efavirenz: prescribing information – dosing, contraindications, interactions, side effects

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

Efavirenz has not been adequately studied in patients with advanced HIV disease, namely in patients with 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 present insufficient data on the efficacy of subsequent use of PI-based combination therapy after failure of regimens containing efavirenz.

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.

Posology

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 is recommended (see section 4.8).

Adults and adolescents over 40 kg
The recommended dose of efavirenz in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily.

Efavirenz film-coated tablets are not suitable for children weighing less than 40 kg. Other formulations are available for these patients.

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

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

Special populations

Renal impairment
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 impairment
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 system symptoms (see sections 4.3 and 4.4).

Method of administration

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency 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 the potential for serious and/or life-threatening adverse reactions [for example, cardiac arrhythmias, prolonged sedation or respiratory depression] (see section 4.5).

Co-administration with elbasvir (EBR) and grazoprevir (GZR) due to the potential for significant decreases in plasma concentrations of EBR and GZR (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 arrhythmias 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 (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.

Summary of the safety profile

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 reactions 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 reactions associated with efavirenz are rash and nervous system symptoms. 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 efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (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 duration 180 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 not associated with any new safety concerns.

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).

Immune system disorders
Uncommon hypersensitivity
Metabolism and nutrition disorders
Common hypertriglyceridaemia*
Uncommon hypercholesterolaemia*
Psychiatric disorders
Common 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 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 common aspartate aminotransferase (AST) increased*, alanine aminotransferase (ALT) increased*, gamma-glutamyltransferase (GGT) increased*

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

Description of selected adverse reactions

Information regarding post-marketing surveillance

†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).

Rash
In clinical studies, 26% of patients treated with 600 mg of efavirenz experienced skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment-related in 18% of patients 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 two weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with efavirenz within one month. Efavirenz can be re-initiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is restarted.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is 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. In controlled 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 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.

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 system symptoms of moderate-to-severe intensity were experienced by 19% (severe 2%) of patients compared to 9% (severe 1%) of patients receiving control regimens. In clinical studies 2% of patients treated with efavirenz discontinued therapy due to such symptoms.

Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous system symptoms may occur more frequently when efavirenz is taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or splitting 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-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the control arm.

Hepatic failure
A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, 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 normal range (ULN) were seen in 3% of 1,008 patients treated with 600 mg of efavirenz (5-8% after long-term treatment in study 006). Similar elevations were seen in patients treated with control regimens (5% after long-term treatment). Elevations of GGT to greater than five times ULN were observed in 4% of all patients treated with 600 mg of efavirenz and 1.5-2% of patients treated with control regimens (7% of efavirenz-treated patients and 3% of control-treated patients after long-term treatment). 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 or biliary system disorders.

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

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Paediatric population

Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (59 of 182 (32%) treated with efavirenz) and was more often of higher grade than in adults (severe rash was reported in 6 of 182 (3.3%) of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.

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 controls, 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. 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 is not recommended, unless needed for dose adjustment (for example, with rifampicin).

Coadministration of sofosbuvir/velpatasvir with efavirenz is not recommended (see section 4.5).
Concomitant administration of velpatasvir/sofosbuvir/voxilaprevir with efavirenz is not recommended (see section 4.5).

Coadministration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma concentrations 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 the corresponding Summary of Product Characteristics.

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

Rash

Mild-to-moderate rash has been reported in clinical studies with efavirenz and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with efavirenz. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Efavirenz must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting therapy 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 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.

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).

Nervous system symptoms

Symptoms including, but not limited to dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported adverse reactions in patients receiving efavirenz 600 mg daily in clinical studies (see section 4.8). Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2-4 weeks. Patients should be informed that if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms.

Seizures

Convulsions have been observed in adult and paediatric 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.

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.

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.

Effect of food

The administration of efavirenz 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). It is recommended that efavirenz 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). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Weight and metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Special populations

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 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).

The safety and efficacy of efavirenz has not been established in patients with significant underlying liver disorders. 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. 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).

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Renal impairment
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 4.2). There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population.

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

Paediatric population
Efavirenz Teva film-coated tablets are not suitable for children under the age of 3 years or weighing less than 40 kg.

Rash was reported in 59 of 182 children (32%) treated with efavirenz and was severe in six patients.
Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.

Excipients
Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

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

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with efavirenz. In vitro efavirenz is also an inhibitor of CYP3A4. Theoretically, efavirenz may therefore initially increase the exposure to CYP3A4 substrates and caution is warranted for CYP3A4 substrates with narrow 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 with substrates of these enzymes is not clear (see section 5.2).

Efavirenz exposure may be increased when given with medicinal products (for example, ritonavir) or food (for example, grapefruit juice), which inhibit CYP3A4 or CYP2B6 activity. Compounds or herbal preparations (for example Ginkgo biloba extracts and St. John’s wort) which induce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John’s wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.4).

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).

Paediatric population

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).

Elbasvir/grazoprevir
Concomitant administration of efavirenz with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. (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. Plasma levels of efavirenz can be reduced by concomitant use of St. John’s wort due to induction of drug-metabolising enzymes and/or transport proteins by St. John’s wort. If a patient is

already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible efavirenz levels.
Efavirenz levels may increase on stopping St. John’s wort and the dose of efavirenz may need adjusting. The inducing effect of St. John’s wort may persist for at least 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.

Table 1: Interactions between efavirenz and other medicinal products in adults
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
HIV antivirals
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 doses, similar findings are expected with recommended doses Darunavir:
AUC: ↓ 13%
Cmin: ↓ 31%
Cmax: ↓ 15%
(CYP3A4 induction)
Efavirenz:
AUC: ↑ 21%
Cmin: ↑ 17%
Cmax: ↑ 15%
(CYP3A4 inhibition)
Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in suboptimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. This combination should be used with caution. See also ritonavir row below.
Fosamprenavir/ritonavir/ efavirenz
(700 mg twice daily/100 mg twice daily/600 mg once daily)
No clinically significant pharmacokinetic interaction
No dose adjustment is necessary for any of these medicinal products. See also ritonavir row below.
Fosamprenavir/nelfinavir/ efavirenz

Interaction not studied
No dose adjustment is necessary for any of these medicinal products.
Fosamprenavir/saquinavir/ efavirenz
Interaction not studied

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
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 dose 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
Substantial decrease in lopinavir exposure.
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 dose adjustment might be insufficient in some patients. The dose 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.
(400/100 mg twice daily/ 600 mg once daily)
Lopinavir concentrations: ↓ 30-40%
(500/125 mg twice daily/ 600 mg once daily)
Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz 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 dose 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: ↔
When using efavirenz with low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, due

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
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.
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 dose 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.
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 dose 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.
Hepatitis C antivirals
Boceprevir/efavirenz
(800 mg 3 times daily/600 mg once daily)
Boceprevir:
AUC: ↔ 19%*
Cmax: ↔ 8%
Plasma trough concentrations of boceprevir were decreased when administered with efavirenz. The clinical outcome of this observed

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

Cmin: ↓ 44%
Efavirenz:
AUC: ↔ 20%
Cmax: ↔ 11%
(CYP3A induction - effect on boceprevir)
*0-8 hours
No effect (↔) equals a decrease in mean ratio estimate of ≤20% or increase in mean ratio estimate of ≤25% reduction of boceprevir trough concentrations has not been directly assessed.
Telaprevir/efavirenz
(1,125 mg q8h/600 mg once daily)

Telaprevir
(relative to
750 mg q8h):
AUC: ↓ 18% (↓ 8 to ↓ 27)
Cmax: ↓ 14% (↓ 3 to ↓ 24)
Cmin: ↓ 25% (↓ 14 to ↓ 34)%
Efavirenz:
AUC: ↓ 18% (↓ 10 to ↓ 26)
Cmax: ↓ 24% (↓ 15 to ↓ 32)
Cmin: ↓ 10% (↑ 1 to ↓ 19)%
(CYP3A induction by efavirenz)
If efavirenz and telaprevir are co- administered, telaprevir 1,125 mg every 8 hours should be used.
Simeprevir/efavirenz
(150 mg once daily /600 mg once daily)
Simeprevir:
AUC: ↓71% (↓67 to ↓74)
Cmax: ↓51% (↓46 to ↓56)
Cmin: ↓91% (↓88 to ↓92)
Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
No effect (↔) equals a decrease in mean ratio estimate of ≤20% or increase in mean ratio estimate of ≤25% (CYP3A4 enzyme induction) Concomitant administration of simeprevir with efavirenz resulted in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by efavirenz, which may result in loss of therapeutic effect of simeprevir.
Co-administration of simeprevir with efavirenz is not recommended.
Sofosbuvir/velpatasvir
↔sofosbuvir
↓velpatasvir
↔efavirenz
Concomitant administration of sofosbuvir/velpatasvir with efavirenz resulted in a reduction (approximately 50%) in the systemic exposure of velpatasvir. The mechanism of the effect on velpatasvir is induction of CYP3A and CYP2B6 by efavirenz.
Coadministration of sofosbuvir/velpatasvir with efavirenz is not recommended.
Refer to the prescribing information for sofosbuvir/velpatasvir for more information.

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
Velpatasvir/sofosbuvir/voxilap revir
↓velpatasvir
↓voxilaprevir
Concomitant administration of velpatasvir/sofosbuvir/ voxilaprevir with efavirenz is not recommended, as it may decrease concentrations of velpatasvir and voxilaprevir.
Refer to the prescribing information for velpatasvir/sofosbuvir/ voxilaprevir for more information.
Protease inhibitor :
Elbasvir/grazoprevir

↓elbasvir
↓grazoprevir
↔efavirenz
Concomitant administration of efavirenz with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. Refer to the prescribing information for elbasvir/grazoprevir for more information.
Glecaprevir/pibrentasvir
↓glecaprevir
↓ pibrentasvir
Concomitant administration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect.
Coadministration of glecaprevir/pibrentasvir with efavirenz is not recommended.
Refer to the prescribing information for glecaprevir/pibrentasvir for more information.
Antibiotics
Azithromycin/efavirenz
(600 mg single dose/400 mg once daily)
No clinically significant pharmacokinetic interaction
No dose 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:
The clinical significance of these changes in clarithromycin plasma levels is not known. Alternatives to clarithromycin (e.g.
azithromycin) may be considered.
No dose adjustment is necessary for efavirenz.

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
AUC: ↔
Cmax: ↑ 11% (↑ 3 to ↑19)
(CYP3A4 induction)
Rash developed in 46% of uninfected volunteers receiving efavirenz and clarithromycin.
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. 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).
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.
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%
Concomitant use of posaconazole and efavirenz should be avoided

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
(UDP-G induction) unless the benefit to the patient outweighs the risk.
Voriconazole/efavirenz
(200 mg twice daily/400 mg once daily)
Voriconazole:
AUC: ↓ 77%
Cmax: ↓ 61%

Efavirenz:
AUC: ↑ 44%
Cmax: ↑ 38%

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 dose of efavirenz should be restored.
Voriconazole/efavirenz
(400 mg twice daily/300 mg once daily)
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)
Fluconazole/efavirenz
(200 mg once daily/400 mg once daily)
No clinically significant pharmacokinetic interaction
No dose adjustment is necessary for either medicinal product.
Ketoconazole and other imidazole antifungals
Interaction not studied
No data are available to make a dose recommendation.
Antimalarials
Artemether/lumefantrine/efaviren z
(20/120 mg tablet, 6 doses of 4 tablets each over 3 days/600mg once daily)
Artemether:
AUC: ↓ 51%
Cmax: ↓ 21%
Dihydroartemisinin:
AUC: ↓ 46%
Cmax: ↓ 38%
Lumefantrine:
AUC: ↓ 21%
Cmax: ↔
Efavirenz:
AUC: ↓ 17%
Cmax: ↔
(CYP3A4 induction)
Since decreased concentrations of artemether, dihydroartemisinin, or lumefantrine may result in a decrease of antimalarial efficacy, caution is recommended when efavirenz and artemether/lumefantrine tablets are coadministered.
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.
Antiparasitics
Praziquantel
Significant decrease in plasma concentrations of praziquantel with risk of treatment failure due to Concomitant use with praziquantel is not recommended.
In case the combination is needed,

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 increased hepatic metabolism by efavirenz.
an increased dose of praziquantel could be considered.
ACID-REDUCING AGENTS
Aluminium hydroxide- magnesium hydroxide- simethicone antacid/efavirenz
(30 ml 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.
Famotidine/efavirenz
(40 mg single dose/400 mg single dose)
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 dose adjustment is necessary for either medicinal product.
ANTICOAGULANTS
Warfarin/efavirenz
Acenocoumarol/efavirenz

Interaction not studied. Plasma concentrations and effects of warfarin or acenocoumarol are potentially increased or decreased by efavirenz.
Dose adjustment of warfarin or acenocoumarol may be required.
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 dose 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 dose adjustment is necessary for efavirenz. Patients should be monitored for seizure control.

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
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 dose 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 dose adjustment is necessary for efavirenz.
Paroxetine/efavirenz
(20 mg once daily/600 mg once daily)
No clinically significant pharmacokinetic interaction
No dose 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 dose adjustment is necessary for either medicinal product.
Norepinephrine and dopamine reuptake inhibitor
Bupropion/efavirenz
[150 mg single dose (sustained release)/600 mg once daily]
Bupropion:
AUC: ↓ 55% (↓ 48 to ↓ 62)
Cmax: ↓ 34% (↓ 21 to ↓ 47)
Hydroxybupropion:
AUC: ↔
Cmax: ↑ 50% (↑ 20 to ↑ 80)
(CYP2B6 induction)
Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. No dose adjustment is necessary for efavirenz.
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 dose 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)
Dose adjustments of diltiazem should be guided by clinical response (refer to the Summary of Product Characteristics for diltiazem). No dose adjustment is necessary for efavirenz.

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
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.
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 CoA 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 CoA reductase inhibitors:
AUC: ↓ 34% (↓ 21 to ↓ 41)
Cmax: ↓ 20% (↓ 2 to ↓ 26)
Cholesterol levels should be periodically monitored. Dose adjustment of atorvastatin may be required (refer to the Summary of Product Characteristics for atorvastatin). No dose 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. Dose adjustment of pravastatin may be required (refer to the Summary of Product Characteristics for pravastatin). No dose 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
Cholesterol levels should be periodically monitored. Dose adjustment of simvastatin may be required (refer to the Summary of Product Characteristics for simvastatin). No dose adjustment is necessary for efavirenz.

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 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.
Rosuvastatin/efavirenz
Interaction not studied. Rosuvastatin is largely excreted unchanged via the faeces, therefore interaction with efavirenz is not expected.
No dose 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
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).

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
IMMUNOSUPPRESSANTS
Immunosuppressants metabolized by CYP3A4 (e.g. 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.
NON-OPIOID ANALGESICS
Metamizole/efavirenz
Co-administration of efavirenz with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of efavirenz with potential decrease in clinical efficacy.
Therefore, caution is advised when metamizole and efavirenz.
are administered concurrently;
clinical response and/or drug levels should be monitored as appropriate.
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.
Concomitant administration with efavirenz should be avoided due to the risk for QTc prolongation (see section 4.3).
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.

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

Women of childbearing potential

See below and section 5.3. Efavirenz should not be used during pregnancy, unless the patient’s clinical condition requires such treatment. Women of childbearing potential should undergo pregnancy testing 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.

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.

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

Breast-feeding

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

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.

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

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein-bound, dialysis is unlikely to remove significant quantities of it from blood.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors. ATC code: J05AG03

Mechanism of action

Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or δ).

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).

Antiviral activity

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

Resistance

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild-type viral strains. The single substitutions which led to the highest resistance 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-fold resistance). 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 who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medicines used in combination with efavirenz.

Cross-resistance

Absorption

Peak efavirenz plasma concentrations of 1.6-9.1 microM were attained by 5 hours following single oral doses 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 suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3-5 hours) did not change 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 with 200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 microM (29%) [mean ± S.D. (% C.V.)], steady-state Cmin was 5.6 ± 3.2 microM (57%), and AUC was 184 ± 73 microM·h (40%).

Effect of food

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

Distribution

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

Biotransformation