Efferven

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFERVEN (EFFERVEN)

Composition:

Active substance: efavirenz;

1 tablet contains 600 mg of efavirenz;

Excipients: microcrystalline cellulose; sodium croscarmellose; hydroxypropylcellulose; sodium lauryl sulfate; lactose monohydrate; magnesium stearate;

Coating: Opadry Yellow 03B52874: (hypromellose, titanium dioxide (E 171), polyethylene glycol 400, iron oxide yellow (E 172), iron oxide red (E 172)).

Pharmaceutical form. Coated tablets.

Pharmacotherapeutic group.
Antiviral agents for systemic use. Non-nucleoside reverse transcriptase inhibitors. ATC code J05AG03.

Clinical characteristics.

Indications.

In combination with antiretroviral therapy for the treatment of diseases caused by human immunodeficiency virus (HIV-1) in adults and children with body weight ≥ 40 kg.

Contraindications.

• Hypersensitivity to the active substance or any of the excipients of the medicinal product.
• Severe hepatic impairment (Child-Pugh class C).
• Concomitant use with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine), as competition by efavirenz for CYP3A4 may lead to inhibition of metabolism of these drugs and predispose to severe and/or life-threatening adverse events (e.g., cardiac arrhythmias, prolonged sedative effects, or respiratory depression).
• Concomitant use with herbal products containing St. John's wort (Hypericum perforatum) due to the potential for decreased plasma concentrations and reduced clinical efficacy of efavirenz.

Administration and Dosage

Treatment must be prescribed only by a physician experienced in the management of HIV infection.

Concomitant antiretroviral therapy. Efavirenz is used in combination with other antiretroviral agents.

It is recommended to take Efavirenz on an empty stomach. Administration of Efavirenz with food has been shown to increase plasma concentrations of Efavirenz, which may lead to an increased incidence of adverse effects.

To improve tolerability of adverse events related to the central nervous system, it is recommended to take the medication at bedtime.

Adults. The recommended dose of Efavirenz in combination with nucleoside reverse transcriptase inhibitors, with or without a protease inhibitor, is 600 mg orally once daily.

Children. Efavirenz 600 mg tablets are recommended only for children with body weight ≥ 40 kg.

The recommended dose of efavirenz for children with body weight ≥ 40 kg is 600 mg once daily.

Children with body weight less than 40 kg should receive other pharmaceutical forms of efavirenz.

Dose adjustment: when Efavirenz is coadministered with voriconazole, the maintenance dose of the latter should be increased to 400 mg every 12 hours; the dose of Efavirenz should be reduced by 50%, e.g., to 300 mg once daily. Upon discontinuation of voriconazole therapy, the initial Efavirenz dosage should be restored.

When Efavirenz is coadministered with rifampicin in patients weighing 50 kg or more, it is recommended to increase the Efavirenz dose to 800 mg once daily. To achieve the appropriate dosage, Efavirenz in another pharmaceutical form should be prescribed.

Renal impairment: The pharmacokinetics of efavirenz in patients with renal impairment has not been studied. However, since less than 1% of efavirenz is excreted unchanged in urine, impaired renal function is not expected to significantly affect efavirenz elimination.

Hepatic disease: Patients with mild to moderate hepatic impairment may receive the standard recommended dose of efavirenz. Patients should be closely monitored for drug-related adverse events, particularly symptoms related to the central nervous system.

Adverse Reactions

Nervous system disorders: pathological dreams, attention disorder, dizziness, headache, insomnia, somnolence, feelings of anxiety, amnesia, ataxia, coordination disturbances, confusion, convulsions, pathological thinking, tremor, hot flushes.

Symptoms related to the nervous system usually occur during the first or second day of therapy and in most cases resolve within the first 2–4 weeks. These symptoms may occur more frequently when efavirenz is taken with food, possibly due to increased plasma concentrations of efavirenz. To improve tolerability of these symptoms, the drug should be taken at bedtime during the first weeks of therapy. This dosing schedule is also recommended for patients in whom these symptoms persist. Dose reduction or divided daily dosing generally does not provide beneficial effects.

Eye disorders: blurred vision.

Ear and labyrinth disorders: vertigo, tinnitus.

Gastrointestinal disorders: abdominal pain, diarrhea, nausea, vomiting, pancreatitis.

Skin and subcutaneous tissue disorders: rash, pruritus, exudative multiform erythema, Stevens-Johnson syndrome. Maculopapular rashes of mild to moderate severity are usually observed within the first 2 weeks after initiation of efavirenz therapy. In most patients, the rash resolves with continued efavirenz administration within 1 month. Reinitiation of efavirenz may be considered in patients who previously discontinued the drug due to rash. When reinitiating efavirenz, concomitant administration of appropriate antihistamines and/or corticosteroids is recommended.

General disorders: increased fatigue.

Immune system disorders: allergic reactions.

Hepatobiliary disorders: acute hepatitis.

Reproductive system disorders: gynecomastia.

Psychiatric disorders: anxiety, depression, affective lability, aggression, euphoric mood, hallucinations, mania, paranoia, suicide attempts, suicidal ideation.

Patients with a history of psychiatric disorders are at increased risk of developing severe psychiatric adverse events, with incidence rates ranging from 0.3% for manic reactions to 2% for severe depression and suicidal ideation. There are also reports of suicide, delusions, and psychosis-like behavior.

Immune Reconstitution Inflammatory Syndrome (IRIS): in HIV-infected patients with advanced immune deficiency, initiation of combination antiretroviral therapy (cART) may lead to an inflammatory response against asymptomatic or residual opportunistic pathogens.

Lipodystrophy and metabolic disturbances: combination antiretroviral therapy is considered to cause redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and fat accumulation in the dorsocervical region (buffalo hump).

Combination antiretroviral therapy has also been associated with metabolic disturbances such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia.

Osteonecrosis: cases of osteonecrosis have been reported, particularly in patients with well-known risk factors, AIDS, or those on long-term cART. The frequency of occurrence is unknown.

Laboratory abnormalities: elevated AST and ALT activities, increased γ-glutamyl transferase (GGT) levels. Isolated elevation of GGT in patients receiving efavirenz may indicate enzyme induction. Asymptomatic increases in serum amylase concentrations, as well as elevated levels of total cholesterol, high-density lipoprotein cholesterol, and triglycerides, have been observed. The magnitude of lipid level changes may be influenced by factors such as duration of treatment and other components of the antiretroviral regimen.

The clinical significance of asymptomatic elevation of serum amylase concentrations is unknown.

Interaction with cannabinoid testing: efavirenz does not bind to cannabinoid receptors; however, there have been reports of false-positive urine cannabinoid test results in non-infected volunteers treated with efavirenz. False-positive results were observed only with the CEDIA DAU Multi-Level THC assay used for screening and were not observed with other cannabinoid tests, including confirmatory assays.

Additional adverse events observed in clinical trials in patients receiving combination antiretroviral therapy including efavirenz were delusions, liver failure, neurosis, photoallergic dermatitis, psychosis, and suicide.

Pediatric population: adverse events in children are generally similar to those in adults. Rash occurs more frequently and tends to be more severe in children than in adults. Prophylactic administration of appropriate antihistamines prior to starting efavirenz therapy in children may be beneficial to prevent rash. Although young children may have difficulty describing neurological symptoms, such events occur less frequently in children and are mostly of moderate severity. In clinical studies, moderate-intensity neurological symptoms, primarily dizziness, were observed. Severe symptoms were not reported in any child, and discontinuation of the drug due to neurological symptoms was not required in any case.

Overdose

In some patients who accidentally took 600 mg twice daily, an increase in nervous system-related symptoms was observed. One patient experienced involuntary muscle contractions.

Treatment: In case of efavirenz overdose, treatment should consist of general supportive measures, including monitoring of vital signs and clinical observation of the patient. Activated charcoal may be used to eliminate unabsorbed drug. There is no specific antidote. Because efavirenz is highly protein-bound, dialysis is unlikely to remove a significant amount of the drug from the blood.

Use during pregnancy or breastfeeding

Pregnancy

Women taking efavirenz must avoid pregnancy. Barrier contraception should always be used in combination with other contraceptive methods (e.g., oral or hormonal contraceptives). Women of reproductive age should undergo a pregnancy test before starting efavirenz. Efavirenz must not be used during pregnancy except when no alternative treatment options are available.

Breastfeeding

Study data indicate that efavirenz may be excreted in breast milk; therefore, women taking Efavirenz during lactation are advised to discontinue breastfeeding. Some experts believe that HIV-infected mothers should never breastfeed to avoid transmission of HIV.

Pediatric use

The drug in this pharmaceutical form is indicated for children with body weight ≥ 40 kg.

Special precautions.

There are insufficient clinical data on the use of Efaviren in patients with advanced HIV infection, specifically in patients with CD4 cell counts < 50 cells/mm³, as well as in cases of protease inhibitor therapy failure. Cross-resistance between efavirenz and protease inhibitors has not been observed; however, there are currently insufficient data on the efficacy of protease inhibitor-based combination therapy after lack of clinical response to combination therapy containing efavirenz.

Efaviren should not be used as a single agent for the treatment of HIV infection, nor should it be added as a single agent to an ineffective regimen. As with other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges very rapidly when efavirenz is used as monotherapy. When selecting a new antiretroviral agent to be used in combination with efavirenz, potential cross-resistance of the virus should be taken into account.

When prescribing other medicinal products concomitantly with Efaviren, physicians should refer to the instructions for use of these products.

Patients should be informed that antiretroviral therapy they are receiving, including efavirenz, does not prevent the risk of HIV transmission through sexual contact or blood. Patients should continue to use appropriate preventive measures.

In cases where administration of any other antiretroviral drug within combination therapy is discontinued due to suspected intolerance, careful consideration should be given to discontinuing all antiretroviral drugs simultaneously. All discontinued antiretroviral drugs should be resumed immediately after disappearance of intolerance symptoms. Intermittent immunotherapy with repeated re-administration of antiretroviral drugs is not recommended due to increased risk of emergence of mutant viruses resistant to therapy.

Psychiatric symptoms

Serious psychiatric adverse effects have been reported in patients receiving efavirenz treatment for more than 1.5 years: severe depression, suicidal thoughts, non-fatal suicide attempts, aggressive behavior, paranoid reactions, manic reactions. There have also been isolated reports of suicides, delirium, and psychosis-like behavior. Patients experiencing serious psychiatric adverse symptoms require immediate medical evaluation to assess the possible association of these symptoms with efavirenz use. If such an association is confirmed, it should be determined whether the risk of continuing therapy outweighs the benefit of treatment.

Neurological symptoms

Adverse effects on the central nervous system have been reported: dizziness, insomnia, difficulty concentrating, somnolence, abnormal dreams, and hallucinations. These symptoms usually begin on the first or second day of treatment and resolve completely within the first 2–4 weeks of therapy. Patients should be informed that these common symptoms usually diminish with continued therapy and are not a harbinger of the later development of rarer psychiatric symptoms. Taking the drug before bedtime may improve tolerance of these neurological symptoms.

Patients receiving efavirenz should be warned about possible additive effects on the central nervous system when efavirenz is taken concomitantly with alcohol or psychotropic drugs.

Seizures: seizures have been reported very rarely in patients receiving efavirenz therapy, mostly in patients with a history of seizures. Patients taking concomitant anticonvulsant drugs predominantly metabolized in the liver, such as phenytoin, carbamazepine, and phenobarbital, should undergo periodic monitoring of plasma concentrations. In interaction studies, plasma concentrations of carbamazepine decreased when co-administered with efavirenz. Efavirenz should be prescribed with caution in patients with a history of seizures.

Lipid levels

Efavirenz treatment has led to increased concentrations of total cholesterol and triglycerides. Cholesterol and triglyceride levels should be analyzed before initiation of efavirenz therapy and periodically during therapy.

Immune reconstitution syndrome

Immune reconstitution syndrome has been reported in patients receiving combination antiretroviral therapy, including efavirenz. In the initial phase of combination antiretroviral therapy, patients whose immune system responds to treatment may develop an inflammatory reaction to latent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii-induced pneumonia, or tuberculosis), which may require further evaluation and treatment.

Fat redistribution

Redistribution/accumulation of body fat, including central obesity, fat deposition in the dorsocervical region (buffalo hump), peripheral fat wasting, facial lipoatrophy, breast enlargement, and Cushingoid appearance, has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Osteonecrosis

Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have been reported most frequently in patients with advanced stages of HIV disease and/or prolonged exposure to combination antiretroviral therapy (cART).

Rashes

The drug is not recommended for patients who previously experienced a life-threatening skin reaction (e.g., Stevens-Johnson syndrome).

Skin rashes associated with blistering, moist desquamation, and ulceration may occur.

Typically, maculopapular rash of mild to moderate severity develops within the first 2 weeks after initiation of efavirenz therapy. In most patients, the rash resolves within 1 month (mean duration – 16 days) if efavirenz treatment is continued. Patients who interrupted therapy due to rash may resume efavirenz. Efavirenz should be discontinued in patients who develop severe rash associated with blistering, peeling, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve tolerance and accelerate resolution of the rash.

Food intake: administration of Efaviren with food may lead to increased elimination time of the drug, which in turn may lead to increased frequency of adverse effects. Efaviren should be taken on an empty stomach, preferably before bedtime.

Liver disease: since efavirenz metabolism occurs primarily via the cytochrome P450 system, and due to limited clinical experience with the drug in patients with chronic liver disease, efavirenz should be prescribed with caution in patients with mild to moderate liver disease. Close monitoring for adverse events related to drug use, particularly neurological symptoms, is required. Liver function should be periodically assessed by laboratory tests.

The safety and efficacy of efavirenz in patients with severe liver function impairment have not been established. Efavirenz is contraindicated in patients with severe liver function impairment. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at increased risk of developing severe and potentially life-threatening hepatic adverse events. In patients with a history of liver function abnormalities, including chronic active hepatitis, the frequency of liver function disturbances during combination antiretroviral therapy is significantly increased; therefore, monitoring according to current practice is required. If signs of worsening liver condition occur or serum transaminase activity persistently exceeds the upper limit of normal by more than 5 times, the potential benefit of continuing efavirenz therapy versus the potential risk of serious hepatotoxic injury should be carefully weighed. For such patients, interruption or discontinuation of treatment should be considered.

In patients taking other drugs with hepatotoxic effects, monitoring of liver enzyme activity is also recommended. In cases of concomitant antiviral therapy for hepatitis B or C, refer to the appropriate information for these drugs.

Renal impairment: the pharmacokinetics of efavirenz in patients with renal impairment have not been studied; however, since less than 1% of efavirenz is excreted unchanged in urine, renal impairment is not expected to significantly affect efavirenz elimination. There is no experience with the use of the drug in patients with severe renal impairment; therefore, careful safety assessment is recommended in such patients.

Elderly patients: no studies have been conducted.

Efavirenz tablets, film-coated, are not used in patients with rare hereditary conditions: galactose intolerance or glucose-galactose malabsorption (Lapp's disease). Patients with these conditions may take the efavirenz oral solution, which does not contain lactose.

Potential risk to the reproductive system

Pregnancy. Category D: efavirenz may cause fetal harm when used during the first trimester of pregnancy. Pregnancy should be avoided in women receiving efavirenz. Barrier contraception should always be used in combination with other contraceptive methods (e.g., oral or other hormonal contraceptives). Due to the long half-life of efavirenz, adequate contraceptive measures are recommended for 12 weeks after discontinuation of efavirenz. Women of reproductive age should undergo a pregnancy test before starting efavirenz. If this drug is used during the first trimester of pregnancy or if a patient becomes pregnant while taking this drug, she should be informed about the potential risk to the fetus.

Efavirenz may be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus, particularly in the absence of other therapeutic options.

Ability to influence reaction speed when driving or operating machinery.

No special studies have been conducted to assess the possible effect of efavirenz on the ability to drive or operate machinery. Efavirenz may cause dizziness, reduced concentration, and/or somnolence. If such symptoms occur, patients should refrain from driving or operating machinery.

Interaction with other medicinal products and other types of interactions.

Efavirenz is an inducer of CYP3A4 and CYP2B6. When efavirenz is used concomitantly with other drugs that are substrates of CYP3A4 and CYP2B6, decreased plasma concentrations of these drugs may occur. Changes in efavirenz action may also occur when used concomitantly with drugs or food products affecting CYP3A4 activity (e.g., grapefruit juice).

Efavirenz should not be used concomitantly with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine).

Concomitant antiretroviral agents

Protease inhibitors

Ampranavir: when efavirenz is used in combination with amprenavir (600 mg twice daily) and ritonavir (100 or 200 mg twice daily), dose adjustment is not required. Additionally, when efavirenz is used concomitantly with amprenavir and nelfinavir, dose adjustment for either drug is also not required. The use of efavirenz in combination with amprenavir and saquinavir is not recommended, as the efficacy of both protease inhibitors may be significantly reduced. Regarding the use of amprenavir in combination with another protease inhibitor and efavirenz in children and patients with renal impairment, no dosage recommendations can be given.

Such combinations should be avoided in patients with liver function impairment.

Atazanavir: concomitant use of efavirenz and atazanavir in combination with ritonavir may lead to enhanced efavirenz elimination, which may worsen the tolerability profile of efavirenz. The use of efavirenz 600 mg with atazanavir in combination with low-dose ritonavir leads to a significant reduction in atazanavir exposure, requiring atazanavir dose adjustment.

Indinavir: dose adjustment of efavirenz when indinavir or indinavir/ritonavir is prescribed is not required. For co-administration of efavirenz with low-dose ritonavir in combination with protease inhibitors, see below.

LoPINAVIR/ritonavir: in combination therapy with efavirenz and two nucleoside reverse transcriptase inhibitors, lopinavir/ritonavir dosing of 533/133 mg twice daily showed similar lopinavir plasma concentrations compared to lopinavir/ritonavir 400/100 mg twice daily without efavirenz. When used concomitantly with efavirenz, lopinavir/ritonavir doses may need to be increased by 33% (4 capsules/6.5 mL twice daily instead of 3 capsules/5 mL twice daily). Dose adjustment should be performed with particular caution, as dose increase may be contraindicated in some patients. For co-administration of efavirenz with low-dose ritonavir in combination with protease inhibitors, see below.

Nelfinavir: when used in combination with efavirenz, the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of nelfinavir increased by 20% and 21%, respectively. In most cases, this combination was well tolerated. Dose adjustment is not required when efavirenz is prescribed in combination with nelfinavir.

Ritonavir: concomitant use of efavirenz and ritonavir at doses of 500 mg or 600 mg twice daily was associated with poor tolerability (dizziness, nausea, paresthesia, and increased liver enzyme activity were observed). Data on tolerability of efavirenz in combination with low-dose ritonavir (100 mg twice daily) are lacking. When efavirenz is used in regimens including low-dose ritonavir, possible increased incidence of adverse events associated with efavirenz due to potential pharmacodynamic interaction should be considered.

Saquinavir: when saquinavir (1200 mg three times daily in soft capsules) was used in combination with efavirenz, AUC and Cmax of saquinavir decreased by 62% and 50%, respectively. Using efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.

Saquinavir/ritonavir: data on possible interaction between efavirenz and the combination of saquinavir + ritonavir are lacking. For co-administration of efavirenz with low-dose ritonavir in combination with protease inhibitors, see above.

Nucleoside reverse transcriptase inhibitors: studies evaluating interaction between efavirenz and the combination of zidovudine + lamivudine were conducted in HIV-infected patients. No clinically significant pharmacokinetic interactions were observed. Specific studies evaluating interactions between efavirenz and other nucleoside reverse transcriptase inhibitors have not been conducted. Clinically significant pharmacokinetic interactions are not expected, as the metabolic pathway of nucleoside reverse transcriptase inhibitors differs from that of efavirenz, making competition for the same metabolic enzymes and elimination pathways unlikely.

Non-nucleoside reverse transcriptase inhibitors: studies evaluating efavirenz use in combination with other non-nucleoside reverse transcriptase inhibitors have not been conducted; therefore, data on possible pharmacokinetic or pharmacodynamic interactions are lacking.

Antimicrobial agents

Rifampicin: in non-infected volunteers, rifampicin reduced efavirenz AUC by 26% and Cmax by 20%. In patients with body weight of 50 kg or more receiving efavirenz concomitantly with rifampicin, efavirenz dose should be increased to 800 mg once daily. Dose adjustment of rifampicin is not required when used concomitantly with efavirenz. In one study involving non-infected volunteers, efavirenz caused a reduction in AUC and Cmax of rifabutin by 32% and 38%, respectively. Rifabutin had no significant effect on efavirenz pharmacokinetics. Based on these data, it can be concluded that the daily dose of rifabutin should be increased by 50% when used concomitantly with efavirenz, and the dose of rifabutin may be doubled in regimens where rifabutin is administered two or three times weekly in combination with efavirenz.

Macrolide antibiotics

Azithromycin: concomitant administration of single doses of azithromycin and multiple doses of efavirenz in non-infected volunteers did not result in any clinically significant pharmacokinetic interaction. Dose adjustment is not required when azithromycin is prescribed in combination with efavirenz.

Clarithromycin: concomitant use of 400 mg efavirenz once daily and clarithromycin 500 mg every 12 hours for 7 days showed a significant effect of efavirenz on clarithromycin pharmacokinetics. When used concomitantly with efavirenz, AUC and Cmax of clarithromycin decreased by 39% and 26%, respectively, while AUC and Cmax of the active dihydroxy metabolite of clarithromycin increased by 34% and 49%, respectively. The clinical significance of these changes in clarithromycin plasma concentrations is not established. Skin rashes occurred in 46% of non-infected volunteers receiving the combination of efavirenz and clarithromycin. Dose adjustment of efavirenz is not required when clarithromycin is prescribed concomitantly. Alternative agents to clarithromycin may be considered.

The use of other macrolide antibiotics, such as erythromycin, in combination with efavirenz has not been studied.

Antifungal agents

Voriconazole: concomitant administration of efavirenz (400 mg daily orally) and voriconazole (200 mg twice daily orally) to non-infected volunteers resulted in two types of interaction. AUC and Cmax of voriconazole decreased by an average of 77% and 61%, respectively, while in the second case, AUC and Cmax of efavirenz increased by an average of 44% and 38%, respectively. Concomitant administration of efavirenz and standard doses of voriconazole is contraindicated.

Furthermore, concomitant administration of efavirenz (300 mg daily orally) and voriconazole (200 mg twice daily orally) to non-infected volunteers resulted in a 7% decrease in AUC and a 23% increase in Cmax of voriconazole compared to administration of 200 mg voriconazole twice daily alone. The differences were not considered clinically significant. AUC of efavirenz increased by 17%, and Cmax was equivalent to that observed with 600 mg efavirenz daily alone.

When efavirenz is prescribed with voriconazole, the maintenance dose of voriconazole should be increased to 400 mg twice daily, and the efavirenz dose should be reduced by 50%, i.e., to 300 mg daily. When voriconazole treatment is discontinued, the original efavirenz dose should be restored.

itraconazole: concomitant administration of efavirenz (600 mg daily orally) with itraconazole (200 mg orally every 12 hours) to non-infected volunteers resulted in a decrease in AUC, Cmax, and Cmin of itraconazole by 39%, 37%, and 44%, respectively, and of hydroxyitraconazole by 37%, 35%, and 43%, respectively, compared to administration of itraconazole alone. The pharmacokinetics of efavirenz were not altered. Since no dosage recommendations for itraconazole have been established, alternative therapy should be considered.

Other antifungal agents: when fluconazole and efavirenz were administered concomitantly to non-infected volunteers, no clinically significant pharmacokinetic interactions were observed. Possible interactions between efavirenz and other antifungal agents of the imidazole class, such as ketoconazole, have not been studied.

Antacids/famotidine: antacids containing aluminum hydroxide or magnesium, and famotidine, did not alter efavirenz absorption in non-infected volunteers. Based on these data, changes in gastric pH due to other medicinal products are unlikely to affect efavirenz absorption.

Anticonvulsants

Carbamazepine: concomitant administration of efavirenz (600 mg orally once daily) and carbamazepine (400 mg once daily) to non-infected volunteers resulted in two types of interaction. AUC, Cmax, and Cmin of carbamazepine decreased by 27%, 20%, and 35%, respectively, while AUC, Cmax, and Cmin of efavirenz decreased by 36%, 22%, and 47%, respectively. AUC, Cmax, and Cmin of the active carbamazepine metabolite epoxide remained unchanged. Plasma levels of carbamazepine should be monitored periodically. There are no data on concomitant use of high doses of the drug. Thus, there are no dosage recommendations, and alternative therapy should be considered.

Other anticonvulsants: data on possible interaction between efavirenz and phenytoin, phenobarbital, or other anticonvulsants metabolized by CYP450 enzymes are lacking. When these drugs are prescribed concomitantly with efavirenz, there is a possibility of decreased or increased plasma concentrations of each drug; therefore, periodic monitoring of plasma concentrations is necessary. Specific studies on interaction between efavirenz and vigabatrin or gabapentin have not been conducted. Clinically significant interactions are not expected, as vigabatrin and gabapentin are excreted unchanged in urine and are unlikely to share the same elimination pathways as efavirenz.

Drugs lowering lipid levels

Concomitant administration of efavirenz and HMG-CoA reductase inhibitors—atorvastatin, pravastatin, or simvastatin—resulted in decreased plasma concentrations of statins in healthy volunteers. Cholesterol levels should be monitored periodically. Dose adjustment of statins may be recommended (see instructions for use of these drugs).

Atorvastatin: concomitant administration of efavirenz (600 mg orally once daily) and atorvastatin (10 mg orally once daily) in healthy volunteers resulted in a decrease in AUC and Cmax of atorvastatin by 43% and 12%, respectively, 2-hydroxyatorvastatin by 35% and 13%, 4-hydroxyatorvastatin by 4% and 47%, and total HMG-CoA reductase inhibitory activity by 34% and 20%, respectively, compared to atorvastatin alone.

Pravastatin: concomitant use of efavirenz (600 mg orally once daily) and pravastatin (40 mg orally once daily) in healthy volunteers resulted in a decrease in AUC and Cmax of atorvastatin by 40% and 18%, respectively, compared to pravastatin alone.

Simvastatin: concomitant use of efavirenz (600 mg orally once daily) and simvastatin (40 mg orally once daily) in healthy volunteers resulted in a decrease in AUC and Cmax of atorvastatin by 69% and 76%, respectively, simvastatin acid by 58% and 51%, and total HMG-CoA reductase inhibitory activity by 60% and 70%, respectively, compared to simvastatin alone.

Concomitant use of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect AUC or Cmax levels. There is no need for dose adjustment of efavirenz.

Other interactions

Antacids/famotidine: neither antacids containing aluminum hydroxide/magnesium nor famotidine affected efavirenz absorption in healthy volunteers. These data indicate that changes in gastric acidity due to other medicinal products should not affect efavirenz absorption.

Oral contraceptives: the only component of oral contraceptives studied was ethinylestradiol. AUC after a single dose of ethinylestradiol increased (by 37%) after multiple doses of efavirenz. No significant changes in Cmax of ethinylestradiol were observed. The clinical significance of these effects is unknown. No effect on Cmax or AUC of efavirenz was observed after a single dose of ethinylestradiol. Possible interaction between efavirenz and oral contraceptives has not been sufficiently studied; therefore, in addition to oral contraceptives, patients should use other reliable barrier methods of contraception.

Methadone: in a study of HIV-infected patients who used intravenous drugs, concomitant administration of efavirenz and methadone resulted in decreased methadone plasma concentrations and symptoms of opioid withdrawal. To alleviate withdrawal symptoms, the methadone dose was increased by an average of 22%. Patients should be monitored for withdrawal symptoms, and if necessary, their methadone dose may be increased to alleviate symptoms.

St. John's wort (Hypericum perforatum): see section "Contraindications".

Antidepressants: when paroxetine and efavirenz were used concomitantly, no clinically significant changes in pharmacokinetic parameters were observed. Dose adjustment of these drugs is not required when paroxetine is used in combination with efavirenz. Fluoxetine has a metabolic profile similar to paroxetine, namely, it is a strong inhibitor of CYP2D6; therefore, interaction between fluoxetine and efavirenz is unlikely. Sertraline, a substrate of CYP3A4, does not significantly affect the pharmacokinetics of efavirenz. Efavirenz, in turn, reduces Cmax, C24, and AUC of sertraline by 28.6% to 46.3%. Sertraline dose increase should be performed with monitoring of clinical response.

Cetirizine: the H1-histamine receptor blocker did not have a clinically significant effect on efavirenz pharmacokinetic parameters. Efavirenz reduces cetirizine Cmax by 24% but does not alter cetirizine AUC. These changes are not clinically significant. Dose adjustment of these drugs is not required when efavirenz and cetirizine are used concomitantly.

Lorazepam: efavirenz increases Cmax and AUC of lorazepam by 16.3% and 7.3%, respectively. These changes are not clinically significant. Dose adjustment of these drugs is not required when efavirenz and lorazepam are prescribed concomitantly.

Calcium channel blockers: concomitant administration of efavirenz (600 mg orally once daily) and diltiazem (240 mg orally once daily) to non-infected volunteers resulted in decreases in AUC, Cmax, and Cmin of diltiazem by 69%, 60%, and 63%, respectively; decreases in AUC, Cmax, and Cmin of deacetyl-diltiazem by 75%, 64%, and 62%, respectively; and decreases in AUC, Cmax, and Cmin of N-demethyl-diltiazem by 37%, 28%, and 37%, respectively, compared to diltiazem alone. Dose adjustment of diltiazem should be based on clinical response (see diltiazem prescribing information).

Although efavirenz pharmacokinetic parameters were slightly reduced (11–16%), these changes are not considered clinically significant; therefore, no dose adjustment of efavirenz is needed when used with diltiazem.

There are no data on possible interaction between efavirenz and other calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, felodipine, nifedipine, nicardipine). When efavirenz is prescribed with one of these drugs, decreased plasma concentrations of calcium channel blockers are possible. Dose adjustment of diltiazem should be based on clinical response (see prescribing information for calcium channel blockers).

Bupropion and acenocoumarol: concomitant administration of efavirenz (600 mg orally once daily) with bupropion (single 150 mg dose of sustained-release formulation) to non-infected volunteers reduced AUC and Cmax of bupropion by 55% and 34%, respectively, compared to bupropion alone. AUC of hydroxybupropion was unchanged, while Cmax of hydroxybupropion increased by 50%. The effect of efavirenz on bupropion exposure is believed to occur via stimulation of bupropion metabolism. Bupropion dose adjustment should be based on clinical response, but the maximum recommended bupropion dose should not be exceeded. No dose adjustment of efavirenz is required.

Warfarin or acenocoumarol: efavirenz may potentially increase or decrease plasma concentrations and effects.

Drug interaction studies were conducted only in adult patients.

Pharmacological Properties.

Pharmacodynamics. Efavirenz is an antiviral agent, a non-nucleoside reverse transcriptase inhibitor, active against human immunodeficiency virus type 1 (HIV-1). The drug's mechanism of action involves competitive inhibition of nucleosides and nucleoside triphosphates.

Pharmacokinetics.

Absorption. Maximum efavirenz concentration in blood plasma at the level of 1.6–1.9 µM is reached approximately 5 hours after oral administration of single doses ranging from 00 to 1600 mg. Increases in C_max and AUC associated with dose escalation are observed up to 1600 mg; increases in C_max and AUC with dose escalation from 200 to 400 and 600 mg are proportional. At doses exceeding 600 mg per day, increases are no longer proportional, indicating reduced absorption efficiency.

The time to reach C_max in plasma (3–5 hours) remains unchanged with repeated dosing, and steady-state plasma concentrations are achieved within 6–7 days. Administration of any dose with food increases C_max and AUC compared to administration of the same dose on an empty stomach.

Distribution. The drug is highly bound to plasma proteins (primarily albumin), with a binding rate of 99.5–99.75%. It is mainly metabolized by the cytochrome P450 system into hydroxylated metabolites, which are subsequently glucuronidated. The primary isoenzymes responsible for metabolism are CYP3A4 and CYP2B6. Efavirenz exerts direct effects on cytochrome P450 isoenzymes: it inhibits CYP2C9, 2C19, and 3A4, and at concentrations significantly higher than therapeutic levels, it also inhibits CYP2D6 and CYP1A2. It induces CYP2E1 and CYP3A4, which in turn leads to accelerated auto-metabolism.

Elimination. Efavirenz has a relatively long elimination half-life—52–76 hours after a single dose and 40–50 hours after multiple doses. Approximately 14–34% is excreted in urine as metabolites (1% unchanged) and 16–34% in feces.

In patients with severe hepatic impairment, elimination half-life is prolonged, which may lead to greater accumulation.

In pediatric patients, the pharmacokinetics of efavirenz are similar to those in adults. In children receiving a dose equivalent to the adult dose of 600 mg (dose adjusted according to body weight), steady-state C_max was 14.1 µM, C_min was 5.6 µM, and AUC was 216 µM·h.

Pharmaceutical Characteristics.

Basic physicochemical properties: peach-colored, capsule-shaped, biconvex tablets coated with an enteric coating, imprinted with "RC68" on one side.

Shelf life: 36 months.

Storage Conditions.

Store in a dry, child-resistant place at a temperature not exceeding 25 °C.

Packaging.

30 tablets per bottle.

Prescription Category. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Address.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.