Stocrin^® (Tablets, Capsules) Instructions for Use

ATC Code

J05AG03 (Efavirenz)

Active Substance

Efavirenz (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Mechanism of action

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

Antiviral activity

The antiviral efficacy of efavirenz in vitro was evaluated in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. The inhibitory concentration (IC) of efavirenz required for 90-95% inhibition (IC_90-95) of wild-type strains or laboratory clinical isolates resistant to zidovudine ranges from 0.46 to 6.8 nmol/L.

Resistance

The antiviral efficacy of efavirenz in cell culture against virus variants with amino acid substitutions in reverse transcriptase at positions 48, 108, 179, 181, or 236, as well as against variants with amino acid substitutions in protease, was similar to that against wild-type viral strains. The only substitutions that led to the greatest resistance to efavirenz in cell culture are the substitution of leucine for isoleucine at position 100 (L100I, 17-22-fold increase in resistance) and lysine for asparagine at position 103 (K103N, 18-33-fold increase in resistance). A more than 100-fold decrease in virus susceptibility to the drug was observed for HIV variants expressing the K103N substitution in addition to other amino acid substitutions in reverse transcriptase.

The K103N substitution was the most frequently observed substitution in the reverse transcriptase of viral strains obtained from patients who experienced a significant increase in plasma viral load (rebound viremia) in clinical studies of efavirenz in combination with indinavir or in combination with zidovudine and lamivudine. This mutation was observed in 90% of patients with efavirenz therapy failure. Also, although less frequently and often only in combination with K103N, substitutions in reverse transcriptase at positions 98, 100, 101, 108, 138, 188, 190, and 225 were observed. The type of amino acid substitutions in reverse transcriptase associated with resistance to efavirenz did not depend on other antiviral drugs used in combination with efavirenz.

Cross-resistance

Studies of cross-resistance profiles of efavirenz, nevirapine, and delavirdine in cell cultures have shown that the K103N substitution leads to loss of susceptibility to all three nucleoside reverse transcriptase inhibitors. Two of the three delavirdine-resistant clinical isolates studied had cross-resistance to efavirenz and contained the K103N substitution. The third isolate, which had a substitution in reverse transcriptase at position 236, did not have cross-resistance to efavirenz.

Viral isolates from peripheral blood mononuclear cells of patients enrolled in clinical studies of efavirenz who experienced therapy failure (increase in viral load) were investigated for susceptibility to NNRTIs. Thirteen isolates that were preliminarily characterized as resistant to efavirenz were also resistant to nevirapine and delavirdine. Five of these NNRTI-resistant isolates were found to contain the K103N substitution or a valine to isoleucine substitution at position 108 (V108I) in reverse transcriptase. Among the isolates tested after efavirenz therapy failure, three isolates remained sensitive to efavirenz in cell cultures and also had sensitivity to nevirapine and delavirdine.

The likelihood of cross-resistance between efavirenz and protease inhibitors is low due to different target enzymes. The presence of cross-resistance between efavirenz and nucleoside reverse transcriptase inhibitors is also unlikely due to different target binding sites and different mechanisms of action.

Pharmacokinetics

Absorption

In healthy volunteers, the C_max of efavirenz in plasma at a level of 1.6-9.1 µmol/L was reached 5 hours after a single oral dose of the drug in doses from 100 mg to 1600 mg. A dose-dependent increase in C_max and AUC was noted when taking the drug in doses up to 1600 mg; however, no dose-proportional increase in these indicators was observed, so it can be assumed that absorption decreases at higher doses. The time to reach C_max in plasma (3-5 hours) did not change after multiple doses of the drug, and the equilibrium concentration in plasma was reached after 6-7 days.

In HIV-infected patients, upon reaching the equilibrium concentration of the drug in plasma, the mean values of C_max, C_min and AUC were linear when taking 200 mg, 400 mg and 600 mg of efavirenz once daily. In 35 patients taking Efavirenz at a dose of 600 mg once daily, the C_max at steady state was 12.9±3.7 µmol/L, C_min – 5.6±3.2 µmol/L, AUC – 184±73 µmol/L/h.

Effect of food on absorption

When healthy volunteers took a single dose of efavirenz 600 mg as film-coated tablets with a high-fat meal, there was an increase in AUC by 28% and C_max by 79% compared to these indicators when taking the drug on an empty stomach.

Distribution

Efavirenz is highly bound to plasma proteins (approximately 99.5-99.75%), primarily to albumin. In HIV-1 infected patients (n=9) who received Efavirenz at doses from 200 to 600 mg once daily for at least one month, the concentration of the drug in the cerebrospinal fluid ranged from 0.26 to 1.19% (on average 0.69%) of the corresponding plasma concentration. This figure is approximately 3 times higher than the concentration of the unbound (free) fraction of efavirenz in plasma.

Metabolism

Clinical studies and in vitro studies using human liver microsomes have shown that Efavirenz is metabolized primarily by the cytochrome P450 system to hydroxylated derivatives, which are then conjugated with glucuronic acid to form glucuronides. These metabolites are mostly inactive against HIV-1. In vitro studies suggest that the CYP3A4 and CYP2B6 isoenzymes are the main isoenzymes that metabolize efavirenz. In vitro studies have shown that Efavirenz at concentrations corresponding to those in plasma inhibits the 2C9, 2C19 and 3A4 isoenzymes of the cytochrome P450 system. In in vitro studies, Efavirenz did not inhibit the CYP2E1 isoenzyme and inhibited the CYP2D6 and CYP1A2 isoenzymes only at concentrations much higher than those in clinical practice.

Plasma exposure to efavirenz may be increased in patients homozygous for the G516T gene polymorphism of the CYP2B6 isoenzyme. The clinical significance of this change is unknown, but the possibility of an increased risk of development and increased severity of adverse reactions to efavirenz cannot be ruled out.

Efavirenz has been shown to induce CYP3A4 and CYP2B6 isoenzymes, leading to induction of its own metabolism, which may be clinically expressed in some patients. When healthy volunteers took multiple doses of efavirenz at a dose of 200-400 mg/day for 10 days, a lower degree of accumulation of efavirenz was observed (22-42% lower than the expected values) and a shorter T_1/2 – 40-55 hours (T_1/2 of a single dose is 52-76 hours). Efavirenz has also been shown to induce the 1A1 isoform of uridine diphosphate glucuronosyltransferase (UDP-GT1A1), so the plasma concentration of raltegravir**, which is a substrate of UDP-GT1A1, decreases when used concomitantly with efavirenz.

Although in vitro studies Efavirenz inhibited CYP2C9 and CYP2C19 isoenzymes, in vivo studies observed both an increase and a decrease in the exposure of substrates of these enzymes when used concomitantly with efavirenz. The final effect of this interaction has not been established.

Excretion

Efavirenz has a relatively long T_1/2, which is less than 52 hours after a single dose and 40-55 hours after multiple doses. Approximately 14-34% of the administered dose of efavirenz is excreted by the kidneys, less than 1% of the dose of efavirenz is excreted by the kidneys unchanged.

Pharmacokinetics in special patient groups

Impaired liver function

A twofold increase in the T_1/2 of efavirenz was observed in one patient with severe hepatic impairment (Child-Pugh class C) after a single dose of the drug, indicating an increased degree of accumulation in such cases. In multiple doses of the drug, no significant effect of liver damage on the pharmacokinetics of efavirenz was detected in patients with mild hepatic impairment (Child-Pugh class A) compared with patients in the control group. There are currently insufficient data to conclude whether moderate and severe hepatic impairment (Child-Pugh class B and C) affect the pharmacokinetics of efavirenz (see “With caution”).

Impaired renal function

The pharmacokinetics of efavirenz in patients with renal failure have not been studied, however, since less than 1% of the administered dose of efavirenz is excreted unchanged by the kidneys, impaired renal function should not have a significant effect on the excretion of efavirenz (see “Special instructions”).

Gender and race

Similar pharmacokinetic parameters of efavirenz were observed in men and women, as well as in patients of different races.

Elderly patients

No pharmacokinetic differences were found in patients 65 years and older and younger patients, although clinical studies of Efavirenz did not include a sufficient number of patients 65 years and older.

Children

The use of efavirenz has not been studied in children under 3 years of age and patients weighing less than 13 kg. The pharmacokinetic parameters of efavirenz in children and adults were similar. In 49 children taking Efavirenz at a dose equivalent to 600 mg (dose calculated based on body weight), the C_max value was 14.1 µmol/L, C_min – 5.6 µmol/L and AUC – 216 µmol/L/h.

Indications

• As part of combined antiviral therapy for the treatment of adults, adolescents and children infected with human immunodeficiency virus (HIV-1).

ICD codes

Dosage Regimen

Capsules

Stocrin^® should be prescribed in combination with other antiretroviral drugs (protease inhibitors and/or nucleoside reverse transcriptase inhibitors /NRTIs/).

For adults the recommended dose of Stocrin^® is 600 mg/day orally.

For children and adolescents (from 3 to 17 years) the doses of the drug are set depending on age and body weight.

The recommended dose for children weighing more than 40 kg is 600 mg/day.

Stocrin^® should be prescribed only to children who can easily swallow capsules. In children under 3 years of age and weighing less than 13 kg the use of Stocrin^® has not been studied.

Frequency of administration once/day. The drug can be taken regardless of meals.

To improve the tolerability of nervous system side effects during the first 2-4 weeks of treatment, as well as in patients who continue to experience these symptoms, it is recommended to take the drug before bedtime.

Tablets

The drug Stocrin^® is taken orally. It is recommended to take the drug before bedtime on an empty stomach. An increase in the concentration of efavirenz in the blood observed when using the drug Stocrin^® during meals may lead to an increase in the frequency of adverse reactions.

Therapy with the drug Stocrin^® should be prescribed by a doctor experienced in the treatment of HIV infection. The drug Stocrin^® should be prescribed in combination with other antiretroviral drugs.

Orally, the drug is recommended to be taken before bedtime on an empty stomach.

Therapy should be prescribed by a doctor experienced in the treatment of HIV infection.

Adults

The drug Stocrin^® is prescribed in combination with NRTIs with or without an HIV protease inhibitor at a dose of 600 mg once/day.

Dosage adjustment

If the drug Stocrin^® is used simultaneously with voriconazole, the dose of voriconazole should be increased to 400 mg twice/day, and the dose of the drug Stocrin^® should be reduced by 50%, i.e. to 300 mg* once/day. After discontinuation of voriconazole therapy, the initial dose of efavirenz (600 mg) should be used (see “Interaction with other drugs”).

* when using the drug Stocrin^® and voriconazole simultaneously, it should be borne in mind that tablets with a low dose of efavirenz are not registered in the Russian Federation.

If the drug Stocrin^® is used simultaneously with rifampicin in patients weighing 50 kg or more, it may be necessary to increase the dose of the drug Stocrin^® to 800 mg once/day (see “Interaction with other drugs”).

Children from 3 years old

The drug Stocrin^® is prescribed in combination with an HIV protease inhibitor and/or NRTIs. For children from 3 years of age, doses are selected depending on body weight (see Table 1).

The drug Stocrin^® can only be prescribed to children who can swallow tablets. The safety and efficacy of the drug Stocrin^® in children under 3 years of age or weighing less than 13 kg have not been established.

Table 1. Doses for children when prescribing the drug Stocrin^® once/day*

* doses for patients weighing less than 40 kg are provided for information and are not applicable for 600 mg tablets.

Patients with renal impairment

The pharmacokinetics of efavirenz in patients with renal impairment have not been studied, however, since less than 1% of the administered dose of efavirenz is excreted unchanged by the kidneys, impaired renal function should not have a significant effect on the excretion of efavirenz (see “Special instructions”).

Patients with hepatic impairment

In patients with mild liver disease, no dose adjustment of efavirenz is required. However, patients should be carefully monitored for the occurrence of adverse reactions, especially from the nervous system (see “Contraindications” and “Special instructions”).

The use of the drug Stocrin^® in patients with moderate hepatic impairment is not recommended, since there is currently insufficient data to determine whether dose adjustment is necessary in such cases.

Adverse Reactions

Overall safety profile

Overall, Efavirenz was well tolerated in clinical studies. In a subgroup of patients taking Efavirenz at a dose of 600 mg once/day in combination with HIV protease inhibitors and/or NRTIs, the most frequent (in at least 5% of patients) adverse reactions of at least moderate severity were skin rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and increased fatigue (5.5%).

The most noticeable adverse events associated with efavirenz were skin rash and nervous system symptoms. Nervous system symptoms usually appeared soon after the start of therapy and, as a rule, disappeared after the first 2-4 weeks of therapy. Also, in patients taking Efavirenz, severe skin reactions such as Stevens-Johnson syndrome and exudative erythema multiforme were observed; mental disorders, including severe depression, death due to suicide and psychotic-like behavior, as well as convulsive seizures. When using the drug Stocrin^® with food, the systemic exposure of efavirenz may increase, which may lead to an increase in the frequency of adverse reactions (see “Special instructions”).

The safety profile during long-term therapy including Efavirenz was assessed in a controlled study in which patients received either Efavirenz+zidovudine+lamivudine for 180 weeks, or Efavirenz+indinavir for 102 weeks, or indinavir+zidovudine+lamivudine for 76 weeks. Long-term use of efavirenz in this study was not accompanied by any new safety data.

Below are moderate and severe adverse reactions for which a possible causal relationship with the therapy regimen used was established (in the opinion of the researchers) and which were observed during clinical studies of efavirenz used at the recommended dose as part of combined ART.

Adverse events that were reported in the post-registration period of efavirenz use as part of combination therapy are highlighted in italics. The frequency of adverse events is given according to the following classification: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000).

Immune system disorders: uncommon – hypersensitivity.

Metabolism and nutrition disorders: common – hypertriglyceridemia¹; uncommon – hypercholesterolemia¹.

Psychiatric disorders common – abnormal dreams, anxiety, depression, insomnia¹; uncommon – affect lability, aggressiveness, confusion, euphoric mood, hallucinations, mania, paranoid behavior, psychosis², suicide attempt, suicidal ideation; rarely – delusion³, neurosis³, death due to suicide^1,3.

Nervous system disorders often – impaired cerebellar coordination and balance², disturbance in attention (3.6%), dizziness (8.5%), headache (5.7%), somnolence (2.0%)¹; infrequently – anxiety agitation, amnesia, ataxia, impaired coordination, convulsions, thinking impaired, tremor².

Eye disorders infrequently – blurred vision.

Ear and labyrinth disorders infrequently – tinnitus², vertigo.

Vascular disorders infrequently – flushing².

Gastrointestinal disorders often – abdominal pain, diarrhoea, nausea, vomiting; infrequently – pancreatitis.

Hepatobiliary disorders often – increased AST¹, ALT¹ and gamma-glutamyltransferase (GGT)¹; infrequently – acute hepatitis; rarely – hepatic failure^1,3.

Skin and subcutaneous tissue disorders very often – skin rash (11.6%)¹; often – pruritus; infrequently – erythema multiforme, Stevens-Johnson syndrome¹; rarely – photoallergic dermatitis².

Reproductive system and breast disorders infrequently – gynaecomastia.

General disorders and administration site conditions often – fatigue.

¹ See below for a more detailed description.

² These adverse reactions were identified during post-marketing surveillance; the frequency of these reactions was determined using data from 16 clinical trials (involving 3969 patients).

³These adverse reactions were identified during post-marketing surveillance**, however, they were not reported as drug-related in patients receiving Efavirenz in 16 clinical trials. According to the frequency classification, these adverse events were considered as “rarely observed” (based on the assessment of the upper limit of the 95% confidence interval for 0 events per the number of patients who received Efavirenz in the aforementioned clinical trials (n=3969)).

Description of selected adverse reactions

Skin rash: in clinical trials, skin rash was observed in 26% of patients receiving Efavirenz 600 mg, compared with 17% of patients in control groups. In 18% of patients, the skin rash was associated with efavirenz use**, and in 1.7% of patients, the drug was discontinued due to skin rash. The incidence of erythema multiforme and Stevens-Johnson syndrome was approximately 0.1%.

Cases of skin rash were reported in 58 out of 182 children (32%) receiving efavirenz treatment in 3 clinical trials with a median duration of 123 weeks. In 6 children, the rash was severe. Prior to initiating efavirenz therapy in children, appropriate antihistamine therapy may be recommended as prophylaxis. Usually, mild to moderate maculopapular skin rashes develop, appearing within the first two weeks after starting efavirenz therapy. In most patients, the skin rash resolves with continued efavirenz therapy within one month. Efavirenz may be re-administered to patients who discontinued it due to skin rash. Upon re-initiation of efavirenz therapy, it is recommended to also take appropriate H1-histamine receptor blockers and/or corticosteroids.

There is limited experience with efavirenz in patients who discontinued therapy with other NNRTI antiretroviral drugs. The frequency of skin rash recurrence after switching from nevirapine therapy to efavirenz therapy, mainly assessed from published retrospective data, ranged from 13% to 18%, and is comparable to the frequency identified in patients receiving Efavirenz in clinical trials (see “Special Precautions”).

Psychiatric symptoms: some patients receiving Efavirenz experienced serious psychiatric adverse events. In controlled clinical trials, the incidence of specific serious psychiatric adverse events was as follows: severe depression 1.6% in the group of patients receiving combination ART with efavirenz; 0.6% in the control group of patients, 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%) respectively.

Patients with a history of psychiatric disorders are at increased risk of developing these serious psychiatric adverse events, with the incidence of each of the above events ranging from 0.3% for manic reactions to 2.0% for severe depression and suicidal ideation. Also, post-marketing reports have been received of deaths due to suicide, delusional disorders, and psychosis-like behaviour.

Nervous system symptoms: in patients receiving Efavirenz 600 mg – within controlled clinical trials, the following adverse reactions were frequently observed: dizziness, insomnia, somnolence, impaired concentration, abnormal dreams. Other adverse events were also observed. Moderate and severe nervous system symptoms were observed in 19% (severe in 2%) of patients, whereas in patients receiving control therapy, this figure was 9% (severe in 1%). In clinical trials, 2% of patients receiving Efavirenz discontinued therapy due to the aforementioned symptoms.

Nervous system symptoms are usually observed during the first or second day after starting therapy and in most cases resolve within the first 2-4 weeks. In a study involving uninfected volunteers, a representative nervous system symptom occurred on average 1 hour after drug intake and lasted on average 3 hours. Nervous system symptoms occurred more frequently if Efavirenz was taken with food. This may be due to increased plasma concentrations of efavirenz under such conditions (see “Pharmacokinetics”). To improve drug tolerability regarding these symptoms during the first weeks of therapy, it is recommended to take the drug at bedtime. This dosing regimen is also recommended for those patients who continue to experience these symptoms (see “Dosage and Administration”). Dose reduction or divided daily dosing usually does not provide a beneficial effect.

Analysis of long-term drug use data showed that after 24 weeks of therapy, the incidence of newly occurring nervous system symptoms in patients receiving Efavirenz was generally similar to that in the control group.

Hepatic failure: during post-marketing surveillance, several cases of hepatic failure have been reported, including cases with no history of liver disease and no other identified risk factors. These cases were characterized by a fulminant course; in a number of cases, liver transplantation was required or patient death was reported.

Immune reconstitution syndrome: in HIV-infected patients with severe immunodeficiency at the initiation of combination ART, the risk of inflammatory reactions to inactive or residual opportunistic infections may increase (see “Special Precautions”),

Lipodystrophy and metabolic abnormalities: combination ART is associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of peripheral and facial subcutaneous fat, its accumulation in the intra-abdominal space, internal organs, back of the neck (“buffalo hump”) and breast hypertrophy.

Combination ART may cause metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see “Special Precautions”).

Osteonecrosis: cases of osteonecrosis have been observed, mainly in patients with well-known risk factors, with long-term HIV infection, and in patients who have received long-term combination ART. However, the frequency of this complication has not been established (see “Special Precautions”).

Laboratory parameters

Liver enzymes increase in AST and ALT activity to more than 5 times the upper limit of normal (ULN) was observed in 3% of patients out of 1008 receiving Efavirenz 600 mg/day (5-8% with long-term ART with efavirenz). A similar increase was observed in control group patients (5% with long-term ART without efavirenz ). Increase in GGT activity to more than 5 times ULN was observed in 4% of all patients receiving 600 mg efavirenz, and in 1.5-2% of patients in control groups (7% with long-term ART with efavirenz and 3% with long-term ART without efavirenz). Isolated increase in GGT activity in patients taking Efavirenz may indicate enzyme induction. In a clinical trial with long-term ART, approximately 1% of patients in each study group discontinued therapy due to hepatobiliary disorders.

Amylase asymptomatic increase in serum amylase activity, more than 1.5 times ULN, was detected in 10% of patients receiving Efavirenz and in 6% of patients in control groups. The clinical significance of asymptomatic increase in serum amylase activity is unknown.

Lipids: a 10-20% increase in total cholesterol (TC) concentration was observed in uninfected volunteers taking Efavirenz. In clinical trials of various combination ART regimens with efavirenz in treatment-naive patients, over 48 weeks of treatment, an increase in TC concentration of 21-31%, high-density lipoprotein cholesterol (HDL-C) of 23-34% and triglycerides of 23-49% was observed. The proportion of patients with a TC/HDL-C ratio greater than 5 did not change. The magnitude of lipid concentration changes may be influenced by factors such as duration of therapy and the use of other medicinal products as part of combination ART.

Interaction with cannabinoid tests Efavirenz does not bind to cannabinoid receptors, but there have been reports of false-positive urine cannabinoid test results in uninfected volunteers and HIV-infected patients taking Efavirenz. A positive cannabinoid screening test result should be confirmed using specific methods such as gas chromatography or mass spectrometry.

Children and adolescents

The type and frequency of adverse events in children are generally comparable to those observed in adult patients, except for skin rash, which is more common in children (in 46% of children) than in adults and more pronounced (severe skin rash was observed in 5.3% of children). To prevent rash, it may be appropriate to prescribe appropriate H1-histamine receptor blockers to children prior to initiating efavirenz therapy. Although nervous system symptoms are difficult to detect in young children, it is believed that such symptoms are less common in children and are usually mild. Moderate nervous system symptoms were observed in 3.5% of patients, predominantly dizziness. No child experienced severe symptoms or required discontinuation of therapy due to nervous system symptoms.

Other special patient groups

Liver enzyme activity in patients co-infected with hepatitis B or C

Among patients seropositive for hepatitis B and/or C, an increase in AST activity to more than 5 times ULN was observed in 13% of patients receiving Efavirenz and in 7% of patients in the control group, and an increase in ALT activity to more than 5 times ULN was observed in 20% and 7% of patients, respectively. Among patients with co-infection, 3% of patients receiving Efavirenz and 2% of patients in the control group discontinued therapy due to liver function disorders (see “Special Precautions”).

Contraindications

• Hypersensitivity to any component of the drug;
• Severe hepatic impairment ) (see “Pharmacodynamics”, “Pharmacokinetics in special patient groups”);
• Children with body weight less than 40 kg (for this dosage form and strength);
• Concomitant use with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine or methylergonovine), since competitive interaction of efavirenz with the CYP3A4 isoenzyme may lead to inhibition of the metabolism of these drugs and create prerequisites for the occurrence of serious and/or life-threatening adverse events (e.g., arrhythmias, prolonged sedative effect or respiratory depression) (see “Drug interactions”);
• Concomitant use with drugs/herbal products containing St. John’s wort (Hypericum perforatum), as plasma concentrations of efavirenz are decreased and, consequently, clinical effect is reduced (see “Drug interactions”);
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

• Patients with a history of psychiatric disorders, who are at increased risk of developing serious psychiatric adverse events;
• Patients with mild to moderate hepatic impairment;
• Patients with a history of seizures;
• Patients taking concomitant anticonvulsant drugs that are primarily metabolized in the liver, such as phenytoin, carbamazepine and phenobarbital (periodic monitoring of their blood concentrations is necessary).

Use in Pregnancy and Lactation

Pregnancy should be avoided during treatment with efavirenz. Reliable barrier methods of contraception should be used in combination with other methods (including oral or other hormonal contraceptives). Since Efavirenz has a long half-life, reliable contraceptive methods should be used for 12 weeks after discontinuation of efavirenz treatment. Before starting treatment with efavirenz, women of childbearing potential should undergo a pregnancy test. Efavirenz should not be used during pregnancy, except when the potential benefit to the mother outweighs the possible risk to the fetus and there are no other alternative treatment methods. If a woman takes Efavirenz during the first trimester of pregnancy or becomes pregnant while using efavirenz, she should be warned about the potential harm to the fetus.

Adequate and controlled clinical studies in pregnant women have not been conducted. During the post-marketing period, reports have been received of the use of efavirenz as part of combination antiretroviral therapy (ART) in the first trimester of pregnancy. No specific features (increase in frequency) of birth defects in newborns were reported. Only a few reports contained information on cases of neural tube defects, including meningomyelocele. Most of these reports were retrospective, and causality was not investigated.

Efavirenz has been shown to be excreted in the breast milk of nursing women. There is insufficient information on the effect of efavirenz on newborns and infants. Breastfeeding is not recommended for women taking Efavirenz during lactation. To avoid transmission of HIV, HIV-infected mothers are not recommended to breastfeed under any circumstances.

Use in Hepatic Impairment

In patients with mild hepatic impairment, no dose adjustment of efavirenz is required. However, patients should be carefully monitored for the occurrence of adverse reactions, especially from the nervous system.

In patients with mild to moderate hepatic impairment, no change in the dose of efavirenz is required. However, patients should be carefully monitored for the occurrence of adverse reactions, especially from the nervous system.

Use in Renal Impairment

The pharmacokinetics of efavirenz have not been studied in patients with renal impairment, however, since less than 1% of the efavirenz dose is excreted unchanged by the kidneys, impaired renal function should not significantly affect the elimination of efavirenz. There is no experience with the use of efavirenz in patients with severe renal impairment, therefore, such patients should be carefully monitored for the safety of the drug.

Pediatric Use

For children aged 3 years and older, doses are selected based on body weight. Stocrin^® can only be prescribed to children who are able to swallow tablets.

The safety and efficacy of Stocrin^® in children under 3 years of age or weighing less than 13 kg have not been established.

Geriatric Use

Elderly patients since a small number of elderly patients were included in clinical trials, there is no reason to assume that the effect of the drug in elderly patients differs from that in younger patients.

Special Precautions

Efavirenz should not be used as a single drug for the treatment of HIV infection, nor should it be added as a single agent to an ineffective treatment regimen. As with other NNRTIs, resistance may develop rapidly when efavirenz is used in monotherapy. When selecting new antiretroviral drugs for use in combination with efavirenz, the possibility of cross-resistance should be considered (see “Pharmacodynamics”).

The use of efavirenz concomitantly with fixed-dose combination tablets containing efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended unless dose adjustment is required (e.g., when used concomitantly with rifampicin).

When prescribing drugs for concomitant use with Stocrin^®, the physician should refer to the prescribing information of those medicinal products.

During ART, the risk of transmitting HIV to others through sexual contact or blood cannot be excluded. Therefore, appropriate precautions should be taken.

Concomitant antiretroviral therapy if any antiretroviral agent within combination ART is discontinued due to suspected intolerance, the possibility of discontinuing all antiretroviral agents simultaneously should be considered. All discontinued antiretroviral drugs should be resumed immediately after the intolerance symptoms resolve. Intermittent monotherapy and sequential re-administration of antiretroviral agents is not recommended due to the increased likelihood of therapy-resistant virus emergence.

Skin rash in clinical trials of efavirenz, mild and moderate rashes were observed, which usually resolve with continued therapy. Administration of appropriate H1-histamine receptor blockers and/or corticosteroids may improve tolerability and promote faster resolution of the skin rash. Severe skin rash accompanied by blistering, desquamation or ulceration was observed in less than 1% of patients taking Efavirenz. Erythema multiforme or Stevens-Johnson syndrome occurred in 0.1% of patients. If patients develop a severe rash accompanied by blistering, desquamation involving mucous membranes, or fever, efavirenz should be discontinued immediately. Efavirenz is not recommended for patients who have had a life-threatening skin reaction (e.g., Stevens-Johnson syndrome). If efavirenz therapy is discontinued, consideration should be given to discontinuing other antiretroviral agents to avoid the emergence of therapy-resistant virus (see “Adverse Reactions”)

Cases of skin rash were reported in 58 out of 182 children (32%) receiving efavirenz treatment in 3 clinical trials with a median duration of 123 weeks. The rash was severe in 6 children. The median time to onset of rash in children was 27 days (range 3-1504 days). Prior to initiating efavirenz therapy, children may be advised to receive appropriate antihistamine therapy as prophylaxis.

Experience with efavirenz in patients who have discontinued other antiretroviral agents from the NNRTI class is limited (see “Adverse Reactions”). Efavirenz is not recommended for patients who have previously experienced life-threatening skin reactions (e.g., Stevens-Johnson syndrome) while taking other NNRTIs.

Psychiatric Symptoms There are reports of psychiatric adverse events in patients taking Efavirenz. Patients with a history of psychiatric disorders are at increased risk of developing serious psychiatric adverse events. In particular, severe depression was most frequently observed in patients with a history of depression. There are also post-marketing reports of severe depression, suicidal death, delirium, and psychosis-like behavior. Patients should be advised that if they develop symptoms such as severe depression, psychosis, or suicidal ideation, they should immediately inform their doctor. The physician should determine the possible relationship of these symptoms to efavirenz intake, and if this relationship is confirmed, assess the risk-benefit ratio for the patient of continuing therapy versus the potential benefit of taking the drug (see “Adverse Reactions”).

Nervous System Symptoms In patients taking Efavirenz at a dose of 600 mg once daily in clinical trials, the following symptoms were frequently observed: dizziness, insomnia, drowsiness, impaired concentration, and dream abnormalities, as well as other adverse events (see “Adverse Reactions”). Nervous system symptoms were usually observed during the first or second day of therapy and in most cases resolved after the first 2-4 weeks. Patients should be informed that such symptoms, if they occur, usually resolve with continued therapy and are not a sign of possible, less common psychiatric disturbances.

Seizures Seizures have been reported in patients taking Efavirenz, particularly in patients with a history of seizures. When co-administered with anticonvulsant medications that are metabolized primarily in the liver, such as phenytoin, carbamazepine, and phenobarbital, plasma concentrations of these drugs should be periodically monitored. A drug interaction study showed that when carbamazepine was co-administered with efavirenz, plasma carbamazepine concentrations decreased (see “Drug Interactions”). Patients with a history of seizures should be closely monitored.

Hepatic Adverse Events During post-marketing surveillance, a small number of reports of hepatic failure have been received in patients with no history of liver disease and no other identified risk factors (see “Adverse Reactions”). In this regard, it is recommended to monitor liver enzyme activity even in patients without a history of liver dysfunction or other risk factors.

Effect of Food When Stocrin^® is taken with food, the exposure to efavirenz may increase (see “Pharmacodynamics”), which may lead to an increased frequency of adverse reactions (see “Adverse Reactions”). Therefore, it is recommended to take Stocrin^® on an empty stomach, preferably at bedtime.

Immune Reconstitution Syndrome This syndrome has been observed in patients with severe immunodeficiency at any time after initiation of combination antiretroviral therapy (cART). As a result of the immune response enhancement due to therapy, an inflammatory reaction to latent or residual opportunistic infections, such as cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia (formerly Pneumocystis carinii), may develop within weeks or months of starting treatment. Such inflammatory symptoms require further evaluation and appropriate treatment.

Autoimmune disorders (such as Graves’ disease) have been observed in the context of immune reconstitution; however, the time of initial manifestation varied greatly and the disease could occur many months after starting therapy.

Lipodystrophy and Metabolic Abnormalities Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of this phenomenon are currently unknown and its mechanism is not fully understood. A relationship is suggested between visceral lipomatosis and the use of protease inhibitors, and between lipoatrophy and the use of NRTIs. An increased risk of developing lipodystrophy may be associated with both individual factors, such as older age, and drug-related factors, such as prolonged antiretroviral therapy and associated metabolic disorders. Therefore, during clinical examination of the patient, a physical examination should be performed, paying attention to the redistribution of body fat, and fasting serum lipid concentrations and blood glucose concentrations should be determined. Lipid metabolism disorders should be managed according to clinical manifestations (see “Adverse Reactions”).

Osteonecrosis Although the etiology of this condition is recognized as multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, increased BMI), cases of osteonecrosis have been observed predominantly in patients with long-standing HIV infection and/or in patients receiving long-term combination antiretroviral therapy. Patients should promptly consult a doctor if they experience joint pain, stiffness, or difficulty walking.

Special Patient Populations

Patients with Liver DiseaseEfavirenz is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see “Contraindications”, “Pharmacodynamics”) and is not recommended for patients with moderate hepatic impairment, as there is currently insufficient data to determine whether dose adjustment is necessary in such cases. Due to the extensive metabolism of efavirenz by the cytochrome P450 system and limited clinical experience with the drug in patients with chronic liver disease, caution should be exercised when prescribing Stocrin^® to patients with mild liver disease. These patients should be monitored for the timely detection of dose-dependent adverse reactions, especially those related to the nervous system. Laboratory tests to assess liver status should also be performed at regular intervals (see “Dosage and Administration”).

The safety and efficacy of efavirenz have not been established in patients with significant pre-existing liver dysfunction. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy **, are at risk of developing severe, potentially fatal hepatic adverse reactions. In patients with a history of liver dysfunction, including chronic active hepatitis, the frequency of liver function abnormalities during combination antiretroviral therapy is increased, so such patients should be monitored according to standard practice. In patients with worsening liver disease or a persistent increase in serum transaminase activity **, exceeding 5 times the upper limit of normal (ULN), the benefit of continuing efavirenz therapy should be weighed against the potential risk of hepatotoxicity. For such patients, the advisability of interrupting or discontinuing antiretroviral therapy should be considered (see “Adverse Reactions”).

When co-administered with other medications with known hepatotoxicity, monitoring of liver enzyme activity is recommended. Patients with hepatitis B or C receiving combination antiviral therapy should also follow the instructions for use of the prescribed medications for hepatitis B or C.

Patients with Renal Impairment The pharmacokinetics of efavirenz have not been studied in patients with renal impairment; however, since less than 1% of the administered efavirenz dose is excreted unchanged by the kidneys, impaired renal function is not expected to significantly affect the elimination of efavirenz (see “Pharmacodynamics”). There is no experience with efavirenz in patients with severe renal impairment; therefore, careful monitoring of the safety of the drug should be performed in such patients.

Elderly Patients Since a small number of elderly patients were included in clinical trials, there is no reason to assume that the effect of the drug on elderly patients differs from that on younger patients.

Children The use of efavirenz in children under 3 years of age or weighing less than 13 kg has not been studied.

Effect on Ability to Drive and Operate Machinery

No studies have been conducted to evaluate the effect on the ability to drive and operate machinery. Efavirenz may cause dizziness, impaired concentration, insomnia, and other adverse drug reactions affecting the CNS. Patients should be warned that if they experience any of these symptoms, they should avoid driving and operating machinery.

Overdose

Some patients who accidentally took Efavirenz at a dose of 600 mg twice daily experienced an increase in nervous system symptoms. One patient experienced involuntary muscle contractions.

In case of efavirenz overdose, treatment should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Activated charcoal can be used to remove unabsorbed drug. There is no specific antidote for the treatment of efavirenz overdose. Since Efavirenz is highly protein-bound, it is unlikely that significant removal of the drug from the blood can be achieved by dialysis.

Drug Interactions

Efavirenz in vivo is an inducer of the CYP3A4, CYP2B6, and UGT1A1 isoenzymes. The plasma concentration of compounds that are substrates of these isoenzymes may decrease when co-administered with efavirenz. Efavirenz may be an inducer of the CYP2C19 and CYP2C9 isoenzymes; however, inhibition of these isoenzymes has also been observed in vitro. The effect observed when efavirenz is co-administered with substrate compounds of these isoenzymes is not fully understood (see “Pharmacodynamics”, “Pharmacokinetics”).

The exposure to efavirenz may increase when the drug is taken concomitantly with certain medications (e.g., ritonavir) or food (e.g., grapefruit juice) that inhibit the CYP3A4 or CYP2B6 isoenzymes. Compounds that induce these isoenzymes may lead to a decrease in efavirenz plasma concentration.

Contraindicated Combination Therapy

Concomitant use of efavirenz with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, and ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergometrine, and methylergometrine) is contraindicated, as inhibition of their metabolism by efavirenz can cause serious, life-threatening consequences (see “Contraindications”).

St. John’s wort (Hypericum perforatum): Patients taking Efavirenz should not take preparations/products containing St. John’s wort. The plasma concentration of efavirenz may decrease when co-administered with St. John’s wort, as it induces enzymes and/or transport proteins responsible for drug metabolism. If a patient is already taking preparations/products containing St. John’s wort, its use should be discontinued, the viral load should be checked, and, if possible, the efavirenz blood concentration should be measured. After discontinuation of preparations/products containing St. John’s wort, the efavirenz concentration may increase, and then adjustment of the efavirenz dose may be required. The enzyme-inducing effect of St. John’s wort may persist for at least 2 weeks after its discontinuation (see “Contraindications”).

Other Interactions

Interactions between efavirenz and HIV protease inhibitors, other antiretroviral drugs besides HIV protease inhibitors, as well as between efavirenz and non-antiretroviral drugs are listed in Table 2 below. An increase in the parameter is indicated by an “↑” arrow, a decrease by a “↓” arrow, and if the parameter remains unchanged, by a “↔” arrow; if the drug was administered every 8 or 12 hours, this is denoted as “q8h” or “q12h”. If necessary, 90% and 95% confidence intervals are presented in parentheses. Studies were usually conducted in healthy volunteers unless otherwise specified.

Table 2. Interactions between efavirenz and other drugs

^a90% confidence intervals, unless otherwise stated.
^b95% confidence intervals.
UDP – uridine diphosphate.
HMG-CoA reductase – 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Children

Interaction studies have been conducted only in adults.

Storage Conditions

Store the drug at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Do not use the drug after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.