| 2. Qualitative and quantitative composition
Each film‑coated tablet contains 600 mg of efavirenz.
Excipient: each film-coated tablet contains 249.6 mg of lactose monohydrate.
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 Ctrough 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 Ctrough 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 Ctrough 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, Cmin, 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 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 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 Cmin of carbamazepine decreased by 27%, 20% and 35%, respectively, while the steady-state AUC, Cmax and Cmin of efavirenz decreased by 36%, 21%, and 47%, respectively. The steady-state AUC, Cmax and Cmin 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/.
|
