannot be estimated from the available data).

Immune system disordersuncommon hypersensitivity

Metabolism and nutrition disorderscommon hypertriglyceridaemia*uncommon hypercholesterolaemia*

Psychiatric disorderscommon abnormal dreams, anxiety, depression, insomnia*uncommon affect lability, aggression, confusional state,euphoric mood, hallucination, mania, paranoia,psychosis‡, suicide attempt, suicide ideation,catatonia*rare delusion‡‡, neurosis‡‡, completed suicide‡‡*

Nervous system disorderscommon cerebellar coordination and balancedisturbances‡, disturbance in attention (3.6 %),dizziness (8.5 %), headache (5.7 %), somnolence(2.0 %)*uncommon agitation, amnesia, ataxia, coordination abnormal,convulsions, thinking abnormal, tremor‡not known encephalopathy

Eye disordersuncommon vision blurred

Ear and labyrinth disordersuncommon tinnitus‡, vertigo

Vascular disordersuncommon flushing‡

Gastrointestinal disorderscommon abdominal pain, diarrhoea, nausea, vomitinguncommon pancreatitis

Hepatobiliary disorderscommon aspartate aminotransferase (AST) increased*,alanine aminotransferase (ALT) increased*,gamma-glutamyltransferase (GGT) increased*uncommon hepatitis acuterare hepatic failure‡‡*

Skin and subcutaneous tissue disordersvery common rash (11.6 %)*common pruritusuncommon erythema multiforme, Stevens-Johnsonsyndrome*rare photoallergic dermatitis‡

Reproductive system and breast disordersuncommon gynaecomastia

General disorders and administration site conditionscommon fatigue

*,‡ ,‡‡ See section Description of selected adverse reactions for more details.

Information regarding post-marketing surveillance‡ These adverse reactions were identified through post-marketing surveillance; however, thefrequencies were determined using data from 16 clinical trials (n=3,969).

‡‡These adverse reactions were identified through post-marketing surveillance but not reported asdrug-related events for efavirenz-treated patients in 16 clinical trials. The frequency category of 'rare'was defined per A Guideline on Summary of Product Characteristics (SmPC) (rev. 2, Sept 2009) onthe basis of an estimated upper bound of the 95% confidence interval for 0 events given the number ofpatients treated with efavirenz in these clinical trials (n=3,969).

In clinical studies, 26 % of patients treated with 600 mg of efavirenz experienced skin rash comparedwith 17 % of patients treated in control groups. Skin rash was considered treatment related in 18 % ofpatients treated with efavirenz. Severe rash occurred in less than 1 % of patients treated with efavirenz,and 1.7 % discontinued therapy because of rash. The incidence of erythema multiforme or

Stevens-Johnson syndrome was approximately 0.1 %.

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first twoweeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy withefavirenz within one month. Efavirenz can be reinitiated in patients interrupting therapy because ofrash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz isrestarted.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI classis limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy,primarily based on retrospective cohort data from published literature, range from 13 to 18 %,comparable to the rate observed in patients treated with efavirenz in clinical studies. (See section 4.4.)

Psychiatric symptoms

Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. Incontrolled trials the frequency of specific serious psychiatric events were:

Efavirenz regimen Control regimen(n=1,008) (n=635)

- severe depression 1.6 % 0.6 %

- suicidal ideation 0.6 % 0.3 %

- non-fatal suicide attempts 0.4 % 0 %

- aggressive behaviour 0.4 % 0.3 %

- paranoid reactions 0.4 % 0.3 %

- manic reactions 0.1 % 0 %

Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatricadverse reactions with frequencies of each of the above events ranging from 0.3 % for manic reactionsto 2.0 % for both severe depression and suicidal ideation. There have also been post-marketing reportsof death by suicide, delusions, psychosis-like behaviour and catatonia.

Nervous system symptoms

In clinical controlled trials, frequently reported adverse reactions included, but were not limited to:dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous systemsymptoms of moderate-to-severe intensity were experienced by 19 % (severe 2.0 %) of patientscompared to 9 % (severe 1 %) of patients receiving control regimens. In clinical studies 2 % ofpatients treated with efavirenz discontinued therapy due to such symptoms.

Nervous system symptoms usually begin during the first one or two days of therapy and generallyresolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous systemsymptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervoussystem symptoms may occur more frequently when efavirenz 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 and can be recommended during the first weeks of therapyand in patients who continue to experience these symptoms (see section 4.2). Dose reduction orsplitting the daily dose has not been shown to provide benefit.

Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onsetnervous system symptoms among efavirenz-treated patients were generally similar to those in thecontrol arm.

Ataxia and encephalopathy associated with high levels of efavirenz, occurring months to years afterbeginning efavirenz therapy have been reported post-marketing (see section 4.4).

Hepatic failure

A few of the post-marketing reports of hepatic failure, including cases in patients with no pre-existinghepatic disease or other identifiable risk factors, were characterised by a fulminant course, progressingin some cases to transplantation or death.

In HIV infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (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 combination antiretroviral therapy (CART).

The frequency of this is unknown (see section 4.4).

Laboratory test abnormalities

Liver enzymes: Elevations of AST and ALT to greater than five times the upper limit of the normalrange (ULN) were seen in 3 % of 1,008 patients treated with 600 mg of efavirenz (5-8 % afterlong-term treatment in study 006). Similar elevations were seen in patients treated with controlregimens (5 % after long-term treatment). Elevations of GGT to greater than five times ULN wereobserved in 4 % of all patients treated with 600 mg of efavirenz and 1.5 - 2 % of patients treated withcontrol regimens (7 % of efavirenz-treated patients and 3 % of control-treated patients after long-termtreatment). Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction.

In the long-term study (006), 1 % of patients in each treatment arm discontinued because of liver orbiliary system disorders.

Amylase: In the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levelsgreater than 1.5 times the upper limit of normal were seen in 10 % of patients treated with efavirenzand 6 % of patients treated with control regimens. The clinical significance of asymptomatic increasesin serum amylase is unknown.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4).

Undesirable effects in children were generally similar to those of adult patients. Rash was reportedmore frequently in children (in a clinical study including 57 children who received efavirenz during a48-week period, rash was reported in 46 %) and was more often of higher grade than in adults (severerash was reported in 5.3 % of children). Prophylaxis with appropriate antihistamines prior to initiatingtherapy with efavirenz in children may be considered. Although nervous system symptoms aredifficult for young children to report, they appear to be less frequent in children and were generallymild. In the study of 57 children, 3.5 % of patients experienced nervous system symptoms of moderateintensity, predominantly dizziness. No child had severe symptoms or had to discontinue because ofnervous system symptoms.

Liver enzymes in hepatitis B or C co-infected patients

In the long-term data set from study 006, 137 patients treated with efavirenz-containing regimens(median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration,56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis

C antibody positive). Among co-infected patients in study 006, elevations in AST to greater than fivetimes ULN developed in 13 % of efavirenz treated patients and in 7 % of controls, and elevations in

ALT to greater than five times ULN developed in 20 % and 7 % respectively. Among co-infectedpatients, 3 % of those treated with efavirenz and 2 % in the control arm discontinued because of liverdisorders (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 twice daily have reported increased nervous systemsymptoms. One patient experienced involuntary muscle contractions.

Treatment of overdose with efavirenz should consist of general supportive measures, includingmonitoring of vital signs and observation of the patient’s clinical status. Administration of activatedcharcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote foroverdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to removesignificant quantities of it from blood.

Pharmacotherapeutic group: Antivirals for systemic use. Non-nucleoside reverse transcriptaseinhibitors. ATC code: J05A G03

Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reversetranscriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (, , or ).

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).

The free concentration of efavirenz required for 90 to 95 % inhibition of wild type orzidovudine-resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM inlymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocytecultures.

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar tothat observed against wild type viral strains. The single substitutions which led to the highestresistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position 100(L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-foldresistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing

K103N in addition to other amino acid substitutions in RT.

K103N was the most frequently observed RT substitution in viral isolates from patients whoexperienced a significant rebound in viral load during clinical studies of efavirenz in combination withindinavir or zidovudine + lamivudine. This mutation was observed in 90 % of patients receivingefavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or225 were also observed, but at lower frequencies, and often only in combination with K103N. Thepattern of amino acid substitutions in RT associated with resistance to efavirenz was independent ofthe other antiviral medicinal products used in combination with efavirenz.

Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the

K103N substitution confers loss of susceptibility to all three NNRTIs. Two of threedelavirdine-resistant clinical isolates examined were cross-resistant to efavirenz and contained the

K103N substitution. A third isolate which carried a substitution at position 236 of RT was notcross-resistant to efavirenz.

Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showedevidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteenisolates previously characterised as efavirenz-resistant were also resistant to nevirapine anddelavirdine. Five of these NNRTI-resistant isolates were found to have K103N or avaline-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatmentfailure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive tonevirapine and delavirdine.

The potential for cross resistance between efavirenz and PIs is low because of the different enzymetargets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of thedifferent binding sites on the target and mechanism of action.

Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namelywith CD4 counts < 50 cells/mm3, or in PI or NNRTI experienced patients. Clinical experience incontrolled studies with combinations including didanosine or zalcitabine is limited.

Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz incombination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit ofquantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and

NRTI-experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experiencedpatients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose ofindinavir was 1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when usedwithout efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of

NRTIs given every 12 hours were used in each of these studies.

Study 006, a randomised, open-label trial, compared efavirenz + zidovudine + lamivudine orefavirenz + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required tobe efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell countwas 341 cells/mm3 and the mean baseline HIV-RNA level was 60,250 copies/mL. Efficacy results forstudy 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 3.

In the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients whoterminated the study early for any reason, or who had a missing HIV-RNA measurement that waseither preceded or followed by a measurement above the limit of assay quantification were consideredto have HIV-RNA above 50 or above 400 copies/mL at the missing time points.

Table 3: Efficacy results for study 006

Responder rates (NC = Fa) Mean change

Plasma HIV-RNA frombaseline-CD4cell count< 400 copies/mL < 50 copies/mL cells/mm3(95 % C.I.b) (95 % C.I.b) (S.E.M.c)

Treatment n 48 weeks 48 weeks 48 weeks

Regimend

EFV + 202 67 % 62 % 187

ZDV + 3TC (60 %, 73 %) (55 %, 69 %) (11.8)

Responder rates (NC = Fa) Mean change

Plasma HIV-RNA frombaseline-CD4cell count< 400 copies/mL < 50 copies/mL cells/mm3(95 % C.I.b) (95 % C.I.b) (S.E.M.c)

EFV + IDV 206 54 % 48 % 177(47 %, 61 %) (41 %, 55 %) (11.3)

IDV + 206 45 % 40 % 153

ZDV + 3TC (38 %, 52 %) (34 %, 47 %) (12.3)a NC = F, noncompleter = failure.b C.I., confidence interval.c S.E.M., standard error of the mean.d EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir.

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with

EFV +IDV, 196 patients with EFV + ZDV + 3TC and 127 patients with IDV + ZDV + 3TC,respectively), suggest durability of response in terms of proportions of patients with HIV RNA< 400 copies/mL, HIV RNA < 50 copies/mL and in terms of mean change from baseline CD4 cellcount.

Efficacy results for studies ACTG 364 and 020 are found in Table 4. Study ACTG 364 enrolled196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowedto change their patient’s NRTI regimen upon entry into the study. Responder rates were highest inpatients who switched NRTIs.

Table 4: Efficacy results for studies ACTG 364 and 020

Responder rates (NC = Fa) Mean change from

Plasma HIV-RNA baseline-CD4 cell count

Study Number/ n % (95 % C.I.c) % (95 % C.I.) cells/mm3 (S.E.M.d)

Treatment Regimensb

Study ACTG 364 < 500 copies/mL < 50 copies/mL48 weeks

EFV + NFV + NRTIs 65 70 (59, 82) --- --- 107 (17.9)

EFV + NRTIs 65 58 (46, 70) --- --- 114 (21.0)

NFV + NRTIs 66 30 (19, 42) --- --- 94 (13.6)

Study 020 < 400 copies/mL < 50 copies/mL24 weeks

EFV + IDV + NRTIs 157 60 (52, 68) 49 (41, 58) 104 (9.1)

IDV + NRTIs 170 51 (43, 59) 38 (30, 45) 77 (9.9)a NC = F, noncompleter = failure.b EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor;

NFV, nelfinavir.c C.I., confidence interval for proportion of patients in response.d S.E.M., standard error of the mean.

- --, not performed.

Paediatric population: ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experiencedpaediatric patients (3 - 16 years) which characterises the pharmacokinetics, antiviral activity and safetyof efavirenz in combination with nelfinavir (20 - 30 mg/kg given three times a day) and one or more

NRTIs. The starting dose of efavirenz was the equivalent of a 600 mg dose (adjusted from calculatedbody size based on weight). The response rate, based on the NC = F analysis of the percentage ofpatients with plasma HIV-RNA < 400 copies/mL at 48 weeks was 60 % (95 %, C.I. 47, 72), and 53 %(C.I. 40, 66) based on percentage of patients with plasma HIV-RNA < 50 copies/mL. The mean CD4cell counts were increased by 63  34.5 cells/mm3 from baseline. The durability of the response wassimilar to that seen in adult patients.

Peak efavirenz plasma concentrations of 1.6 - 9.1 M were attained by 5 hours following single oraldoses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in Cmax and

AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggestingdiminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours) did notchange following multiple dosing and steady-state plasma concentrations were reached in 6 - 7 days.

In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steadystate Cmax was 12.9 ± 3.7 M (29 %) [mean ± S.D. (% C.V.)], steady state Cmin was 5.6 ± 3.2 M(57 %), and AUC was 184 ± 73 M·h (40 %).

The AUC and Cmax of a single 600 mg dose of efavirenz film-coated tablets in uninfected volunteerswas increased by 28 % (90 % CI: 22 - 33 %) and 79 % (90 % CI:58 - 102 %), respectively, whengiven with a high fat meal relative to when given under fasted conditions (see section 4.4).

Efavirenz is highly bound (approximately 99.5 - 99.75 %) to human plasma proteins, predominantlyalbumin. In HIV-1 infected patients (n = 9) who received efavirenz 200 to 600 mg once daily for atleast one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19 % (mean 0.69 %) of thecorresponding plasma concentration. This proportion is approximately 3-fold higher than thenon-protein-bound (free) fraction of efavirenz in plasma.

Studies in humans and in vitro studies using human liver microsomes have demonstrated thatefavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites withsubsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentiallyinactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the majorisozymes responsible for efavirenz metabolism and that it inhibited P450 isozymes 2C9, 2C19, and3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only atconcentrations well above those achieved clinically.

Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variantof the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however,the potential 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 - 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation(22 - 42 % lower) and a shorter terminal half-life compared with single dose administration (seebelow). 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 2).

Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have beencontradictory reports of both increased and decreased exposures to substrates of these enzymes whencoadministered with efavirenz in vivo. The net effect of co-administration is not clear.

Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and40 - 55 hours after multiple doses. Approximately 14 - 34 % of a radiolabelled dose of efavirenz wasrecovered in the urine and less than 1 % of the dose was excreted in urine as unchanged efavirenz.

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

Gender, race, elderly

Although limited data suggest that females as well as Asian and Pacific Island patients may havehigher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokineticstudies have not been performed in the elderly.

In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted fromcalculated body size based on weight), steady state Cmax was 14.1 M, steady state Cmin was 5.6 M,and AUC was 216 M·h. The pharmacokinetics of efavirenz in paediatric patients were similar toadults.

Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays.

Efavirenz induced foetal resorptions in rats. Malformations were observed in3 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, microphthalmiawas observed in another foetus, and cleft palate was observed in a third foetus. No malformations wereobserved in foetuses from efavirenz-treated rats and rabbits.

Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for ≥ 1 year at a doseresulting in mean AUC values approximately 2-fold greater than those in humans given therecommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis hasbeen observed in rats. Non-sustained convulsions were observed in some monkeys receiving efavirenzfor ≥ 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given therecommended dose (see sections 4.4 and 4.8).

Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in femalemice, but not in male mice. The mechanism of tumour formation and the potential relevance forhumans are not known.

Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenicpotential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs thepotential carcinogenic risk to humans.

STOCRIN 600 mg film-coated tablets

Tablet core: Croscarmellose sodium, Microcrystalline cellulose, Sodium laurilsulfate,

Hydroxypropylcellulose, Lactose monohydrate, Magnesium stearate

Film coating: Hypromellose (E464), Titanium dioxide (E171), Macrogol 400, Yellow iron oxide(E172), Carnauba wax

STOCRIN 50 mg film-coated tablets

Tablet core: Croscarmellose sodium, Microcrystalline cellulose, Sodium laurilsulfate,

Hydroxypropylcellulose, Lactose monohydrate, Magnesium stearate

Film coating: Hypromellose (E464), Titanium dioxide (E171), Macrogol 400, Yellow iron oxide(E172), Carnauba wax

STOCRIN 200 mg film-coated tablets

Tablet core: Croscarmellose sodium, Microcrystalline cellulose, Sodium laurilsulfate,

Hydroxypropylcellulose, Lactose monohydrate, Magnesium stearate

Film coating: Hypromellose (E464), Titanium dioxide (E171), Macrogol 400, Yellow iron oxide(E172), Carnauba wax

Not applicable.

For bottles: 3 years

This medicinal product does not require any special storage conditions.

STOCRIN 600 mg film-coated tablets

HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of30 film-coated tablets.

STOCRIN 50 mg film-coated tablets

HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of30 film-coated tablets.

STOCRIN 200 mg film-coated tablets

HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of90 film-coated tablets.

No special requirements for disposal.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/99/111/008

EU/1/99/111/010

EU/1/99/111/011

Date of first authorisation: 28 May 1999

Date of latest renewal: 23 April 2014

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu.