Sustiva 50 mg , 100 mg , 200 mg Hard Capsules

SmPC:

 

4.3     Contraindications

 

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-administraion 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 the potential 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 decreased plasma 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 on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.

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

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

 

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

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.

 

4.4     Special warnings and precautions for use

…

Psychiatric symptoms

 

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions. 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 symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits (see section 4.8).

…

QTc Prolongation

 

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

 

Consider alternatives to efavirenz for coadministration 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.

 

4.5     Interaction with other medicinal products and other forms of interaction

…

QT Prolonging Drugs

 

Efavirenz is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval and Torsade de Pointes) such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, 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).

…

Rifampicin/Efavirenz (600 mg once daily/600 mg once daily)

Efavirenz: AUC: ↓ 26% (↓ 15 to ↓ 36) Cmax: ↓ 20% (↓ 11 to ↓ 28) Cmin: ↓ 32% (↓ 15 to ↓ 46) (CYP3A4 and CYP2B6 induction)

When taken with rifampicin in patients weighing 50 kg or greater, increasing efavirenz daily dose to 800 mg may provide exposure similar to a daily dose of 600 mg when taken without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment (see section 5.2). No dose adjustment is necessary for rifampicin, including 600 mg

…

 

Atovaquone and proguanil hydrochloride/Efavirenz (250/100 mg single dose/600 mg once daily)

Atovaquone: AUC: ↓ 75% (↓ 62 to ↓ 84) Cmax: ↓ 44% (↓ 20 to ↓ 61) Proguanil: AUC: ↓ 43% (↓ 7 to ↓ 65) Cmax: ↔

Concomitant administration of atovaquone/proguanil with efavirenz should be avoided. whenever possible.

…

Methadone/Efavirenz (stable maintenance, 35-100 mg once daily/600 mg once daily)

Methadone: AUC: ↓ 52% (↓ 33 to ↓ 66) Cmax: ↓ 45% (↓ 25 to ↓ 59) (CYP3A4 induction) In a study of HIV infected intravenous drug users, co-administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.

Concomitant administration with efavirenz should be avoided due to the risk for QTc prolongation (see section 4.3). Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

 

4.6       Fertility, pregnancy and lactationbreast-feeding

 

4.8     Undesirable effects

…

uncommon

affect lability, aggression, confusional state, euphoric mood, hallucination, mania, paranoia, psychosis†, suicide attempt, suicide ideation, catatonia*

 

…

Psychiatric symptoms

…

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

…

5.1     Pharmacodynamic properties

…

Cardiac Electrophysiology

 

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

date of revision updated from Jan 2016 to October 2016

§ 4.4 and 4.8

- any reference to lipodystrophy has been deleted

- the class labeling sentence on lipodystrophy and metabolic abnormalities has been replaced by a new class labeling sentence on weight and metabolic parameters

- the paragraph on laboratory test abnormalities for lipids has been deleted

-QRD template updated

Extension of paediatric indication to include children from 3 months of age and weighing at least 3.5 kg.

Added information in table section 4.2 for paediatric dose to be administered once daily (as the oral solution pharmaceutical form of the product was deleted)

SmPC update as per type II variation (WS/604) related to revision of section 4.5 to include information about the potential interaction between simeprevir with efavirenz.
Changes approved as part of renewal R/120 included in relevant sections.

This procedure was submitted further to a CHMP request following additional questions coming from the assessment of the last submitted PSUR. It amends section 4.6 of the SmPC on the number of pregnancies and on the number of Neural Tube Defects (NTD) cases reported in subjects exposed to efavirenz-based products to reflect the Antiretroviral Pregnancy Registry (APR) reports. Section 2 of the PL was updated accordingly.

The following text has been revised in Section 4.8:
Pregnancy: There have been seven retrospective reports of findings consistent with neural tube defects, including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-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 been reported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate. A causal relationship of these events to the use of efavirenz has not been established, and the denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy.

 

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live births. One child was reported to have a neural tube defect, and the frequency and pattern of other birth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as well as those in HIV negative controls. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births.

This variation includes:

• Changes to Section 4.5
  • to include interaction with rifabutin and the new HCV protease inhibitors telaprevir and boceprevir
• Changes to Section 10
  • Update date of revision

Update to sections 4.5 and 4.8.

The following text has been updated to section 4.6 of the SPC:

Women of childbearing potential: see below and section 5.3. Efavirenz should not be used during pregnancy, unless there are no other appropriatethe patient’s clinical condition requires such treatment options.

 

. Women of childbearing potential:  should undergo pregnancy should be avoided in women treated withtesting before initiation of efavirenz.

 

Contraception in males and females: barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives, see section 4.5). Because of the long half‑life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended.  Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz.

 

Pregnancy: there are limited amount as of data from the use of efavirenz in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, outcomes for more than 400July 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 718 pregnancies with first -trimester exposure to efavirenz as part of a combination antiretroviral regimen have been prospectively -containing regimens, resulting in 604 live births. One child was reported with no specific malformation to have a neural tube defect, and the frequency and pattern observed. A small number of cases of of other birth defects were similar to those seen in children exposed to non‑efavirenz‑containing regimens, as well as those in HIV negative controls. The incidence of neural tube defects in the general population ranges from 0.5‑1 case per 1,000 live births. All together there have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele, have been reported via the registry. Most neural tube defects were isolated retrospectively reported cases, and causality cannot be ruled out but has all in mothers exposed to efavirenz‑containing regimens in the first trimester. A causal relationship of these events to the use of efavirenz has not been established. Studies in animals have shown reproductive toxicity including marked teratogenic effects, and the denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy.

 

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

 

Breastfeeding: it is unknown whether efavirenz is excreted in human milk. Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. It is Risk to the infant can not known whether efavirenz is excreted in human milk. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking efavirenz do not breast feed their infants.be excluded. Breastfeeding should be discontinued during treatment with SUSTIVA. It is recommended that HIV infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives).

The following text has been added to section 4.4:

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

 

Hepatic events:  a few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be considered for patients without pre-existing hepatic dysfunction or other risk factors.

Liver disease: efavirenz is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2) and not recommended in patients with moderate hepatic impairment because of insufficient data to determine whether dose adjustment is necessary. Because of the extensive cytochrome P450‑mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering efavirenz to patients with mild‑to‑moderate liver disease hepatic impairment. Patients should be 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).

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

The following text has beena dded to section 4.6:

Fertility: the effect of efavirenz on male and female fertility in rats has only been evaluated at doses that achieved systemic drug exposures equivalent to or below those achieved in humans given recommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility of male or 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 given efavirenz was not affected.

The following text has beena dded to section 4.6:
The following text has been added to section 438:

 Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first 2 ‑ 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and seizures have been reported in patients treated with efavirenz. The administration of SUSTIVA with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see section 4.4).

b. Tabulated list of adverse reactions

 

Adverse reactions of moderate or greater severity with at least possible relationship to treatment regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens. Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); or very rare (< 1/10,000); or not known (cannot be estimated from the available data).

 

Immune system disorders
uncommon	hypersensitivity
Psychiatric disorders
common	abnormal dreams, anxiety, depression, insomnia*
uncommon	affect lability, aggression, confusional state, euphoric mood, hallucination, mania, paranoia, psychosis†, suicide attempt, suicide ideation*
rare	delusion ‡, neurosis ‡, completed suicide‡,*
Nervous system disorders
common	cerebellar coordination and balance disturbances†, disturbance in attention (3.6%), dizziness (8.5%), headache (5.7%), somnolence (2.0%)*
uncommon	agitation, amnesia, ataxia, coordination abnormal, convulsions, thinking abnormal,* tremor†
Eye disorders
uncommon	vision blurred
Ear and labyrinth disorders
uncommon	tinnitus†, vertigo
Vascular disorders
uncommon	flushing†
Gastrointestinal disorders
common	abdominal pain, diarrhoea, nausea, vomiting
uncommon	pancreatitis
Hepatobiliary disorders
uncommon	hepatitis acute
rare	hepatic failure‡,*
Skin and subcutaneous tissue disorders
very common	rash (11.6%)*
common	pruritus
uncommon	erythema multiforme, Stevens-Johnson syndrome*
rare	photoallergic dermatitis†
Reproductive system and breast disorders
uncommon	gynaecomastia
General disorders and administration site conditions
common	fatigue
common	fatigue

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

^†These adverse reactions were identified through post-marketing surveillance; however, the frequencies were determined using data from 16 clinical trials (n=3,969).

^‡These adverse reactions were identified through post-marketing surveillance but not reported as drug-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) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of patients treated with efavirenz in these clinical trials (n=3,969).

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinuedReported rates of recurrent rash following a switch from nevirapine because of rash have been treated withto efavirenz. Nine of these patients developed mild‑to‑moderate rash while receiving therapy with efavirenz, and two discontinued because of rash.

, 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.)

e. Other special populations

 

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 five times ULN developed in 13% of efavirenz-treated patients and in 7% of control, and elevations in ALT to greater than five times ULN developed in 20% and 7%, respectively. Among co‑infected patients, 3% of those treated with efavirenz and 2% in the control arm discontinued because of liver disorders (see section 4.4).

The following text has been added to section 5.2:

Hepatic impairment: 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.  A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls.  There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.

Paediatric population

In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from calculated body size based on weight), steady state Cmax was 14.1 μM, steady state C_min was 5.6 μM, and AUC was 216 μM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.

Addition of 100 mg strength

4.5     Interaction with other medicinal products and other forms of interaction

 

Table 2: Interactions between efavirenz and other medicinal products

 

Medicinal product by therapeutic areas (dose)	Effects on drug levels Mean percent change in AUC, Cmax, Cmin with confidence intervals if availablea (mechanism)	Recommendation concerning co‑administration with efavirenz
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors (PI)
Atazanavir/ ritonavir/Efavirenz (400 mg once daily/100 mg once daily/600 mg once daily, all administered with food)	Atazanavir (pm): AUC: ↔* (↓9 to ↑10) Cmax: ↑17%* (↑8 to ↑27) Cmin: ↓42%* (↓31 to ↓51)	Co-administration of efavirenz with atazanavir/ritonavir is not recommended. If the co-administration of atazanavir with an NNRTI is required, an increase in the dose of both atazanavir and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.
Atazanavir/ritonavir/Efavirenz (400 mg once daily/200 mg once daily/600 mg once daily, all administered with food)	Atazanavir (pm): AUC: ↔*/** (↓10 to ↑26) Cmax: ↔*/** (↓5 to ↑26) Cmin: ↑ 12%*/** (↓16 to ↑49) (CYP3A4 induction). * When compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. ** based on historical comparison
ANTICOAGULANTS
Warfarin/Efavirenz	Interaction not studied. Plasma concentrations and effects of warfarin are potentially increased or decreased by efavirenz.	Dose adjustment of warfarin may be required.

 

 

4.8     Undesirable effects

 

 

Immune system disorders
uncommon	hypersensitivity
Psychiatric disorders
common	abnormal dreams, anxiety, depression, insomnia
uncommon	affect lability, aggression, confusional state, euphoric mood, hallucination, mania, paranoia, suicide attempt, suicide ideation
Nervous system disorders
common	disturbance in attention, dizziness, headache, somnolence
uncommon	agitation, amnesia, ataxia, coordination abnormal, convulsions, thinking abnormal
Eye disorders
uncommon	vision blurred
Ear and labyrinth disorders
uncommon	vertigo
Gastrointestinal disorders
common	abdominal pain, diarrhoea, nausea, vomiting
uncommon	pancreatitis acute
Hepatobiliary disorders
uncommon	hepatitis acute
Skin and subcutaneous tissue disorders
very common	rash
common	pruritus
uncommon	erythema multiforme, Stevens-Johnson syndrome
Reproductive system and breast disorders
uncommon	gynaecomastia
General disorders and administration site conditions
common	fatigue

 

 

Postmarketing experience with efavirenz has shown the following additional adverse reactions to occur in association with efavirenz-containing antiretroviral treatment regimens: cerebellar coordination and balance disturbances, delusion, flushing, hepatic failure, neurosis, photoallergic dermatitis, psychosis, completed suicide, tinnitus and tremor.

 

 

 

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 28 May 1999
Date of latest renewal: 28 May 2009

 

 

10.     DATE OF REVISION OF THE TEXT

 

December 2009

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.



2.  

 

4.1     Therapeutic indications

 

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

 

 

4.2     Posology and method of administration

 

(....)

 

It is recommended that SUSTIVA be taken on an empty stomach. The increased efavirenz concentrations observed following administration of SUSTIVA with food may lead to an increase in frequency of adverse reactionsevents (see sections 4.4 and 5.2).

 

(....)

 

Dosage adjustment: If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose mustshould be increased to 400 400 mg every 12 hours and the SUSTIVA dose mustshould be reduced by 50%, i.e., to 300 300 mg once daily.  When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see section 4.5).

 

If SUSTIVA is coadministered with rifampicin, an increase in the dose of SUSTIVA must be increased to 800 800 mg/day may be considered (see section 4.5).

 

Renal impairmentinsufficiency: 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 renal impairment on efavirenz elimination should be minimal (see section 4.4).

 

Hepatic impairmentLiver disease: patients with mild to moderate liver disease may be treated with their normally recommended dose of efavirenz. Patients should be monitored carefully for dose‑related adverse reactionsevents, especially nervous system symptoms (see sections 4.3 and 4.4).

 

4.4     Special warnings and precautions for use

 

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non‑nucleoside reverse transcriptase inhibitors (NNRTIs), resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agent(s) to be used in combination with efavirenz should take into consideration the potential for viral cross‑resistance (see section 5.1).

 

Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate is not recommended.

 

When prescribing medicinal products concomitantly with SUSTIVA, physicians should refer to the corresponding Summary of Product Characteristics.

(...)

 

Psychiatric symptoms: psychiatric adverse reactionsexperiences have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions.experiences. 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 and psychosis‑like behaviour. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits (see section 4.8).

(...)

 

Seizures: convulsions have been observed rarely in patients receiving efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures.

 

Effect of food: the administration of SUSTIVA with food may increase efavirenz exposure (see section 5.2) and may lead to an increase in the frequency of adverse reactions (see section 4.8).undesirable effects. It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.

 

Immune Reactivation Syndrome: in HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens 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). pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

 

(...)

Liver disease: because of the extensive cytochrome P450‑mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering efavirenz to patients with mild‑to‑moderate liver disease. Patients should be monitored carefully for dose‑related adverse reactionsevents, 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 underlying liver disorders. Efavirenz is contraindicated in patients with severe hepatic impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse reactions.events. Patients with pre‑existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease or persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered (see section 4.8).

 

(...)

 

Elderly patients: insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.

 

Paediatric patientsChildren: 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.

 

Lactose: patientsthis medicinal product contains 250 mg of lactose in each 600‑mg daily dose. This quantity is not likely to induce symptoms of lactose intolerance.

 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Individuals with these conditions may take efavirenz oral solution, which is free from lactose.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP450 isoenzymesCYP isozymes including CYP3A4 (see section 5.2). Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co‑administered with efavirenz. Efavirenz exposure may also be altered when given with medicinal products or food (for example, grapefruit juice) which affect CYP3A4 activity.

 

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).

 

St. John’s wort (Hypericum perforatum): co‑administration of efavirenz and St. John’s wort or herbal preparations containing St. John’s wort is contraindicated. PlasmaConcomitant antiretroviral agents:

 

Protease Inhibitors:

 

Amprenavir: although efavirenz has been seen to decrease the Cmax, AUC and Cmin of amprenavir by approximately 40% in adults, when amprenavir is combined with ritonavir, the effect of efavirenz is compensated by the pharmacokinetic booster effect of ritonavir. Therefore, if efavirenz is given in combination with amprenavir (600 mg twice daily) and ritonavir (100 or 200 mg twice daily), no dosage adjustment is necessary. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.

 

Further, if efavirenz is given in combination with amprenavir and nelfinavir, no dosage adjustment is necessary for any of the medicinal products. Treatment with efavirenz in combination with amprenavir and saquinavir is not recommended, as the exposure to both PIs is expected to be significantly decreased. No dose recommendation can be given for the co‑administration of amprenavir with another PI and efavirenz in children and patients with renal impairment. Such combinations should be avoided in patients with hepatic impairment.

 

Atazanavir: co-administration of efavirenz and atazanavir in combination with ritonavir may lead to increases in efavirenz exposure which may worsen the tolerability profile of efavirenz. Co-administration of efavirenz 600 mg with atazanavir in combination with low-dose ritonavir resulted in substantial decreases in atazanavir exposure, necessitating dosage adjustment of atazanavir (refer to the Summary of Product Characteristics for atazanavir).

 

Indinavir: when indinavir (800 mg every 8 hours) was given with efavirenz (200 mg every 24 hours), the indinavir AUC and C_trough were decreased by approximately 31% and 40% respectively. When indinavir at an increased dose (1,000 mg every 8 hours) was given with efavirenz (600 mg once daily) in uninfected volunteers, the indinavir AUC and C_trough were decreased on average by 33 ‑ 46% and 39 ‑ 57%, respectively (ranges represent diurnal variation), compared to when indinavir was given alone at the standard dose (800 mg every 8 hours). Similar differences in indinavir AUC and C_trough were also observed in HIV infected patients who received indinavir (1,000 mg every 8 hours) with efavirenz (600 mg once daily) compared to indinavir given alone (800 mg every 8 hours). While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz and indinavir.

 

When efavirenz 600 mg once daily was given with indinavir/ritonavir 800/100 mg twice daily in uninfected volunteers (n = 14), the indinavir AUC, C_min, and Cmax were decreased by approximately 25%, 50% and 17%, respectively, compared to when indinavir/ritonavir 800/100 mg twice daily were given without efavirenz. The geometric mean C_min for indinavir (0.33 mg/l) when given with ritonavir and efavirenz was higher than the mean historical C_min (0.15 mg/l) when indinavir was given alone at 800 mg every 8 hours. The pharmacokinetics of efavirenz given in combination with indinavir/ritonavir were comparable to efavirenz alone (600 mg once daily).

 

When efavirenz 600 mg once daily was given with indinavir/ritonavir 800/100 mg twice daily in HIV‑1 infected patients (n = 6), the pharmacokinetics of indinavir and efavirenz were generally comparable to these uninfected volunteer data.

 

No adjustment of the dose of efavirenz is necessary when given with indinavir or indinavir/ritonavir. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.

 

Lopinavir/ritonavir: when used in combination with efavirenz and two NRTIs, 533/133 mg lopinavir/ritonavir twice daily yielded similar lopinavir plasma concentrations as compared to lopinavir/ritonavir 400/100 mg twice daily without efavirenz (historical data). When co‑administered with efavirenz, an increase of the lopinavir/ritonavir doses by 33% should be considered (4 capsules/~6.5 ml twice daily instead of 3 capsules/5 ml twice daily). Caution is warranted since this dosage adjustment might be insufficient in some patients. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.

 

Nelfinavir: the AUC and Cmax of nelfinavir are increased by 20% and 21%, respectively when given with efavirenz. The combination was generally well tolerated and no dose adjustment is necessary when nelfinavir is administered in combination with efavirenz.

 

Ritonavir: co-administration of efavirenz and ritonavir may lead to increases in efavirenz exposure. When efavirenz was given with ritonavir 500 mg or 600 mg twice daily, the combination was not well tolerated (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred). Sufficient data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not available. When using efavirenz in a regimen including low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, namely due to possible pharmacodynamic interaction.

 

Saquinavir: when saquinavir (1,200 mg given 3 times a day, soft capsule formulation) was given with efavirenz, the saquinavir AUC and Cmax were decreased by 62% and 50% respectively. Use of efavirenz in combination with saquinavir as the sole PI is not recommended.

 

Saquinavir/ritonavir: no data are available on the potential interactions of efavirenz with the combination of saquinavir and ritonavir. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir above.

 

NRTIs: studies of the interaction between efavirenz and the combination of zidovudine and lamivudine were performed in HIV infected patients. No clinically significant pharmacokinetic interactions were observed. Specific interaction studies have not been performed with efavirenz and other NRTIs. Clinically significant interactions would not be expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.

 

NNRTIs: no studies have been performed with efavirenz in combination with other NNRTIs and the potential for pharmacokinetic or pharmacodynamic interactions is unknown.

 

Antimicrobial agents:

 

Rifamycins: rifampicin reduced efavirenz AUC by 26% and Cmax by 20% in uninfected volunteers. The dose of efavirenz must be increased to 800 mg/day when taken with rifampicin. No dose adjustment of rifampicin is recommended when given with efavirenz. In one study in uninfected volunteers, efavirenz induced a reduction in rifabutin Cmax and AUC by 32% and 38% respectively. Rifabutin had no significant effect on the pharmacokinetics of efavirenz. These data suggest that the daily dose of rifabutin should be increased by 50% when administered with efavirenz and that the rifabutin dose may be doubled for regimens in which rifabutin is given two or three times a week in combination with efavirenz.

 

Macrolide antibiotics:

 

Azithromycin: co‑administration of single doses of azithromycin and multiple doses of efavirenz in uninfected volunteers did not result in any clinically significant pharmacokinetic interaction. No dosage adjustment is necessary when azithromycin is given in combination with efavirenz.

 

Clarithromycin: co‑administration of 400 mg of efavirenz once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted in a significant effect of efavirenz on the pharmacokinetics of clarithromycin. The AUC and Cmax of clarithromycin decreased 39% and 26%, respectively, while the AUC and Cmax of the active clarithromycin hydroxymetabolite were increased 34% and 49%, respectively, when used in combination with efavirenz. The clinical significance of these changes in clarithromycin plasma levels is not known. In uninfected volunteers 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin may be considered.

 

Other macrolide antibiotics, such as erythromycin, have not been studied in combination with efavirenz.

 

Antifungal agents:

 

Voriconazole: co-administration of efavirenz (400 mg orally once daily) with voriconazole (200 mg orally twice daily) in uninfected volunteers resulted in a 2-way interaction. The steady state AUC and Cmax of voriconazole decreased by on average 77% and 61%, respectively, while the steady state AUC and Cmax of efavirenz increased by on average 44% and 38%, respectively. Co-administration of standard doses of efavirenz and voriconazole is contraindicated.

 

Following co-administration of efavirenz (300 mg orally once daily) with voriconazole (400 mg twice daily) in uninfected volunteers, the AUC of voriconazole was decreased by 7% and Cmax was increased by 23% compared to voriconazole 200 mg twice daily alone. These differences were not considered to be clinically significant. The AUC of efavirenz was increased by 17% and Cmax was equivalent compared to efavirenz 600 mg once daily alone.

 

When efavirenz is co-administered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg twice daily and the efavirenz dose should be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.

 

Itraconazole: co-administration of efavirenz (600 mg orally once daily) with itraconazole (200 mg orally every 12 hours) in uninfected volunteers decreased the steady state AUC, Cmax, and Cmin of itraconazole by 39%, 37%, and 44%, respectively, and of hydroxyitraconazole by 37%, 35%, and 43%, respectively, compared to itraconazole administered alone. The pharmacokinetics of efavirenz were not affected. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.

 

Other antifungal agents: no clinically significant pharmacokinetic interactions were seen when fluconazole and efavirenz were co‑administered to uninfected volunteers. The potential for interactions with efavirenz and other imidazole antifungals, such as ketoconazole, has not been studied.

 

Anticonvulsants:

 

Carbamazepine: co-administration of efavirenz (600 mg orally once daily) with carbamazepine (400 mg once daily) in uninfected volunteers resulted in a two-way interaction. The steady-state AUC, Cmax and C_min of carbamazepine decreased by 27%, 20% and 35%, respectively, while the steady-state AUC, Cmax and C_min of efavirenz decreased by 36%, 21%, and 47%, respectively. The steady-state AUC, Cmax and C_min of the active carbamazepine epoxide metabolite remained unchanged. Carbamazepine plasma levels should be monitored periodically. There are no data with co-administration of higher doses of either medicinal product; therefore, no dose recommendation can be made, and alternative anticonvulsant treatment should be considered.

 

Other anticonvulsants: no data are available on the potential interactions of efavirenz with phenytoin, phenobarbital, or other anticonvulsants that are substrates of CYP450 isozymes. When efavirenz is administered concomitantly with these agents, there is a potential for reduction or increase in the plasma concentrations of each agent; therefore, periodic monitoring of plasma levels should be conducted. Specific interaction studies have not been performed with efavirenz and vigabatrin or gabapentin. Clinically significant interactions would not be expected since vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and would be unlikely to compete for the same metabolic enzymes and elimination pathways as efavirenz.

 

Lipid-lowering agents:

 

Co-administration of efavirenz with the HMG-CoA reductase inhibitors atorvastatin, pravastatin, or simvastatin has been shown to reduce the plasma concentration of the statin in uninfected volunteers. Cholesterol levels should be periodically monitored. Dosage adjustments of statins may be required (refer to the Summary of Product Characteristics for the statin).

 

Atorvastatin: co-administration of efavirenz (600 mg orally once daily) with atorvastatin (10 mg orally once daily) in uninfected volunteers decreased the steady-state AUC and Cmax of atorvastatin by 43% and 12%, respectively, of 2-hydroxy atorvastatin by 35% and 13%, respectively, of 4-hydroxy atorvastatin by 4% and 47%, respectively, and of total active HMG-CoA reductase inhibitors by 34% and 20%, respectively, compared to atorvastatin administered alone.

 

Pravastatin: co-administration of efavirenz (600 mg orally once daily) with pravastatin (40 mg orally once daily) in uninfected volunteers decreased the steady-state AUC and Cmax of pravastatin by 40% and 18%, respectively, compared to pravastatin administered alone.

 

Simvastatin: co-administration of efavirenz (600 mg orally once daily) with simvastatin (40 mg orally once daily) in uninfected volunteers decreased the steady-state AUC and Cmax of simvastatin by 69% and 76%, respectively, of simvastatin acid by 58% and 51%, respectively, of total active HMG-CoA reductase inhibitors by 60% and 62%, respectively, and of total HMG-CoA reductase inhibitors by 60% and 70%, respectively, compared to simvastatin administered alone.

 

Co-administration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz AUC or Cmax values. No dosage adjustment is necessary for efavirenz.

 

Other interactions:

 

Antacids/famotidine: neither aluminium/magnesium hydroxide antacids nor famotidine altered the absorption of efavirenz in uninfected volunteers. These data suggest that alteration of gastric pH by other medicinal products would not be expected to affect efavirenz absorption.

 

Oral contraceptives: only the ethinyloestradiol component of oral contraceptives has been studied. The AUC following a single dose of ethinyloestradiol was increased (37%) after multiple dosing of efavirenz. No significant changes were observed in Cmax of ethinyloestradiol. The clinical significance of these effects is not known. No effect of a single dose of ethinyloestradiol on efavirenz Cmax or AUC was observed. Because the potential interaction of efavirenz with oral contraceptives has not been fully characterised, a reliable method of barrier contraception must be used in addition to oral contraceptives.

 

Methadone: in a study of HIV infected IV drug users, co‑administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

 

St. John’s wort (Hypericum perforatum): plasma levels of efavirenz can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort. Herbal preparations containing St. John’s wort must not be used concomitantly with efavirenz. If a patient is already taking St.  John’s wort, stop St. John’s wort, check viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John’s wort and the dose of efavirenz may need adjusting. The inducing effect of St. John’sJohn's wort may persist for at least 2 2 weeks after cessation of treatment (see section 4.3).

 

Other interactions

Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease inhibitors and other non‑antiretroviral medicinal products are listed in Table 1 below (increase is indicated 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 were conducted in healthy subjects unless otherwise noted. Interaction studies have only been performed in adults.

 

Table 1: Interactions between efavirenz and other medicinal products

 

Medicinal product by therapeutic areas (dose)	Effects on drug levels Mean percent change in AUC, Cmax, Cmin with confidence intervals if availablea (mechanism)	Recommendation concerning co‑administration with efavirenz
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors (PI)
Atazanavir/ ritonavir/Efavirenz (400 mg once daily/100 mg once daily/600 mg once daily, all administered with food)	Atazanavir (pm): AUC: ↔* (↓9% to ↑10%) Cmax: ↑17%* (↑8% to ↑27%) Cmin: ↓42%* (↓31% to ↓51%)	Co-administration of efavirenz with atazanavir/ritonavir is not recommended. If the co-administration of atazanavir with an NNRTI is required, an increase in the dose of both atazanavir and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.
Atazanavir/ritonavir/Efavirenz (400 mg once daily/200 mg once daily/600 mg once daily, all administered with food)	Atazanavir (pm): AUC: ↔*/** (↓10% to ↑26%) Cmax: ↔*/** (↓5% to ↑26%) Cmin: ↑ 12%*/** (↓16% to ↑49%) (CYP3A4 induction). * When compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. ** based on historical comparison
Darunavir/ritonavir/Efavirenz (300 mg twice daily*/100 mg twice daily/600 mg once daily)   *lower than recommended dose	Darunavir: AUC: ↓ 13% Cmin: ↓ 31% (CYP3A4 induction) Efavirenz: AUC: ↑ 21% Cmin: ↑ 17% (CYP3A4 inhibition)	The clinical significance of the changes has not been established. Similar findings are expected with the approved darunavir/ritonavir 600/100 mg twice daily dose. This combination should be used with caution. See ritonavir row below.
Fosamprenavir/ritonavir/Efavirenz (700 mg twice daily/100 mg twice daily/600 mg once daily)	No clinically significant pharmacokinetic interaction	No dosage adjustment is necessary for any of these medicinal products. See also ritonavir row below.
Fosamprenavir/Nelfinavir/ Efavirenz	Interaction not studied.	No dosage adjustment is necessary for any of these medicinal products.
Fosamprenavir/Saquinavir/ Efavirenz	Interaction not studied.	Not recommended as the exposure to both PIs is expected to be significantly decreased.
Indinavir/Efavirenz (800 mg q8h/200 mg once daily)	Indinavir: AUC : ↓ 31% (↓ 8 to ↓ 47) Cmin : ↓ 40% A similar reduction in indinavir exposures was observed when indinavir 1000 mg q8h was given with efavirenz 600 mg daily. (CYP3A4 induction) Efavirenz: No clinically significant pharmacokinetic interaction	While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz and indinavir.   No dosage adjustment is necessary for efavirenz when given with indinavir or indinavir/ritonavir.             See also ritonavir row below.
Indinavir/ritonavir/Efavirenz (800 mg twice daily/100 mg twice daily/600 mg once daily)	Indinavir: AUC: ↓ 25% (↓ 16 to ↓ 32) b Cmax: ↓ 17% (↓ 6 to ↓ 26)b Cmin: ↓ 50% (↓ 40 to ↓ 59)b Efavirenz: No clinically significant pharmacokinetic interaction The geometric mean Cmin for indinavir (0.33 mg/l) when given with ritonavir and efavirenz was higher than the mean historical Cmin (0.15 mg/l) when indinavir was given alone at 800 mg q8h. In HIV‑1 infected patients (n = 6), the pharmacokinetics of indinavir and efavirenz were generally comparable to these uninfected volunteer data.
Lopinavir/ritonavir soft capsules or oral solution/Efavirenz   Lopinavir/ritonavir tablets/ Efavirenz   (400/100 mg twice daily/600 mg once daily) (500/125 mg twice daily/600 mg once daily)	Substantial decrease in lopinavir exposure.         Lopinavir concentrations: ↓ 30‑40%   Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz	With efavirenz, an increase of the lopinavir/ritonavir soft capsule or oral solution doses by 33% should be considered (4 capsules/~6.5 ml twice daily instead of 3 capsules/5 ml twice daily). Caution is warranted since this dosage adjustment might be insufficient in some patients. The dosage of lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily when co-administered with efavirenz 600 mg once daily. See also ritonavir row below.
Nelfinavir/Efavirenz (750 mg q8h/600 mg once daily)	Nelfinavir: AUC: ↑ 20% (↑ 8 to ↑ 34) Cmax: ↑ 21% (↑ 10 to ↑ 33) The combination was generally well tolerated.	No dosage adjustment is necessary for either medicinal product.
Ritonavir/Efavirenz (500 mg twice daily/600 mg once daily)	Ritonavir: Morning AUC: ↑ 18% (↑ 6 to ↑ 33) Evening AUC: ↔ Morning Cmax: ↑ 24% (↑ 12 to ↑ 38) Evening Cmax: ↔ Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) b Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) b Efavirenz: AUC: ↑ 21% (↑ 10 to ↑ 34) Cmax: ↑ 14% (↑ 4 to ↑ 26) Cmin: ↑ 25% (↑ 7 to ↑ 46) b (inhibition of CYP-mediated oxidative metabolism) When efavirenz was given with ritonavir 500 mg or 600 mg twice daily, the combination was not well tolerated (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred). Sufficient data on the tolerability of efavirenz with low‑dose ritonavir (100 mg, once or twice daily) are not available.	When using efavirenz with low‑dose ritonavir, the possibility of an increase in the incidence of efavirenz‑associated adverse events should be considered, due to possible pharmacodynamic interaction.
Saquinavir/ritonavir/Efavirenz	Interaction not studied.	No data are available to make a dose recommendation. See also ritonavir row above. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.
CCR5 antagonist
Maraviroc/Efavirenz (100 mg twice daily/600 mg once daily)	Maraviroc: AUC12: ↓ 45% (↓ 38 to ↓ 51) Cmax: ↓ 51% (↓ 37 to ↓ 62) Efavirenz concentrations not measured, no effect is expected.	Refer to the Summary of Product Characteristics for the medicinal product containing maraviroc.
Integrase strand transfer inhibitor
Raltegravir/Efavirenz (400 mg single dose/ -)	Raltegravir: AUC: ↓ 36% C12: ↓ 21% Cmax: ↓ 36% (UGT1A1 induction)	No dosage adjustment is necessary for raltegravir.
NRTIs and NNRTIs
NRTIs/Efavirenz	Specific interaction studies have not been performed with efavirenz and NRTIs other than lamivudine, zidovudine, and tenofovir disoproxil fumarate. Clinically significant interactions are not expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.	No dosage adjustment is necessary for either medicinal product.
NNRTIs/Efavirenz	Interaction not studied.	Since use of two NNRTIs proved not beneficial in terms of efficacy and safety, co‑administration of efavirenz and another NNRTI is not recommended.
Antibiotics
Azithromycin/Efavirenz (600 mg single dose/400 mg once daily)	No clinically significant pharmacokinetic interaction.	No dosage adjustment is necessary for either medicinal product.
Clarithromycin/Efavirenz (500 mg q12h/400 mg once daily)	Clarithromycin: AUC: ↓ 39% (↓ 30 to ↓ 46) Cmax: ↓ 26% (↓ 15 to ↓ 35) Clarithromycin 14‑hydroxymetabolite: AUC: ↑ 34% (↑ 18 to ↑ 53) Cmax: ↑ 49% (↑ 32 to ↑ 69) Efavirenz: AUC: ↔ Cmax: ↑ 11% (↑ 3 to ↑ 19) (CYP3A4 induction) Rash developed in 46% of uninfected volunteers receiving efavirenz and clarithromycin.	The clinical significance of these changes in clarithromycin plasma levels is not known. Alternatives to clarithromycin (e.g. azithromycin) may be considered. No dosage adjustment is necessary for efavirenz.
Other macrolide antibiotics (e.g.,erythromycin)/Efavirenz	Interaction not studied.	No data are available to make a dose recommendation.
Antimycobacterials
Rifabutin/Efavirenz (300 mg once daily/600 mg once daily)	Rifabutin: AUC: ↓ 38% (↓ 28 to ↓ 47) Cmax: ↓ 32% (↓ 15 to ↓ 46) Cmin: ↓ 45% (↓ 31 to ↓ 56) Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↓ 12% (↓ 24 to ↑ 1) (CYP3A4 induction)	The daily dose of rifabutin should be increased by 50% when administered with efavirenz. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week in combination with efavirenz.
Rifampicin/Efavirenz (600 mg once daily/600 mg once daily)	Efavirenz: AUC: ↓ 26% (↓ 15 to ↓ 36) Cmax: ↓ 20% (↓ 11 to ↓ 28) Cmin: ↓ 32% (↓ 15 to ↓ 46) (CYP3A4 and CYP2B6 induction)	When taken with rifampicin, increasing efavirenz daily dose to 800 mg may provide exposure similar to a daily dose of 600 mg when taken without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment (see section 5.2). No dosage adjustment is necessary for rifampicin.
Antifungals
Itraconazole/Efavirenz (200 mg q12h/600 mg once daily)	Itraconazole: AUC: ↓ 39% (↓ 21 to ↓ 53) Cmax: ↓ 37% (↓ 20 to ↓ 51) Cmin: ↓ 44% (↓ 27 to ↓ 58) (decrease in itraconazole concentrations: CYP3A4 induction) Hydroxyitraconazole: AUC: ↓ 37% (↓ 14 to ↓ 55) Cmax: ↓ 35% (↓ 12 to ↓ 52) Cmin: ↓ 43% (↓ 18 to ↓ 60) Efavirenz: No clinically significant pharmacokinetic change.	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Posaconazole/Efavirenz --/400 mg once daily	Posaconazole: AUC: ↓ 50% Cmax: ↓ 45% (UDP-G induction)	Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.
Voriconazole/Efavirenz (200 mg twice daily/400 mg once daily)         Voriconazole/Efavirenz (400 mg twice daily/300 mg once daily)	Voriconazole: AUC: ↓ 77% Cmax: ↓ 61% Efavirenz: AUC: ↑ 44% Cmax: ↑ 38% Voriconazole: AUC: ↓ 7% (↓ 23 to ↑ 13) * Cmax: ↑ 23% (↓ 1 to ↑ 53) * Efavirenz: AUC: ↑ 17% (↑ 6 to ↑ 29) ** Cmax: ↔** *compared to 200 mg twice daily alone ** compared to 600 mg once daily alone (competitive inhibition of oxidative metabolism)	When efavirenz is co-administered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg twice daily and the efavirenz dose must be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Fluconazole/Efavirenz (200 mg once daily/400 mg once daily)	No clinically significant pharmacokinetic interaction	No dosage adjustment is necessary for either medicinal product.
Ketoconazole and other imidazole antifungals	Interaction not studied	No data are available to make a dose recommendation.
ACID REDUCING AGENTS
Aluminium hydroxide-magnesium hydroxide-simethicone antacid/Efavirenz (30 ml single dose/400 mg single dose) Famotidine/Efavirenz (40 mg single dose/400 mg single dose)	Neither aluminium/magnesium hydroxide antacids nor famotidine altered the absorption of efavirenz.	Co-administration of efavirenz with medicinal products that alter gastric pH would not be expected to affect efavirenz absorption.
ANTIANXIETY AGENTS
Lorazepam/Efavirenz (2 mg single dose/600 mg once daily)	Lorazepam: AUC: ↑ 7% (↑ 1 to ↑ 14) Cmax: ↑ 16% (↑ 2 to ↑ 32) These changes are not considered clinically significant.	No dosage adjustment is necessary for either medicinal product.
ANTICONVULSANTS
Carbamazepine/Efavirenz (400 mg once daily/600 mg once daily)	Carbamazepine: AUC: ↓ 27% (↓ 20 to ↓ 33) Cmax: ↓ 20% (↓ 15 to ↓ 24) Cmin: ↓ 35% (↓ 24 to ↓ 44) Efavirenz: AUC: ↓ 36% (↓ 32 to ↓ 40) Cmax: ↓ 21% (↓ 15 to ↓ 26) Cmin: ↓ 47% (↓ 41 to ↓ 53) (decrease in carbamazepine concentrations: CYP3A4 induction; decrease in efavirenz concentrations: CYP3A4 and CYP2B6 induction) The steady-state AUC, Cmax and Cmin of the active carbamazepine epoxide metabolite remained unchanged. Co‑administration of higher doses of either efavirenz or carbamazepine has not been studied.	No dosage recommendation can be made. An alternative anticonvulsant should be considered. Carbamazepine plasma levels should be monitored periodically.
Phenytoin, Phenobarbital, and other anticonvulsants that are substrates of CYP450 isoenzymes	Interaction not studied. There is a potential for reduction or increase in the plasma concentrations of phenytoin, phenobarbital and other anticonvulsants that are substrates of CYP450 isoenzymes when co-administered with efavirenz.	When efavirenz is co-administered with an anticonvulsant that is a substrate of CYP450 isoenzymes, periodic monitoring of anticonvulsant levels should be conducted.
Valproic acid/Efavirenz (250 mg twice daily/600 mg once daily)	No clinically significant effect on efavirenz pharmacokinetics. Limited data suggest there is no clinically significant effect on valproic acid pharmacokinetics.	No dosage adjustment is necessary for efavirenz. Patients should be monitored for seizure control.
Vigabatrin/Efavirenz Gabapentin/Efavirenz	Interaction not studied. Clinically significant interactions are not expected since vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and are unlikely to compete for the same metabolic enzymes and elimination pathways as efavirenz.	No dosage adjustment is necessary for any of these medicinal products.
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz (50 mg once daily/600 mg once daily)	Sertraline: AUC: ↓ 39% (↓ 27 to ↓ 50) Cmax: ↓ 29% (↓ 15 to ↓ 40) Cmin: ↓ 46% (↓ 31 to ↓ 58) Efavirenz: AUC: ↔ Cmax: ↑ 11% (↑ 6 to ↑ 16) Cmin: ↔ (CYP3A4 induction)	Sertraline dose increases should be guided by clinical response. No dosage adjustment is necessary for efavirenz.
Paroxetine/Efavirenz (20 mg once daily/600 mg once daily)	No clinically significant pharmacokinetic interaction	No dosage adjustment is necessary for either medicinal product.
Fluoxetine/Efavirenz	Interaction not studied. Since fluoxetine shares a similar metabolic profile with paroxetine, i.e. a strong CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine.	No dosage adjustment is necessary for either medicinal product.
ANTIHISTAMINES
Cetirizine/Efavirenz (10 mg single dose/600 mg once daily)	Cetirizine: AUC: ↔ Cmax: ↓ 24% (↓ 18 to ↓ 30) These changes are not considered clinically significant. Efavirenz: No clinically significant pharmacokinetic interaction	No dosage adjustment is necessary for either medicinal product.
Cardiovascular Agents
Calcium Channel Blockers
Diltiazem/Efavirenz (240 mg once daily/600 mg once daily)	Diltiazem: AUC: ↓ 69% (↓ 55 to ↓ 79) Cmax: ↓ 60% (↓ 50 to ↓ 68) Cmin: ↓ 63% (↓ 44 to ↓ 75) Desacetyl diltiazem: AUC: ↓ 75% (↓ 59 to ↓ 84) 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) Efavirenz: AUC: ↑ 11% (↑ 5 to ↑ 18) Cmax: ↑ 16% (↑ 6 to ↑ 26) Cmin: ↑ 13% (↑ 1 to ↑ 26) (CYP3A4 induction) The increase in efavirenz pharmacokinetic parameters is not considered clinically significant.	Dose adjustments of diltiazem should be guided by clinical response (refer to the Summary of Product Characteristics for diltiazem). No dosage adjustment is necessary for efavirenz.
Verapamil, Felodipine, Nifedipine and Nicardipine	Interaction not studied. When efavirenz is co-administered with a calcium channel blocker that is a substrate of the CYP3A4 enzyme, there is a potential for reduction in the plasma concentrations of the calcium channel blocker.	Dose adjustments of calcium channel blockers should be guided by clinical response (refer to the Summary of Product Characteristics for the calcium channel blocker).
LIPID LOWERING MEDICINAL PRODUCTS
HMG Co‑A Reductase Inhibitors
Atorvastatin/Efavirenz (10 mg once daily/600 mg once daily)	Atorvastatin: AUC: ↓ 43% (↓ 34 to ↓ 50) Cmax: ↓ 12% (↓ 1 to ↓ 26) 2‑hydroxy atorvastatin: AUC: ↓ 35% (↓ 13 to ↓ 40) Cmax: ↓ 13% (↓ 0 to ↓ 23) 4‑hydroxy atorvastatin: AUC: ↓ 4% (↓ 0 to ↓ 31) Cmax: ↓ 47% (↓ 9 to ↓ 51) Total active HMG Co‑A reductase inhibitors: AUC: ↓ 34% (↓ 21 to ↓ 41) Cmax: ↓ 20% (↓ 2 to ↓ 26)	Cholesterol levels should be periodically monitored. Dosage adjustment of atorvastatin may be required (refer to the Summary of Product Characteristics for atorvastatin. No dosage adjustment is necessary for efavirenz.
Pravastatin/Efavirenz (40 mg once daily/600 mg once daily)	Pravastatin: AUC: ↓ 40% (↓ 26 to ↓ 57) Cmax: ↓ 18% (↓ 59 to ↑ 12)	Cholesterol levels should be periodically monitored. Dosage adjustment of pravastatin may be required (refer to the Summary of Product Characteristics for pravastatin). No dosage adjustment is necessary for efavirenz.
Simvastatin/Efavirenz (40 mg once daily/600 mg once daily)	Simvastatin: AUC: ↓ 69% (↓ 62 to ↓ 73) Cmax: ↓ 76% (↓ 63 to ↓ 79) Simvastatin acid: AUC: ↓ 58% (↓ 39 to ↓ 68) Cmax: ↓ 51% (↓ 32 to ↓ 58) Total active HMG Co‑A reductase inhibitors: AUC: ↓ 60% (↓ 52 to ↓ 68) Cmax: ↓ 62% (↓ 55 to ↓ 78) (CYP3A4 induction) Co‑administration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz AUC or Cmax values.	Cholesterol levels should be periodically monitored. Dosage adjustment of simvastatin may be required (refer to the Summary of Product Characteristics for simvastatin). No dosage adjustment is necessary for efavirenz.
Rosuvastatin/Efavirenz	Interaction not studied. Rosuvastatin is largely excreted unchanged via the faeces, therefore interaction with efavirenz is not expected.	No dosage adjustment is necessary for either medicinal product.
HORMONAL CONTRACEPTIVES
Oral: Ethinyloestradiol + Norgestimate/ Efavirenz (0.035 mg + 0.25 mg once daily/600 mg once daily)	Ethinyloestradiol: AUC: ↔ Cmax: ↔ Cmin: ↓ 8% (↑ 14 to ↓ 25) 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 significant interaction. The clinical significance of these effects is not known.	A reliable method of barrier contraception must be used in addition to hormonal contraceptives (see section 4.6).
Injection: Depomedroxyprogesterone acetate (DMPA)/Efavirenz (150 mg IM single dose DMPA)	In a 3-month drug interaction study, no significant differences in MPA pharmacokinetic parameters were found between subjects receiving efavirenz-containing antiretroviral therapy and subjects receiving no antiretroviral therapy. Similar results were found by other investigators, although the MPA plasma levels were more variable in the second study. In both studies, plasma progesterone levels for subjects receiving efavirenz and DMPA remained low consistent with suppression of ovulation.	Because of the limited information available, a reliable method of barrier contraception must be used in addition to hormonal contraceptives (see section 4.6).
Implant: Etonogestrel/Efavirenz	Interaction not studied. Decreased exposure of etonogestrel may be expected (CYP3A4 induction). There have been occasional postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.	A reliable method of barrier contraception must be used in addition to hormonal contraceptives (see section 4.6).
IMMUNOSUPPRESSANTS
Immunosuppressants metabolized by CYP3A4 (eg, cyclosporine, tacrolimus, sirolimus)/Efavirenz	Interaction not studied. Decreased exposure of the immunosuppressant may be expected (CYP3A4 induction). These immunosuppressants are not anticipated to affect exposure of efavirenz.	Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
OPIOIDS
Methadone/Efavirenz (stable maintenance, 35‑100 mg once daily/600 mg once daily)	Methadone: AUC: ↓ 52% (↓ 33 to ↓ 66) Cmax: ↓ 45% (↓ 25 to ↓ 59) (CYP3A4 induction) In a study of HIV infected intravenous drug users, co‑administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.	Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
Buprenorphine/naloxone/Efavirenz	Buprenorphine: AUC: ↓ 50% Norbuprenorphine: AUC: ↓ 71% Efavirenz: No clinically significant pharmacokinetic interaction	Despite the decrease in buprenorphine exposure, no patients exhibited withdrawal symptoms. Dose adjustment of buprenorphine or efavirenz may not be necessary when co-administered.

^{a 90% confidence intervals unless otherwise noted.}

^{b 95% confidence intervals.}

 

Antidepressants: there were no clinically significant effects on pharmacokinetic parameters when paroxetine and efavirenz were co‑administered. No dose adjustments are necessary for either efavirenz or paroxetine when these medicinal products are co‑administered. Since fluoxetine shares a similar metabolic profile with paroxetine, i.e. a strong CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine. Sertraline, a CYP3A4 substrate, did not significantly alter the pharmacokinetics of efavirenz. Efavirenz decreased sertraline Cmax, C24 and AUC by 28.6 to 46.3%. Sertraline dose increases should be guided by clinical response.

 

Cetirizine: the H1-antihistamine, cetirizine, had no clinically significant effect on efavirenz pharmacokinetic parameters. Efavirenz decreased cetirizine Cmax by 24% but did not alter cetirizine AUC. These changes are not considered to be clinically significant. No dose adjustments are necessary for either efavirenz or cetirizine when these medicinal products are co‑administered.

 

Lorazepam: efavirenz increased lorazepam Cmax and AUC by 16.3% and 7.3% respectively. These changes are not considered to be clinically significant. No dose adjustments are necessary for either efavirenz or lorazepam when these medicinal products are co‑administered.

 

Calcium channel blockers: co-administration of efavirenz (600 mg orally once daily) with diltiazem (240 mg orally once daily) in uninfected volunteers decreased the steady state AUC, Cmax, and Cmin of diltiazem by 69%, 60%, and 63%, respectively; desacetyl diltiazem by 75%, 64%, and 62%, respectively; and N-monodesmethyl diltiazem by 37%, 28%, and 37%, respectively, compared to diltiazem administered alone. Diltiazem dose adjustments should be guided by clinical response (refer to the Summary of Product Characteristics for diltiazem).

Although the pharmacokinetic parameters of efavirenz were slightly increased (11%-16%), these changes are not considered clinically significant and, thus, no dosage adjustment is necessary for efavirenz when administered with diltiazem.

 

No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of the CYP3A4 enzyme (eg, verapamil, felodipine, nifedipine, nicardipine). When efavirenz is administered concomitantly with one of these agents, there is a potential for reduction in the plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the Summary of Product Characteristics for the calcium channel blocker).

 

4.6     Pregnancy and lactation

 

Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options.

 

Women of childbearing potential: pregnancyPregnancy should be avoided in women treated with efavirenz. Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives). Because of the long half‑life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended.

Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz. Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options.

 

Pregnancy: thereThere are limited amount of data from the use no adequate and well-controlled studies of efavirenz in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, outcomes for more than 200 400 pregnancies with first-trimester exposure to efavirenz as part of a combination antiretroviral regimen have been prospectively reported with no specific malformation pattern. observed. ARetrospectively in this registry, a small number of cases of neural tube defects, including meningomyelocele, have been reported via the registry. Most neural tube defects were isolated retrospectively reported cases, and but causality cannot be ruled out but has not been established. Studies in animals have shown reproductive toxicity including marked teratogenic effects (see section 5.3).

 

Lactation: studies Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. It is not known whether efavirenz is excreted in human milk. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking efavirenz do not breast feed their infants. It is recommended that HIV infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

 

4.8     Undesirable effects

 

Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received 600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most frequently reported adverse reactionstreatment‑related undesirable effects of at least moderate severity reported in at least 5% of patients were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). The most notable adverse reactionsundesirable effects associated with efavirenz are rash and nervous system symptoms. The administration of SUSTIVA with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactionsundesirable effects (see section 4.4).

 

(...)

 

Psychiatric symptoms: serious psychiatric adverse reactionsexperiences have been reported in patients treated with efavirenz. In controlled trials of 1,008 patients treated with regimens containing efavirenz for an average of 1.6 years and 635 patients treated with control regimens for an average of 1.3 years, the frequency of specific serious psychiatric events are detailed hereafter:

 

	Efavirenz regimen	Control regimen
- 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 psychiatric adverse reactionsexperiences with frequenciesthe frequency of each of the above events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been post‑marketing reports of death by suicide, delusions and psychosis‑like behaviour.

 

Nervous system symptoms: in clinical controlled trials, frequently reported adverse reactionsundesirable effects in patients receiving 600 mg efavirenz with other antiretroviral agents included, but were not limited to: dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system symptoms of moderate‑to‑severe intensity were experienced by 19.4% of patients compared to 9.0% of patients receiving control regimens. These symptoms were severe in 2.0% of patients receiving efavirenz 600 mg daily and in 1.3% of patients receiving control regimens. In clinical studies 2.1% of patients treated with 600 mg of efavirenz discontinued therapy because of nervous system symptoms.

 

(...)

 

Adverse reactions of moderate or greater severity with at least possible relationship to treatment regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended dose in combination therapy (n = 1,008) are listed below. Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to, < 1/10); uncommon (≥ 1/1,000

to, < 1/100); rare (≥ 1/10,000 to, < 1/1,000); very rare (< 1/10,000) including isolated reports.

 

Nervous system disorders
common	disturbance in attention, dizziness, headache, somnolence
uncommon	agitation, amnesia, ataxia, coordination abnormal, convulsions, thinking abnormal
Eye disorders
uncommon	vision blurred
Ear and labyrinth disorders
uncommon	vertigo
Gastrointestinal disorders
common	abdominal pain, diarrhoea, nausea, vomiting
uncommon	pancreatitis acute
Skin and subcutaneous tissue disorders
very common	rash
common	pruritus
uncommon	erythema multiforme, Stevens-Johnson syndrome
General disorders and administration site conditions
common	fatigue
Immune system disorders
uncommon	hypersensitivity
Hepatobiliary disorders
uncommon	hepatitis acute
Reproductive system and breast disorders
uncommon	gynaecomastia
Psychiatric disorders
common	abnormal dreams, anxiety, depression, insomnia
uncommon	affect lability, aggression, confusional state, euphoric mood, hallucination, mania, paranoia, suicide attempt, suicide ideation

 

Nervous system disorders

common: abnormal dreams, disturbance in attention, dizziness, headache, insomnia, somnolence

uncommon: agitation, amnesia, ataxia, coordination abnormal, confusional state, convulsions, thinking abnormal

 

Eye disorders

uncommon: vision blurred

 

Ear and labyrinth disorders

uncommon: vertigo

 

Gastrointestinal disorders

common: abdominal pain, diarrhoea, nausea, vomiting

uncommon: pancreatitis acute

 

Skin and subcutaneous tissue disorders

very common: rash

common: pruritus

uncommon: erythema multiforme

 

General disorders and administration site conditions

common: fatigue

 

Immune system disorders

uncommon: hypersensitivity

 

Hepatobiliary disorders

uncommon: hepatitis acute

 

Reproductive system and breast disorders

uncommon: gynaecomastia

 

Psychiatric disorders

common: anxiety, depression

uncommon: affect lability, aggression, euphoric mood, hallucination, mania, paranoia, suicide attempt, suicide ideation

 

(...)

 

Postmarketing experience with efavirenz has shown the following additional adverse reactionsevents to occur in association with efavirenz-containing antiretroviral treatment regimens: cerebellar coordination and balance disturbances, delusion, hepatic failure, neurosis, photoallergic dermatitis, psychosis and completed suicide.

 

Paediatric patientsAdolescents and children: undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (in a clinical study including 57 children who received efavirenz during a 48-week period, rash was reported in 46%) and was more often of higher grade than in adults (severe rash was reported in 5.3% of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered. Although nervous system symptoms are difficult for young children to report, they appear to be less frequent in children and were generally mild. In the study of 57 children, 3.5% of patients experienced nervous system symptoms of moderate intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of nervous system symptoms.

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: NonNNRTI (non-nucleoside reverse transcriptase inhibitors).

ATC code: J05AJ05A G03

 

 

(...)

Table 21: Efficacy results for study 006

 

(...)

Table 32: Efficacy results for studies ACTG 364 and 020

 

(...)

5.2     Pharmacokinetic properties

 

(...)

 

Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. In uninfected volunteers, multiple doses 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 of 40 ‑ 55 hours (single dose administration (see belowhalf‑life 52 ‑ 76 hours).

 

Elimination: efavirenz has a relatively long terminal half‑life of at least 52 52 to 76 hours after single doses and 40 ‑ 55 hours after multiple doses. Approximately 14 ‑ 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.

 

(...)

 

Gender, race, elderly: althoughpharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Although limited data suggest that females as well as Asian and Pacific Island patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic studies have not been performed in the elderly.

 

6.5     Nature and content of container

 

HDPE bottles with a child‑resistant polypropylene closure. Each carton contains 1 bottleBottles of 30 film‑coated tablets.

Packs of 30 x 1 or 90 (3 x 30 x 1) film‑coated tablets in aluminium/PVC perforated unit dose blisters.

Not all pack sizes may be marketed.

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

EU/1/99/110/008 - bottle

EU/1/99/110/009 - blister

EU/1/99/110/010 - blister

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 28 May 199922 August 2002
Date of latestlast renewal: 22 29 April 20092004

 

 

10.     DATE OF REVISION OF THE TEXT

 

046/2009

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

 

4.2     Posology and method of administration

 

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

 

Concomitant antiretroviral therapy: SUSTIVA must be given in combination with other antiretroviral medicines (see section 4.5).

 

It is recommended that SUSTIVA be taken on an empty stomach. The increased efavirenz concentrations observed following administration of SUSTIVA with food may lead to an increase in frequency of adverse events (see sections 4.4. and 5.2).

 

In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is recommended (see section 4.8).

 

Adults: the recommended dosage of SUSTIVA in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily.

 

Adolescents and children (3 to 17 years): the recommended dose of SUSTIVA in combination with a PI and/or NRTIs for patients between 3 and 17 years of age is described in Table 1. SUSTIVA hard capsules must only be administered to children who are able to reliably swallow hard capsules. SUSTIVA is not recommended for use in children patients below the age of 3 years or weighing less than 13 kg due to a lack of data on safety and efficacy in that age group (see sections 5.1 and 5.2). For children at least 3 years old and weighing at least 13 kg and adults who cannot reliably swallow hard capsules, SUSTIVA oral solution is the preferred formulation. Administration of the capsule contents with a small amount (1‑2 teaspoons) of food may be considered for patients who cannot tolerate the oral solution. In a palatability study in healthy adults of efavirenz mixed with applesauce, grape jelly, yogurt, or infant formula, grape jelly received the highest rating of good overall taste. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. It is recommended to hold the capsule vertically with the cap facing up and to pull the cap away from the body of the capsule, and to mix the capsule contents with food in a small container. The mixture should be administered as soon as possible, but no more than 30 minutes after mixing. After administration of the efavirenz-food mixture, an additional small amount (approximately 2 teaspoons) of food must be added to the empty mixing container, stirred to disperse any remaining drug residue, and administered to the patient. No additional food should be consumed for up to 2 hours after administration of efavirenz. There are limited safety and tolerability data for administration of the capsule contents in paediatric patients.

 

Table 1

Paediatric dose to be administered once daily*

 

Body Weight	SUSTIVA
kg	Dose (mg)
13 to < 15	200
15 to < 20	250
20 to < 25	300
25 to < 32.5	350
32.5 to < 40	400
¡Ý 40	600

*For information on the bioavailability of the capsule contents mixed with food vehicles, see section 5.2.

 

Dosage adjustment: If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see section 4.5).

 

If SUSTIVA is coadministered with rifampicin, the dose of SUSTIVA must be increased to 800 mg/day (see section 4.5).

 

Renal insufficiency: 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 renal impairment on efavirenz elimination should be minimal (see section 4.4).

 

Liver disease: patients with mild to moderate liver disease may be treated with their normally recommended dose of efavirenz. Patients should be monitored carefully for dose‑related adverse events, especially nervous system symptoms (see sections 4.3 and 4.4).