Efkur-600 - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 240.00 mg, croscarmellose sodium 60.00 mg, giprolose 38.40 mg, sodium lauryl sulfate 12.00 mg, lactose monohydrate 237.60 mg, magnesium stearate 12.00 mg;

Shell composition: opadraj yellow 15В 82855 18,00 mg: (hypromellose 3 сР, hypromellose 6cp, titanium dioxide, macrogol 400, talc, iron oxide yellow, polysorbate 80).

Description:

The tablets covered with a film sheath, yellow, oval in shape, engraved with "EF 600 "on one side.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.G. Non-nucleosides - reverse transcriptase inhibitors

J.05.A.G.03 Efavirenz

Pharmacodynamics:

Mechanism of action: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase and does not significantly inhibit HIV-2 reverse transcriptase and DNA polymerase (α, β, ƴ and δ) of human cells.

Antiviral activity: Antiviral activity of efavirenz in vitro was assessed on lymphoblast cell lines, peripheral mononuclear cells blood and cultures macrophages / monocytes. The concentration of efavirenz needed for 90-95% inhibition (IC_90-95) adapted to laboratory conditions of wild-type strains and clinical isolates resistant to zidovudine, is in the range from 0.46 to 6,8 nmol / l.

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

Replacement K103N was the most frequently observed substitution in RT for viral strains obtained from patients who experienced a significant increase in the number of viral particles in the blood plasma (recurrent viremia) in clinical trials using efavirenz in combination with indinavir or in combination with zidovudine and lamivudine. This mutation was observed in 90% of patients with ineffective efavirenz therapy. Also, although less frequently, and often only in combination with K103N, substitutions in OT at positions 98, 100, 101, 108, 138, 188, 190 and 225 were observed. The type of amino acid substitutions in RT related to resistance to efavirenz did not depend on other antiviral drugs used in combination with efavirenz.

Cross-resistance: the study of cross-resistance profiles of efavirenz, nevirapine and delavirdine on cell cultures showed that replacement K103N leads to loss of susceptibility to all three NNRTIs.Two of the three dovgirdin-resistant clinical isolates exhibited cross-resistance to efavirenz and contained a substitution K103N. The third isolate, having a substitution in the RT at position 236, did not have cross-resistance to efavirenz.

Viral isolates isolated from peripheral blood mononuclear cells of patients enrolled in clinical studies of efavirenz in whom the therapy was ineffective (recurrent virnmia) were investigated for susceptibility to NNRTI. Thirteen isolates, which had previously been characterized as resistant to efavirenz, also proved resistant to nevirapine and delavirdine.

It was found that five of these NNRTI-resistant isolates contained a substitute K103N or the replacement of valine by isoleucine at position 108 (V108I) in RT. Among the tested isolates after ineffective efavirenz therapy, three isolates remained sensitive to both efavirenz and nevirapine and delavirdine, on cell cultures.

The likelihood of cross-resistance between efavirenz and protease inhibitors is low due to differences in target enzymes.The presence of cross-resistance between efavirenz and nucleoside RT inhibitors (NRTIs) is also unlikely due to the difference in binding sites to the target and the mechanisms of action.

Pharmacokinetics:

Suction:

In healthy volunteers, the maximum concentration (FROM_m_Oh) efavirenz at Plasma 1.6-9.1 μmol / l was achieved 5 hours after a single dose of the drug in doses from 100 up to 1600 mg. Dose-dependent increase FROM_m_Oh and the area under the curve "concentration-time" (AUC) was observed when taking the drug in doses up to 1600 mg; while there was no dose-proportional increase in these indicators, so it can be assumed that at higher doses, the absorption decreases. The time to reach the maximum concentration in blood plasma (3-5 h) did not change after repeated administration of the drug, and the equilibrium concentration in blood plasma was reached after 6-7 days.

In HIV-infected patients, when the equilibrium concentration of the drug in the blood plasma is reached, the mean values FROM_m_Oh, minimum concentration (C_min) and AUC were linear at reception 200 mg, 400 mg and 600 mg of efavirenz 1 time per day. In 35 patients who took efavirenz in a dose of 600 mg 1 once a day, C_mOh when the equilibrium concentration was reached, was 12.9 ± 3.7 μmol / l, C_min- 5.6 ± 3.2 μmol / l, AUC - 184 ± 73 μmol / l per hour.

Effect of food intake on absorption

With a single admission of healthy volunteers, efavirenz at a dose of 600 mg in the form of film-coated tablets, along with a poor high-fat diet, there was an increase AUC by 28% and C_mOh on 79% in comparison with the given parameters at reception of a preparation on an empty stomach.

Distribution:

Efavirenz binds to a high degree with blood plasma proteins (approximately 99.5-99.75%), especially with albumin. In HIV-infected patients (N = 9), which were obtained efavirenz in doses from 200 up to 600 mg once daily for at least one month, the concentration of the drug in the cerebrospinal fluid was 0.26 to 1.19% (averaging 0.69%) of the corresponding concentration in the blood plasma. This indicator is approximately 3 times higher than the concentration of the non-protein (free) fraction of efavirenz in the blood plasma.

Metabolism:

Clinical studies and research in vitro using human liver microsomes showed that efavirenz is metabolized mainly by the cytochrome P450 system to hydroxylated derivatives, which then bind to glucuronic acid to form glucuronides. Basically, these metabolites are inactive in relation to HIV-1. Research in vitro suggest that isoenzymes CYP3A4 and CYP2B6 are major isoenzymes that metabolize efavirenz and that efavirenz inhibits isozymes 2S9, 2C19 and 3A4 of the cytochrome P450 system. In studies in vitro efavirenz did not inhibit isoenzyme CYP2E1 and inhibited isoenzymes CYP2D6 and CYP1A2 only in concentrations far exceeding those used in clinical practice. Exposure of efavirenz in the blood plasma may increase in patients homozygous for gene polymorphism G516T isoenzyme CYP2B6. The clinical significance of such a change is not known, but the possibility of increasing risks of development and increasing the severity of unwanted reactions of efavirenz can not be ruled out.

It was shown that efavirenz induces isoenzymes CYP3A4 and CYP2B6, which leads to the induction of its own metabolism, which canclinically expressed in some patients.With repeated administration of efavirenz in a dose of 200-400 mg per day, a lesser degree of cumulation of efavirenz (22-42% lower than expected values) was observed by healthy volunteers during 10 days and a shorter half-life period of 40-55 hours (half-life of a single dose of 52 -76 h). It was also shown that efavirenz induces an isoform 1A1 uridine diphosphate-glucuronyltransferase (UDF-GT1A1), therefore the concentration of raltegravir, which is a substrate of UDF-GT1A1, in blood plasma is reduced with simultaneous use with efavirenz.

Despite the fact that in the studies in vitro efavirenz inhibited isoenzymes CYP2C9 and CYP2C19, in studies in vivo Both an increase and a decrease in the exposure of substrates of these enzymes were observed with simultaneous use with efavirenz. The final effect of this interaction is not established.

Excretion:

Efavirenz has a relatively long half-life, which is at least 52 hours after taking a single dose and 40-55 hours after repeated use.

Approximately 14-34% of the accepted dose of efavirenz is excreted by the kidneys, less than 1% of the dose of efavirenz is excreted by the kidneys in unchanged form.

Pharmacokinetics in specific patient groups

Impaired liver function

With a single administration of the drug, there was a twofold increase in the half-life of efavirenz in one patient with a severe degree of hepatic insufficiency (class C in the Child-Pugh system), indicating an increased degree of cumulation in such cases. With repeated administration of the drug, there was no significant effect of liver damage on the pharmacokinetics of efavirenz in patients with mild liver failure (class A in the Child-Pugh system) compared with the control group. At present, there is insufficient data to conclude whether the average and severe degree of hepatic insufficiency (class B and C in the Child-Pugh system) affect the pharmacokinetics of efavirenz (see the section "With caution").

Impaired renal function

The pharmacokinetics of efavirenz in patients with renal insufficiency has not been studied, but due to the fact that less than 1% of the dose of efavirenz is released in kidneys unaltered, renal dysfunction should not have a significant effect on efavirenz withdrawal (see section "Special instructions").

Sex and race

In men and women, as well as in patients of different racial affinities, the pharmacokinetic parameters of efavirenz are similar.

Elderly patients

There were no pharmacokinetic differences in patients 65 years of age or older and younger patients, although clinical studies of efavirenz did not include sufficient numbers of patients 65 years of age or older.

Children

The use of efavirenz in children under 3 months of age or weighing less than 3.5 kg has not been studied.

The pharmacokinetic parameters of efavirenz in children and adults were similar. 49 children who received a dose of efavirenz, equivalent to 600 mg (the dose was calculated based on body weight), C_mOh was 14.1 μM, C_min - 5.6 μM and the area under the concentration-time curve is 216 μM per hour.

Indications:

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

Contraindications:

- Hypersensitivity to any of the components of the drug;

- severe degree of hepatic insufficiency (functional class C in the Child-Pugh system) (see sections "Pharmacological properties" and "Pharmacokinetics in special patient groups");

- Children weighing less than 40 kg (for this dosage form and dosage);

- simultaneous use with terfenadine, astemizole, cisaprideth, midazolam, triazolam, pimozide, bepridil, ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovin or metergergonovin), since the competitive interaction of efavirenz with isoenzyme CYP3A4 can lead to suppression of the metabolism of these drugs and the emergence of prerequisites for the occurrence of serious and / or life-threatening adverse events (eg, arrhythmia, prolonged sedation or respiratory depression) (see "Interactions with Other Drugs");

- simultaneous use with preparations / products of plant origin, containing St. John's wort perforated (Hypericum perforatum), as the concentration of efavirep in the blood plasma decreases and, as a consequence, the clinical effect (see "Interaction from other drugs ");

- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:

- Patients with a history of psychiatric disorders who are at increased risk for developing serious adverse events from the psyche;

- patients with liver disease of mild and moderate severity;

- Patients with a history of seizures;

- patients taking concomitant anticonvulsants with a predominant metabolism in the liver, such as phenytoin, carbamazepine and phenobarbital (it is necessary to carry out periodic monitoring of their concentrations in the blood);

- with simultaneous use of efavirenz and artemether / lumefantrine.

Pregnancy and lactation:

When treating efavirenz, pregnancy should be avoided. It is necessary to use reliable methods of barrier contraception in combination with other methods (including oral or other hormonal contraceptives). Because the efavirenz has a long half-life, it is necessary to use reliable contraceptive methods for 12 weeks after cessation of treatment with efavirenz. Before starting treatment with efavirenz, women who are capable of giving birth should undergo a pregnancy test. Efavirenz should not be used during pregnancy, except when the potential benefit to the mother exceeds the possible risk to the fetus and there are no other alternative therapies. If a woman takes efavirenz during the first trimester of pregnancy or pregnancy occurs during the use of efavirenz, it should be warned about the potential harm to the fetus.

Adequate and controlled clinical trials involving pregnant women have not been conducted. In the post-marketing period, there were reports of the use of efavirenz in combination antiretroviral therapy (ARVT) in the first trimester of pregnancy. There were no reports of specific features (increased frequency) of malformations in newborns. Only a few reports contained information on cases of neural tube defects, including meningomyelocele. Most of these messages were retrospective, and the causal relationship was not studied.

It was shown that efavirenz is excreted in breast milk of lactating women. There is insufficient information on the effects of efavirenz on newborns and infants. Women receiving efavirenz during lactation, breast-feeding is not recommended. In order to avoid the transmission of HIV, under no circumstances should HIV-infected mothers be breast-fed.

Dosing and Administration:

The drug Efkur-600 is taken internally. It is recommended to take the drug before bedtime on an empty stomach. An increase in the concentration of efavirenz in the blood, observed with the use of the drug during meals, can lead to an increase in the frequency of undesirable reactions.

Therapy with Efkur-600 should be prescribed by a doctor who has experience in the treatment of HIV infection.

Efkur-600 should be administered in combination with other antiretroviral drugs.

Adults

Efkur-600 is administered in combination with NRTIs with or without an HIV protease inhibitor at 600 mg once a day:

Dose correction

If the drug Efkur-600 is used simultaneously with voriconazole, the dose of voriconazole should be increased to 400 mg twice a day, and the dose of Efkur-600 should be reduced by 50%, that is, up to 300 mg 1 once a day. After cessation of therapy with voriconazole, the initial dose of efavirenz (600 mg) should be used (see section "Interaction with other medicinal products").

If Efkur-600 is used concomitantly with rifampicin in patients with a body weight of 50 kg or more, an increase in the dose of Efkur-600 up to 800 mg once a day may be required.section "Interaction with other medicinal products").

Children from 3 years old

Efkur-600 is administered in combination with an HIV protease inhibitor and / or NRTI. For children from 3 years, doses are selected depending on the body weight (see Table 1). Efkur-600 can be administered only to children who swallow tablets. Safety and effectiveness of the drug in children under 3 years of age or body weight less than 13 kg are not established.

Table 1. Doses for children when prescribing Efkur-600 once a day *

Body weight, kg	The dose of Efkur-600 is 600 mg
13-15	200
15-20	250
20-25	300
25-32,5	350
32,5-40	400
From 40 and more	600

* doses for patients with body weight less than 40 kg are given for information and are not applicable for tablets with a dosage of 600 mg.

Patients with renal insufficiency

The pharmacokinetics of efavirenz in patients with renal insufficiency has not been studied, but due to the fact that in the unchanged kidneys less 1% of the dose of efavirenz, renal dysfunction should not have a significant effect on the excretion of efavirenz (see section "Special instructions").

Patients with hepatic insufficiency

Patients with mild liver disease do not require a change in the dose of efavirenz.In this case, patients should be carefully monitored for any occurrence of undesired side reactions, especially on the part of the nervous system (see. Section "Special instructions").

It is not recommended to use the drug in patients with hepatic insufficiency of moderate severity, as there is currently insufficient data to determine whether the need in such cases dosage adjustment.

Side effects:

Generally efavirenz well tolerated. Side effects may be causally related to the use of the drug, presented below.

The incidence of adverse events is given in the following classification: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10000, < 1/1000); very rarely (< 1/10000).

Immune system disorders

Infrequent: hypersensitivity.

Metabolic disorders

Often: hypertriglyceridemia.

Infrequently: hypercholesterolemia.

Disorders of the psyche

Often: pathological dreams, anxiety, depression, insomnia.

Uncommon: propensity to affect, aggression, confusion, mood with a tendency to euphoria, hallucinations, delusions, paranoid behavior, psychosis, suicide attempt, suicidal ideation.

Rarely: delirium, neurosis, death due to suicide.

Disturbances from the nervous system

Often: disorders of cerebellar coordination and balance, attention disorder, dizziness, headaches, drowsiness.

Infrequent: anxiety, amnesia, ataxia, impaired coordination of movements, convulsions, impaired thinking, tremor.

Disturbances on the part of the organ of sight

Infrequent: blurred vision.

Hearing disorders and labyrinthine disorders

Infrequent: noises in the ears, vertigo.

Disturbances from the respiratory system

Rarely: shortness of breath.

Vascular disorders

Infrequently: the "tides" of blood to the skin of the face.

Disorders from the gastrointestinal tract

Often: abdominal pain, diarrhea, nausea, vomiting.

Infrequently: pancreatitis.

Disturbances from the liver and bile ducts

Often: increased activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT).

Infrequently: acute hepatitis.

Rarely: hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues

Very often: skin rash.

Often: itchy skin.

Infrequently: polyphoremnaexudative erythema, Stevens-Johnson syndrome.

Rarely: photoallergic dermatitis.

Violations of the genitals and mammary gland

Infrequently: gynecomastia.

General disorders

Often: increased fatigue.

Description of individual undesirable phenomena

Skin rash. In clinical trials, skin rash was observed in 26% of patients taking efavirenz in a dose of 600 mg, but compared with 17% of patients in control groups. In 18% of patients, skin rash was associated with efavirenz, while 1.7% of patients were stopped because of a skin rash. The incidence of multiforme exudative erythema and Stevens-Johnson syndrome was approximately 0,1%.

Cases of skin rash were recorded in 59 of 182 children (32%) who received efavirenz treatment in 3 clinical trials with an average duration of 123 weeks. Have 6 children rash was severe. Before the beginning of efavirenz therapy in children, they can be recommended appropriate antihistamine therapy as a prophylaxis. Usually, mild or moderately expressed maculopapular skin rash develops, which appear within the first two weeks after initiation of efavirenz therapy.In most patients, a skin rash disappears when continuing with efavirenz therapy for one month. Efavirenz can be re-assigned to patients who stopped taking it because of a skin rash. When resuming efavirenz therapy, it is also recommended to take appropriate blockers H₁histamine receptors and / or corticosteroids.

There is limited experience with efavirenz in patients who discontinued therapy with other antiretroviral drugs from the NNRTI group. The incidence of recurrence of skin rash after switching from nevirapine therapy to efavirenz therapy, generally estimated from published retrospective data, was 13% to 18%, and comparable to the frequency found in patients taking efavirenz in clinical trials (see "Special instructions").

Symptoms from the side of the psyche. In some patients who took efavirenz, there were serious undesirable phenomena on the part of the psyche. In controlled clinical trials, the incidence of certain serious adverse events from the psyche was as follows: severe depression 1,6% in the group of patients who took combined ARVT with efavirenz and 0.6% in the control group of patients, suicidal intentions 0.6% and 0.3%, suicide attempts without lethal outcome 0.4% and 0%, aggressive behavior 0.4 % and 0.3%, paranoid reactions of 0.4% and 0.3%, manic reactions of 0.1% and 0% respectively.

Patients with a history of mental disorders are at increased risk of developing these serious adverse events from the psyche with a frequency of occurrence of each of the above events from 0.3% for manic reactions to 2.0% for severe depression and suicidal intentions. Also in the post-marketing period, reports of deaths as a result of suicide, delusional disorders and psychotic behavior have been reported.

Symptoms from the nervous system. In patients who took efavirenz in a dose of 600 mg in controlled clinical trials, the following undesirable reactions were often observed: dizziness, insomnia, drowsiness, attention disturbance, nightmares. Other undesirable phenomena were also observed. Severe and severe symptoms from the nervous system were observed in 19% (severe- in 2%) patients, whereas in patients receiving control therapy, this indicator was 9% (severe in 1%). In clinical trials, 2% of patients who took efavirenz, discontinued therapy because of the above symptoms.

Symptoms from the nervous system were usually observed during the first or second day after the initiation of therapy and in most cases disappeared within the first 2-4 weeks. In a study involving uninfected volunteers, a representative symptom from the nervous system arose on average through 1 h after taking the drug and lasted an average of 3 hours. Symptoms from the nervous system developed more often if efavirenz taken during meals. Perhaps this is due to an increase in the concentration of efavirenz in the blood plasma under such conditions (see "Pharmacokinetics"). To improve the tolerability of the drug for these symptoms during the first weeks of therapy, it is recommended to take the drug at bedtime. This regimen is also recommended for patients who continue to have these symptoms (see "Dosage and Administration"). Dose reduction or fractional intake of a daily dose usually do not give a favorable effect.

Analysis of data on long-term use of the drug showed that after 24 weeks of therapy the incidence of first-time symptoms from the nervous system in patients taking efavirenz, was generally similar to that in the control group.

Liver failure. During the post-registration period, several cases of hepatic insufficiency were reported, including cases without evidence of liver disease in the anamnesis, and without other identified risk factors. These cases were characterized by a lightning current; in a number of cases liver transplantation was required or the death of the patient was reported.

Immunodeficiency Syndrome. In HIV-infected patients with severe immunodeficiency, the onset of combined ARV therapy may increase the risk of inflammatory reactions to inactive or residual opportunistic infections (see "Special instructions").

Lipodystrophy and metabolic disorders: combined ARVT is associated with the redistribution of adipose tissue (lipodystrophy) in HIV-infected patients,including depletion of peripheral and facial subcutaneous fat, its accumulation in the intraperitoneal space, internal organs, the back of the neck ("buffalo hump") and hypertrophy of the mammary glands.

Combined ARVT can cause metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia (see "Special instructions").

Osteonecrosis. There have been cases of osteonecrosis, mainly in patients with well-known risk factors, with long-term HIV infection, as well as in patients who have been taking long-term combined ARVT. However, the frequency of this complication is not established (see Special instructions).

Laboratory indicators

"Hepatic" enzymes: an increase in AST and ALT activity more than 5 times higher than the upper limit of the norm (UGN) was observed in 3% of the 1008 patients who took efavirenz in a dose of 600 mg per day (5-8% with prolonged ARVT with efavirenz). A similar increase was observed in the control group (5% with prolonged ARVT without efavirenz). The increase in GGT activity was more than 5-fold higher than ULN observed in 4% of all patients taking 600 mg of efavirenz and 1.5-2% of patients in the control group (7% with prolonged ARVT with efavirenz and 3% with prolonged ARV without efavirenz ).Isolated increase in GGT activity in patients taking efavirenz, can indicate the induction of enzymes. In a clinical study with prolonged ARVT, about 1% of patients in each study group discontinued therapy due to violations from the liver and bile ducts.

Amylase: an asymptomatic increase in serum amylase activity, more than 1.5 times that of UHN, was detected in 10% of patients taking efavirenz, and y 6% of patients in control groups. The clinical significance of the asymptomatic increase in serum amylase activity is unknown.

Lipids: an increase in the concentration of total cholesterol (OCS) by 10-20% was observed in uninfected volunteers who took efavirenz. In clinical trials, the combined use of various ART efavirenz in patients previously treated with HAART for 48 weeks of treatment, there was an increase in total cholesterol concentration of 21-31%, cholesterol of high density lipoproteins (HDL) for triglycerides and 23-34% in 23- 49%. The percentage of patients in which the ratio of total cholesterol / HSLPVP was more than 5, has not changed. The magnitude of the change in lipid concentrations can be due to such factors,as the duration of therapy and the intake of other drugs in the combined ARVT.

Interaction in a cannabinoid test: Efavirenz does not bind to cannabinoid receptors, but there are reports of false positive urine tests for cannabinoids in uninfected volunteers and in HIV-infected patients who took efavirenz. The positive result of the cannabinoid screening test is recommended to be confirmed using special methods such as gas chromatography or mass spectrometry.

Children and teens

The type and incidence of adverse events in children are generally comparable to those observed in adult patients, with the exception of skin rash, which is more common in children (46% of children) than in adults and more severe (a severe skin rash was seen in 5.3% of children ). For the purpose of prophylaxis of the rash, it may be advisable to designate appropriate blockers H₁-gystamine receptors for children before the initiation of efavirenz therapy. Although the symptoms of the nervous system in young children are difficult to identify, it is believed that such symptoms are more rare in children and usually are mild.In 3.5% of patients, symptoms of moderate severity from the nervous system were observed, mainly dizziness. No child had severe symptoms and did not need to cancel therapy because of symptoms from the nervous system.

Other special patient groups

Activity of "hepatic" enzymes in patients simultaneously infected with hepatitis B or C

Among patients seropositive for hepatitis B and / or C, an increase in ACT activity more than 5 times higher than ULN was observed in 13% of patients taking efavirenz, and 7% of patients in the control group, and an increase in ALT activity was more than 5 times higher than ULN observed in 20% and 7% of patients, respectively. Among patients with co-infection 3% of patients taking efavirenz, and 2% of patients in the control group discontinued therapy because of violations of liver function (see "Special instructions").

Overdose:

In some patients who accidentally took efavirenz in a dose of 600 mg twice a day, there was an increase in symptoms from the nervous system. One patient experienced involuntary muscle contractions.

In the case of an efavirenz overdose, treatment should consist of general supportive measures,including the control of the basic indicators of vital activity of an organism and supervision over a clinical condition of the patient. To excrete a nonabsorbed preparation, one can use Activated carbon. There is no specific antidote for the treatment of an efavirenz overdose. Because the efavirenz actively binds to proteins, it is unlikely that dialysis can significantly remove the drug from the blood.

Interaction:

Efavirenz in vivo is the inducer of isoenzymes CYP3A4, CYP2B6 and UDF-GT1A1. Concentration in the blood plasma of compounds that are substrates of these isoenzymes may decrease with simultaneous use with efavirenz. In the same time in vitro efavirenz inhibited isoenzyme CYP3A4. Theoretically, this can lead to an increase in the exposure of substrates CYP3A4, therefore, care should be taken when using substrates CYP3A4 with a narrow therapeutic window. Efavirenz can be an inducer of isoenzymes CYP2C19 and CYP2C9, however in vitro there was also an inhibition of these isoenzymes. Until the end, the effect observed with the simultaneous use of efavirenz with substrate compounds of these isoenzymes is not clear (see the sections "Pharmacological properties", "Pharmacokinetics").

Exposure to efavirenz may increase with the use of the drug concomitantly with certain drugs (eg ritonavir) or foods (eg, grapefruit juice) that inhibit isoenzymes CYP3A4 or CYP2B6. Preparations based on the extract of Ginkgo Biloba, which induce these isozymes, can lead to a decrease in the concentration of efavirenz in the blood plasma.

Contraindicated combination therapy

Contraindicated the simultaneous use of efavirenz with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil and ergot alkaloids (eg, ergotamine, dihydroergotamine, ergometrine and methylergometrin), as inhibition of their metabolism by efavirenz can cause serious life-threatening consequences (see " Contraindications ").

St. John's wort perforated (Hypericum perforatum): patients receiving efavirenz, should not take drugs / products containing St. John's wort. The concentration of efavirenz in the blood plasma can decrease with simultaneous application to St. John's Wort, as it causes the induction of enzymes and / or transport proteins responsible for the metabolism of drugs.If the patient is already taking medications / products containing St. John's Wort, the latter should be discarded, the concentration of the virus in the blood should be checked and, if possible, the concentration of efavirenz in the blood. After withdrawal of drugs / products containing St. John's wort, the concentration of efavirenz may increase and then a dose adjustment of efavirenz will be required. The effect of St. John's wort, due to the induction of enzymes, can persist for at least 2 weeks after its cancellation (see section "Contraindications").

Other interactions

Interactions between efavirenz and HIV protease inhibitors, other antiretroviral drugs, in addition to HIV protease inhibitors, as well as between efavirenz and non-ARV drugs, are shown in Table 2 below.

An increase in the indicator value is indicated by the arrow "↑", a decrease in the value by the arrow "↓", if the indicator remains unchanged - by the arrow "↔"; if the drug was injected every 8 or 12 hours, this is designated as "k8h "or" k12h. "If necessary, 90% and 95% confidence intervals are shown in parentheses.Usually, studies were conducted on healthy volunteers, unless otherwise specified.

Table 2. Interactions between efavirenz and other drugs

Drugs, divided by pharmacotherapeutic groups (dose)

Effect on the concentration of the drug in the serum.

Average change in AUC, C_max, C_min(%) and confidence intervals, if applicable^a (mechanism)

Recommendations regarding the possibility of simultaneous use with efavirenz

ANTIMICROBIAL PREPARATIONS

Antiretroviral medications

HIV protease inhibitors

Atazanavir / ritonavir / efavirenz

(400 mg once a day / 100 mg once a day / 600 mg once a day, weights were taken during meals)

Atazanavir (after noon):

AUC: ↔ (from ↓ 9 to ↑ 10)

FROM_m_Oh: ↑ 17% * (from ↑ 8 to ↑ 27)

C_min: ↓ 42% * (from ↓ 31 to ↓ 51)

Simultaneous use of efavirenz with atazanavir / ritonavir Mr.e is recommended. If simultaneous use of atazanavir with NNRTI is required, consideration should be given to increasing the dose of atazanavir to 400 mg and ritonavir to 200 mg, in combination with efavirenz, with careful clinical monitoring.

Atazanavir / ritonavir / efavirenz

(400 mg once a day / 200 mg once a day / 600 mg once a day, all preparations were taken during meals)

Atazanavir (after noon):

AUC: ↔*^/** (from ↓ 10 to ↑ 2 6)

FROM_m_Oh: ↔*^/** (from ↓ 5 to ↑ 26)

C_min: ↑12%*^/** (from ↓ 16 before ↑49)

(induction of CYP3A4).

* When compared with atazanavir 300 mg / ritonavir 100 mg 1 time per day in the evening without efavirenz. Such a decrease in C_min Atazanavir can adversely affect the effectiveness of atazanavir

** based on a historical comparison.

Darunavir / ritonavir / efavirenz

(300 mg twice a day * / 100 mg twice a day / 600 mg once a day)

* Below the recommended dose.

Similar results are expected when applied at the recommended doses.

Darunavir:

AUC: ↓ 13%

C_min: ↓31%

C_max: ↓15%

(induction of CYP3A4)

Efavirenz:

AUC: ↑ 21%

C_min: ↑17%

FROM_m_Oh: ↑15%

(inhibition of CYP3A4)

Simultaneous reception of efavirenz and darunavir / ritonavir (800 mg / 100 mg once a day) can lead to a decrease in C_min darunavir. If efavirenz should be used simultaneously with darunavir / ritonavir, a combination of darunavir / ritonavir in the 600 mg / 100 mg regimen should be used 2 times a day. However, this combination should be administered with caution. See the instructions for the medical use of darunavir / ritonavir.

See also information on ritonavir below.

Fosamprenavir / ritonavir / efavirenz

(700 mg twice a day / 100 mg twice a day / 600 mg once a day)

Clinically significant pharmacokinetic interaction was not revealed.

Correction of the dose of none of these medicines is required.

See also information on ritonavir below.

Fosamprenavir / nelfinavir / efavirenz

The interaction was not studied.

Correction of the dose of none of these medicines is required.

Fosamprenavir / saquinavir / efavirenz

The interaction was not studied.

The use of this combination is not recommended, since a significant reduction in the exposure of both HIV protease inhibitors is expected.

Indinavir / efavirenz

(800 mg k8h / 200 mg once a day)

Indinavir:

AUC: ↓ 31% (from ↓ 8 to ↓ 47)

C_min: ↓40%

A similar decrease in indinavir exposure was observed in cases when indinavir (1000 mg k8h) was administered in combination with efavirenz (600 mg once a day).

(induction of CYP3A4)

Efavirenz:

clinically significant pharmacokinetic interaction was not observed.

Although the clinical significance of reducing the concentration of indinavir is not established, the observed pharmacokinetic interaction should be taken into account when choosing a therapy regimen that includes both efavirenz and indinavir. Correction of the dose of efavirenz is not required if it is administered with indinavir or with indinavir / ritonavir.

See also information on ritonavir below.

Indinavir / ritonavir / efavirenz

(800 mg twice a day / 100 mg twice a day / 600 mg once a day)

Indinavir:

AUC: ↓ 25% (from ↓ 16 to ↓ 32)^b

C_max: ↓17% (from ↓ 6 to ↓ 26)^b

C_min: ↓50% (from ↓ 40 to ↓ 59)^b

Efavirenz:

Clinically significant interaction was not observed.

The geometric mean C_minIndinavir (0.33 mg / L) when used in combination with ritonavir and efavirenz was greater than when applied in monotherapy at 800 mg k8h (C_min 0.15 mg / l).

In patients infected with HIV-1 (n = 6), the indices of pharmacokinetics of indinavir and efavirenz were usually comparable to those of uninfected volunteers

Lopinavir / ritonavir in soft capsules or in oral solution / efavirenz

Significant decrease in exposure to lopinavir.

With simultaneous appointment with efavirenz should consider the increase in doses of lopinavir and ritonavir in soft capsules or in the solution for oral administration by 33% (4 capsules / ~ 6.5 ml 2 times a day instead of 3 capsules / 5 ml 2 times a day) . However, care should be taken because such a dose adjustment may not be sufficient for some patients.

Lopinavir / ritonavir in tablets / efavirenz

(400/100 mg twice a day / 600 mg once a day)

(500/125 mg twice a day / 600 mg once a day)

Concentrations of lopinavir:

↓30-40%

Concentrations of lopinavir are similar to those of lopinavir / ritonavir 400/100 mg twice daily without efavirenz.

The dose of lopinavir and ritonavir in tablets should be increased to 500/125 mg 2 times a day with simultaneous use with efavirenz 600 mg once a day.

See also information on ritonavir below.

Nelfinavir / efavirenz

(750 mg k8h / 600 mg once daily)

Nelfinavir:

AUC: ↑ 20% (from ↑ 8 to ↑ 34)

FROM_m_Oh: ↑21% (from ↑10 before ↑33)

This combination is usually well tolerated.

Correction of the dose of none of these medicines is required.

Ritonavir / efavirenz

(500 mg twice a day / 600 mg once a day)

Ritonavir:

AUC: in the morning: ↑ 18% (↑ 6 - ↑ 33)

AUC in the evening: ↔

FROM_m_Oh in the morning: ↑ 24% (↑ 12 - ↑ 38)

FROM_m_Oh in the evening: ↔

C_min in the morning: ↑ 42% (↑ 9 - ↑ 86)^b

C_min in the evening: ↑ 24% (↑ 3 - ↑ 50)^b

Efavirenz:

AUC: ↑ 21% (↑ 10 - ↑ 34)

FROM_m_Oh: ↑14% (↑4 - ↑26)

C_min: ↑25% (↑7 - ↑46)^b

(inhibition of CYP-mediated oxidative metabolism)

When taking efavirenz in combination with ritonavir 500 mg or 600 mg 2 times a day, the tolerance was low (for example, dizziness, nausea, paresthesia, increased activity of "hepatic" enzymes).

Sufficient data on the tolerability of efavirenz in combination with ritonavir in low doses (100 mg 1 or 2 times a day) are absent.

In the appointment of efavirenz with ritonavir in low doses, the possibility of increasing the frequency of adverse effects associated with efavirenz due to possible pharmacodynamic interaction should be considered.

Saquinavir / ritonavir / efavirenz

The interaction was not studied.

There are no data to develop recommendations for the dosing regimen.

See also information on ritonavir above.

The use of efavirenz in combination with saquinavir as the sole inhibitor of HIV protease is not recommended.

CCR5 chemokine receptor antagonists

Maraviroc / efavirenz

(100 mg twice a day / 600 mg once a day)

Maraviroc:

AUC₁₂: ↓45% (↓38 - ↓51)

FROM_m_Oh: ↓51% (↓37 - ↓62)

Concentrations of efavirenz were not measured, no interaction is expected.

See instructions for medical use of medications that include maraviroc.

HIV integrase inhibitor

Raltegravir / efavirenz

(400 mg single dose / -)

Raltegravir:

AUC: ↓ 36%

FROM₁₂: ↓21%

FROM_m_Oh: ↓36%

(induction of the enzyme UDF-GT1A1)

Correction of doses of raltegravir is not required.

Medicines from groups NOFROM and NNRTIs

NRTI / efavirenz

Research interactions of efavirenz and drugs from the NRTI group were not performed, except for interactions with lamivudine, zidovudine, and tenofovir with dizoproxil fumarate.

Clinically significant interactions are not anticipated, as the metabolism of NRTI drugs proceeds in ways other than those for efavirenz, and it is unlikely that they will compete for the same metabolic enzymes and elimination routes.

Correction of a dose of none of these medicines is required.

NNRTI / efavirenz

The interaction was not studied.

Since the use of two NNRTIs does not provide an advantage in terms of efficacy and safety, simultaneous use of efavirenz and other NNRTI agents is not recommended.

Medicines against hepatitis C virus

Bocepreviir / efavirenz

(800 mg three times a day / 600 mg once a day)

AUC: ↔ 19% *

FROM_m_Oh: ↔ 8%

C_min: ↓44%

Efavirenz:

AUC: ↔ 20%

FROM_m_Oh↔ 11%

C_min: ↓12% (↓24% - ↑1%)

(induction of CYP3A affects boceprevir)

* 0-8 hours

The lack of effect ("->) corresponds to a decrease in the average ratio by no more than 20% or an increase of no more than 25%.

The clinical significance of a decrease in the concentration of bocetrephir in blood plasma is not established.

Telaprevir / efavirenz

(1125 mg every 8 hours / 600 mg once daily)

Telaprevir (relative to 750 mg every 8 hours):

AUC: ↓ 18% (↓ 8 - ↓ 27)

FROM_m_Oh: ↓14% (↓3 - ↓24)

C_min_: ↓25% (↓14 - ↓34)%

Efavirenz:

AUC: ↓ 18% (↓ 10 - ↓ 26)

FROM_m_Oh: ↓24% (↓15 - ↓32)

C_min: ↓10% (↑1 - ↓19)%

(induction of CYP3A4)

When combined use of telaprevir and efavirenz is recommended to increase the dose of telaprevir to 1125 mg every 8 hours.

Symeprevir / efavirenz

(150 mg once a day / 600 mg once a day)

Simeprevir:

AUC: ↓ 71% (↓ 67 - ↓ 74)

FROM_m_Oh: ↓51% (↓46 - ↓56)

C_min: ↓91% (↓88 - ↓92)

Efavirenz:

AUC: ↔,FROM_m_Oh: ↔, C_min: ↔

(induction of CYP3A4)

The simultaneous administration of simeprevir with efavirenz results in a significant decrease in the concentration of the simeprevir in plasma due to the induction of CYP3A with efavirenz, which may lead to a loss of the therapeutic effect of simeprevir. Joint use of simeprevir and efavirenz is not recommended

Antibiotics

Azithromycin / efavirenz

(600 mg as a single dose / 400 mg once daily)

Clinically significant pharmacokinetic interaction was not revealed.

Correction of a dose of none of these medicines is required.

Clarithromycin / efavirenz

(500 mg to 12 hours / 400 mg once daily)

Clarithromycin:

AUC: ↓ 39% (↓ 30 - ↓ 46)

FROM_m_Oh: ↓26% (↓ 15 - ↓35)

14-Hydroxymetabolite of clarithromycin:

AUC: ↑ 34% (↑ 18 - ↑ 53)

FROM_m_Oh: ↑49% (↑32 - ↑69)

Efavirenz:

AUC: ↔

FROM_m_Oh: ↑11% (↑3 - ↑19)

(induction of CYP3A4)

Skin rash was observed in 46% of uninfected volunteers who simultaneously took efavirenz and clarithromycin.

The clinical significance of changes in the concentration of clarithromycin in the blood plasma is not established.

Instead of clarithromycin, one should consider the possibility of using another antibiotic, for example, azithromycin.

Correction of the dose of efavirenz is not required.

Other antibiotics from the macrolide group (eg, erythromycin) / efavirenz

The interaction was not studied.

There are no data to develop recommendations for the dosing regimen.

Anti-tuberculosis drugs

Rifabutin / efavirenz

(300 mg once a day / 600 mg once a day)

Rifabutin:

AUC: ↓ 38% (↓ 28 - ↓ 47)

FROM_m_Oh: ↓32% (↓15 - ↓46)

FROM_min: ↓45% (↓31 - ↓56)

Efavirenz:

AUC: ↔

FROM_m_Oh: ↔

FROM_min: ↓12% (↓24 - ↑1)

(induction of CYP3A4)

The daily dose of rifabutin should be increased by 50% if simultaneous use with efavirenz is planned.

It should also consider the feasibility of doubling the dose of rifabutin when rifabutin is used 2 or 3 times a week in combination with efavirenz.

Rifampicin / Efavirenz

(600 mg once a day / 600 mg once a day)

Efavirenz:

AUC: ↓ 26% (↓ 15 - ↓ 36)

FROM_m_Oh: ↓20% (↓11 - ↓28)

FROM_min: ↓32% (↓15 - ↓46)

(induction of CYP3A4 and CYP2B6)

If efavirenz is used concomitantly with rifampicin in patients with a body weight of 50 kg or more, the daily dose of efavirenz should be increased to 800 mg to provide an exposure similar to that of efavirenz in a daily dose of 600 mg without rifampicin. The clinical effect of such a dose adjustment has not yet been studied.

When adjusting the dose, individual tolerance and virologic response should also be considered (see "Pharmacological properties", "Pharmacokinetics").

Correction of a dose of rifampicin is not required.

Antifungal medicinal facilities

Itraconazole / efavirenz

(200 mg to 12 hours / 600 mg once daily)

Itraconazole:

AUC: ↓ 39% (↓ 21 - ↓ 53)

FROM_m_Oh: ↓37% (↓20 - ↓51)

FROM_min: ↓44% (↓27 - ↓58)

(reduction of the concentrations of itraconazole due to the induction of CYP3A4)

Hydroxyytraconazole:

AUC: ↓ 37% (↓ 14 - ↓ 55)

FROM_m_Oh: ↓35% (↓12 - ↓52)

FROM_min: ↓43% (↓18 - ↓60)

Efavirenz:

there were no clinically significant changes.

Since it is impossible to make recommendations on the dosage regimen of itraconazole, the possibility of using alternative antifungal medicines should be considered.

Posaconazole / efavirenz

- / 400 mg once a day

Posaconazole:

AUC: ↓ 50%

FROM_m_Oh: ↓45%

(induction of UDP-glucuronation)

The simultaneous use of posaconazole and efavirenz should be avoided, unless the expected benefit to the patient does not exceed the possible risk.

Voriconazole / efavirenz

(200 mg twice a day / 400 mg once a day)

Voriconazole:

AUC: ↓ 77%

FROM_m_Oh: ↓61%

Efavirenz:

AUC: ↑ 44%

FROM_m_Oh: ↑38%

With simultaneous use of efavirenz with voriconazole, the maintenance dose of voriconazole should be increased to 400 mg twice a day, and the dose of efavirenz is reduced by 50%, i.e. up to 300 mg once a day.

If the use of voriconazole is discontinued, the dose of efavirenz should be restored to the initial dose.

It should be borne in mind that tablets with a low dose of efavirenz in the Russian Federation are not registered.

Voriconazole / efavirenz

(400 mg twice a day / 300 mg once a day)

Voriconazole:

AUC: ↓ 7% (↓ 23 - ↑ 13) *

FROM_m_Oh: ↑23% (↓1 - ↑53)*

Efavirenz:

AUC: ↑ 17% (↑ 6 - ↑ 29) **

FROM_m_Oh: ↔**

* Compared with 200 mg 2 times a day when used in monotherapy

** Compared with 600 mg once a day when used in monotherapy (competitive inhibition of oxidative metabolism)

Fluconazole / efavirenz

(200 mg once a day / 400 mg once a day)

Clinically significant interaction was not revealed.

Correction of a dose of none of these medicines is required.

Ketoconazole and other antifungal agents - imidazole derivatives

The interaction was not studied.

There are no data that allow to develop recommendations on the dosage regimen.

ANTI-MALIGNANT MEDICINES

Atovahon / proguanil / efavirenz

(250 mg / 100 mg single dose / 600 mg once daily)

Atovahon:

AUC: ↓ 75% (from ↓ 62 to ↓ 84)

FROM_m_Oh: ↓ 44% (from ↓ 20 to ↓ 61)

Proguanil:

AUC: ↓ 43% (from ↓ 7 to ↓ 65)

FROM_m_Oh: ↔

If possible, simultaneous use of atovahona / proguanil with efavirenz should be avoided.

Artemether / lumefantrine / efavirenz

(20 mg / 120 mg, 6 doses of 4 tablets for 3 days / 600 mg once a day)

Artemether:

AUC: ↓ 51%

FROM_m_Oh: ↓21%

Dihydroartemisinin:

AUC: ↓ 46%

FROM_m_Oh: ↓38%

Lumefantrine:

AUC: ↓ 21%

FROM_m_Oh: ↔

Efavirenz AUC: ↓ 17%

FROM_m_Oh: ↔

(induction of CYP3A4)

It is possible to reduce the antimalarial effect due to a decrease in the concentration of artemether and lumefantrine with simultaneous use with efavirenz.

Caution should be exercised while using efavirenz with artemether and lumefantrine.

ANTACIDE MEDICINES

Antacids containing aluminum hydroxide - magnesium hydroxide - simethicone / efavirenz

(30 mL single dose / 400 mg single dose)

Famotidine / efavirenz

(40 mg single dose / 400 mg single dose)

As antacids containing aluminum hydroxide or magnesium hydroxide, and famotidine do not adversely affect the absorption of efavirenz.

It is unlikely that with the use of efavirenz with drugs that affect the pH of gastric contents, the absorption of efavirenz will change.

ANKSIOLITHICS

Lorazepam / efavirenz

(2 mg single dose / 600 mg once daily)

Lorazepam:

AUC: ↑ 7% (↑ 1 - ↑ 14)

FROM_m_Oh: ↑16% (↑2 - ↑ 32)

These changes are not considered clinically significant.

Correction of a dose of none of these medicines is required.

ANTICOAGULANTS

Warfarin / efavirenz

Acenocoumarol / efavirenz

The interaction was not studied. Perhaps both an increase and a decrease in the concentration of warfarin / acenocoumarol in the blood plasma under the influence of efavirenz.

It may be necessary to adjust the dose of warfarin / acenocoumarol.

ANTI-SURGERY MEDICINES

Carbamazepine / efavirenz

(400 mg once a day / 600 mg once a day)

Carbamazepine:

AUC: ↓ 27% (↓ 20 - ↓ 33)

FROM_m_Oh: ↓20% (↓5 - ↓24)

FROM_min: ↓35% (↓24 - ↓44)

Efavirenz:

AUC: ↓ 36% (↓ 32 - ↓ 40)

FROM_m_Oh: ↓21% (↓15 - ↓26)

FROM_min ↓47% (↓41 -↓53)

(decrease in carbamazepine concentrations due to induction of CYP3A4, decrease in efavirenz concentrations due to induction of CYP3A4 and CYP2B6).

Equilibriumth values of AUC, C_m_Oh and C_min the active metabolite of carbamazepine epoxide does not change.

Interaction with the simultaneous use of higher doses of efavirenz or carbamazepine has not been studied.

There is no data on the basis of which it is possible to develop recommendations on the dosage regimen. Consider using another anticonvulsant drug.

It is recommended to carry out periodic monitoring of the concentration of carbamazepine in the blood plasma.

Phenytoin, phenobarbital and other anticonvulsant drugs, which are substrates of the CYP450 isoenzymes

The interaction was not studied. Perhaps both a reduction and an increase in the concentrations of phenytoin, phenobarbital and other anticonvulsant drugs, which are substrates of CYP450 isoenzymes (when used simultaneously with efavirenz).

If efavirenz It is used simultaneously with anticonvulsants, which are substrates of CYP450 isoenzymes, it is necessary to carry out periodic monitoring of concentrations anticonvulsants in the blood.

Valproic acid / efavirenz (250 mg twice a day / 600 mg once a day)

There was no clinically significant effect on the pharmacokinetics of efavirenz.

Limited data show that there is no clinically significant effect on the pharmacokinetics of valproic acid.

Correction of the dose of efavirenz is not required.

Patients should be monitored to monitor seizures.

Vigabatrin / efavirenz

Gabapentin / efavirenz

The interaction was not studied.

Clinically significant interactions are unlikely, since vigabatrin and gabapentin are excreted exclusively by the kidneys in an unchanged form and are unlikely to compete with the metabolizing enzymes and the ways of excretion of efavirenz.

Correction of the dose of none of the these medicines are not required.

ANTI-DEPRESSANTS

Selective serotonin reuptake inhibitors

Sertraline / efavirenz

(50 mg once a day / 600 mg once a day)

Sertraline:

AUC: ↓ 39% (↓ 27 - ↓ 50)

FROM_m_Oh: ↓29% (↓15 - ↓40)

FROM_min: ↓46% (↓31 - ↓58)

Efavirenz:

AUC: ↔

FROM_m_Oh: ↑11% (↑6 - ↑16)

FROM_min: ↔

(induction of CYP3A4).

An increase in the dose of sertraline should be performed taking into account the clinical response.

Correction of the dose of efavirenz is not required.

Paroxetine / efavirenz

(20 mg once a day / 600 mg once a day)

Clinically significant pharmacokinetic interaction was not revealed.

Correction of a dose of none of these medicines is required.

Fluoxetine / efavirenz

The interaction was not studied. Since fluoxetine has the same metabolic profile as paroxetine, i.e. it is a potent inhibitor of CYP2D6, one can expect that fluoxetine also will not interact with efavirenz.

Correction of a dose of none of these medicines is required.

Selective inhibitors of re-uptake of catecholamines (norepinephrine, dopamine)

Bupropion / efavirenz

(150 mg single dose (prolonged action) / 600 mg once daily)

Bupropion:

AUC: ↓ 55% (↓ 48 - ↓ 62)

FROM_m_Oh: ↓34% (↓21 - ↓47)

Hydroxybupropion:

AUC: ↔

FROM_m_Oh: ↑50% (↑20 - ↑80)

(induction of CYP2B6)

An increase in the dose of bupropion should be made taking into account the clinical response, but the dose should not exceed the maximum recommended dose. Correction of the dose of efavirenz is not required.

BLOCKERS H₁-GISTAIN RECEPTORS

Cetirizine / efavirenz

(10 mg single dose / 600 mg once daily)

Cetirizine:

AUC: ↔

FROM_m_Oh: ↓24% (↓18% - ↓30%)

These changes are not considered clinically significant.

Efavirenz:

Clinically significant interaction was not revealed.

Correction of a dose of none of these medicines is required.

CARDIOVASCULAR PREPARATIONS

Blocks of "slow" calcium channels

Diltiazem / efavirenz

(240 mg once a day / 600 mg once a day)

Diltiazem:

AUC: ↓ 69% (↓ 55 - ↓ 79)

FROM_m_Oh: ↓60% (↓50 - ↓68)

FROM_min: ↓63% (↓44 - ↓75)

Deacetylldithiazine:

AUC: ↓ 75% (↓ 59 - ↓ 84)

FROM_m_Oh: ↓64% (↓57 - ↓69)

FROM_min: ↓62% (↓44 - ↓75)

N-monodomethyl-dithiothiazem:

AUC: ↓ 37% (↓ 17 - ↓ 52)

FROM_m_Oh: ↓28% (↓7 - ↓44)

FROM_min: ↓37% (↓17 - ↓52)

Efavirenz:

AUC: ↑11% (↑5 - ↑18)

FROM_m_Oh: ↑ 16% (↑6 - ↑26)

FROM_min: ↑13% (↑1 - ↑26)

(induction of CYP3A4)

The increase in pharmacokinetic parameters of efavirenz was not regarded as clinically significant.

The question of the need for correcting the dose of diltiazem is solved in view of the clinical response (see the instructions for the medical use of diltiazem). Correction of the dose of efavirenz is not required.

Verapamil, felodipine, nifedipine and nicardipine

The interaction was not studied. If efavirenz is used simultaneously with any drug from the group of "slow" calcium channel blockers, which are substrates of the CYP3A4 isoenzyme, it is possible to reduce the concentration of this torus block in the blood plasma.

The question of the need for correction of doses of blockers of "slow" calcium channels is solved taking into account the clinical response (see instructions for the medical use of blockers of "slow" calcium channels).

HYPOLIDEMIC DRUGS

Inhibitors of HMG-CoA reductase

Atorvastatin / efavirenz

(10 mg once a day / 600 mg once a day)

Atorvastatin:

AUC: ↓ 43% (↓ 34 - ↓ 50)

FROM_m_Oh: ↓12% (↓1 - ↓26)

2-Hydroxy-atvastatin:

AUC: ↓ 35% (↓ 13 - ↓ 40)

FROM_m_Oh: ↓13% (↓0 - ↓23)

4-hydroxy-aortastatin:

AUC: ↓ 4% (↓ 0 - ↓ 31)

FROM_m_Oh: ↓47% (↓9 - ↓51)

Total activity of HMG-CoA reductase inhibitors:

AUC: ↓ 34% (↓ 21 - ↓ 41)

FROM_m_Oh: ↓20% (↓2 - ↓26)

Periodic monitoring of cholesterol concentration in the blood should be performed.

It may be necessary to adjust the dose of atorvastatin (see the instructions for the medical use of atorvastatin).

Correction of the dose of efavirenz is not required.

Pravastatin / efavirenz

(40 mg once a day / 600 mg once a day)

Pravastatin:

AUC: ↓ 40% (↓ 26 - ↓ 57)

FROM_m_Oh: ↓18% (↓59 - ↑12)

It should beimplement periodic monitoring of cholesterol concentration in the blood. It may be necessary to correct the dose of pravastatin (see instructions for the medical use of pravastatin).

Correction of the dose of efavirenz is not required.

Simvastatin / efavirenz

(40 mg once a day / 600 mg once a day)

Simvastatin:

AUC: ↓ 69% (↓ 62 - ↓ 73)

FROM_m_Oh: ↓76% (↓63 - ↓79)

Simvastatin acid:

AUC: ↓ 58% (↓ 39 - ↓68)

FROM_m_Oh: ↓51% (↓32 - ↓58)

Total activity of HMG-CoA reductase inhibitors:

AUC: ↓ 60% (↓ 52 - ↓ 68)

FROM_m_Oh: ↓62% (↓55 - ↓78)

(induction of CYP3A4)

With simultaneous use of efavirenz with atorvastatin, pravastatin or simvastatin, the values of AUC and C_m_Oh Efavirenz does not change.

Periodic monitoring of cholesterol concentration in the blood should be performed. It may be required correction of the dose of simvastatin (see the instructions for the medical use of simvastatin).

Correction of the dose of efavirenz is not required.

Rosuvastatin / efavirenz

The interaction was not studied.

Rosuvastatin is excreted mainly unchanged through the gastrointestinal tract with bile, so interaction with efavirenz is not expected.

Correction of a dose of none of these medicines is required.

HORMONAL CONTRACEPTES

For oral administration: Ethinylestradiol + norgestimate / efavirenz

(0.035 mg + 0.25 mg once a day / 600 mg once daily)

Ethinyl estradiol:

AUC: ↔

FROM_m_Oh:↔

C_min:↓8% (↑14 - ↑25)

Norelgestromine (active metabolite):

AUC: ↓ 64% (↓ 62 - ↓ 67)

FROM_m_Oh:↓46% (↓39 - ↓52)

C_min:↓82% (↓79 - ↓85)

Levonorgestrel (active metabolite):

AUC: ↓ 83% (↓ 79 - ↓ 87)

FROM_m_Oh: ↓80% (↓77 - ↓83)

C_min: ↓86% (↓80 - ↓90)

(induction of metabolism)

Efavirenz: clinically significant interaction is not revealed.

The clinical significance of these effects is not known.

In addition to hormonal contraceptives, a reliable method of barrier contraception should be used (see the section on "Application during pregnancy and during breastfeeding").

Prolonged action for intramuscular injection:

Depo-medroxyprogesterone acetate (DMPA) / efavirenz (150 mg of DMPA IM once)

Within 3 months of the study, there were no significant differences in the pharmacokinetic parameters medroxyprogesterone between volunteers receiving ARVT, efavirenz, and volunteers who did not receive ARVT.

In the second study, similar results were obtained, although the concentrations of medroxyprogesterone in the plasma differed to a greater extent. In both studies, plasma progesterone concentrations in volunteers who received efavirenz + depot-medroxyprogesterone acetate, remained low, which corresponded to suppressionMr.of ovulation.

In addition to hormonal contraceptives, a reliable method of barrier contraception should be used (see the section on "Application during pregnancy and during breastfeeding").

Implant:

Etonogestrel / efavirenz

The interaction was not studied. You can expect a decrease in the exposure of etonogestrel (induction CYP3A4).

During the post-registration period of observation, separate reports were received on the lack of contraceptive effect in the use of etonogestrel in patients taking efavirenz.

In addition to hormonal contraceptives, a reliable method of barrier contraception should be used (see the section on "Application during pregnancy and during breastfeeding").

IMMUNODEPRESSANTS

Immunosuppressants, which are metabolized by the isoenzyme CYP3A4 (for example, ciclosporin, tacrolimus, sirolimus) / efavirenz

The interaction was not studied. You can expect a decrease in the exposure of the immunosuppressant (induction of CYP3A4). It is unlikely that these immunosuppressants will affect the exposure of efavirenz.

You may need to adjust the dose of immunosuppressant.

It is recommended that the concentration of the immunosuppressant in the blood be carefully monitored for at least 2 weeks (until steady-state concentrations are established) from the start of efavirenz therapy or from the moment of its withdrawal.

OPIOIDS

Methadone / efavirenz

(stable maintenance dose, 35-100 mg once a day / 600 mg once a day)

Methadone:

AUC: ↓ 52% (↓ 33 - ↓ 66)

FROM_m_Oh:↓45% (↓25 - ↓59)

(induction of CYP3A4)

In a study involving HIV-infected patients who injected narcotics intravenously, it was found that simultaneous use of efavirenz and methadone led to a decrease in the concentration of methadone in the blood plasma and to the appearance of symptoms of opiate withdrawal. To reduce the severity of withdrawal symptoms, the methadone dose was increased by an average of 22%.

Patients should be monitored for the timely detection of withdrawal symptoms.

If necessary, the dose of methadone should be increased to reduce the severity of withdrawal symptoms.

Buprenorphine / naloxone / efavirenz

Buprenorphine:

AUC: ↓ 50%

Norbuprenorphine:

AUC: ↓ 71%

Efavirenz:

Clinically significant pharmacokinetic interaction was not revealed.

Despite a decrease in buprenorphine exposure, no symptoms of withdrawal were observed in patients.

No dosage adjustment is required for any of the medicines with simultaneous administration of buprenorphine and efavirenz.

^a 90% confidence intervals, unless otherwise indicated.

^b 95% confidence intervals.

UDF is uridine diphosphate.

HMG-CoA reductase - 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Children

Interaction studies were conducted only in adults.

Special instructions:

Efavirenz should not be used as a single drug for the treatment of HIV infection, nor should it be added as a single drug to an ineffective therapy regimen. As with other NNRTIs, with the use of efavirenz in monotherapy, the resistance of the virus can develop rapidly. When choosing new antiretroviral drugs for use in combination with efavirenz, the possibility of developing cross-resistance of the virus should be taken into account (see.section "Pharmacodynamics").

It is not recommended to use efavirenz simultaneously with tableted drugs with fixed combinations of efavirenz, emtricitabine and tenofovir dizoproxil fumarate, unless dose adjustment is required (for example, when used simultaneously with rifampicin).

It is not recommended simultaneous use of efavirenz with drugs based on the extract of Ginkgo Biloba.

When appointing drugs for simultaneous use with the drug Efkur-600, a physician should refer to instructions for the medical use of these medications.

Against the background of ARVT, the risk of HIV transmission to others during sexual contact or through blood can not be ruled out. In this regard, appropriate precautions should be observed.

Concomitant antiretroviral therapy: if the taking of any antiretroviral drug in combination ARVT is canceled due to suspicion of intolerance, consideration should be given to the simultaneous withdrawal of all antiretroviral drugs. Admission of all antiretroviral drugs that have been canceled should be resumed immediately after the disappearance of symptoms of intolerance.It is not recommended interrupted monotherapy and sequential re-appointment of antiretroviral agents because of the increased likelihood of the emergence of a resistant to therapy virus.

Skin rash: in clinical studies of efavirenz, there were easily and moderately severe rashes that usually disappear when the therapy is continued. Reception of the corresponding blockers H₁- Histamine receptors and / or glucocorticosteroids can improve tolerance and contribute to the early disappearance of skin rashes. A severe form of skin rash, accompanied by blisters, dsquamacis epithelium or ulceration, was observed in less than the 1% of patients taking efavirenz. Multiple exudative erythema or Stevens-Johnson syndrome occurred in 0.1% of patients. If patients develop a severe form of rash, accompanied by the appearance of blisters, desquamation of the epithelium with the involvement of the mucous membranes or fever, it is necessary to immediately stop taking efavirenz. Efavirenz It is not recommended for patients who have had a life-threatening skin reaction (for example, Stevens-Johnson syndrome).In the event of discontinuation of efavirenz therapy, consideration should be given to stopping the use of other antiretroviral drugs to avoid the emergence of a resistant to therapy virus.

Cases of skin rash were recorded in 59 of 182 children (32%) who received efavirenz treatment in 3 clinical trials with an average duration of 123 weeks. Have 6 children rash was severe. The median time of onset of rash in children was 27 days (3-1504 days). Before the beginning of efavirenz therapy in children, they can be recommended appropriate antihistamine therapy as a prophylaxis.

The experience with efavirenz in patients who have been abolished other antiretroviral drugs from the NNRTI class is limited (see "Side effect").

Efavirenz is not recommended for patients who, earlier on the background of taking other NNRTIs, have developed life-threatening skin reactions (for example, Stevens-Johnson syndrome).

Symptoms from the side of the psyche: there are data on the occurrence of undesirable phenomena on the part of the psyche in patients taking efavirenz. Patients with a history of mental disorders are at increased risk for developing serious adverse events from the psyche.In particular, severe depression was most often observed in patients with a history of depression. There are also post-registration data on cases of severe depression, death as a result of suicide, delirium and psychotic behavior.

Patients should be warned that with the development of such symptoms as severe depression, psychosis or suicidal ideation, they should immediately inform the doctor. The physician should determine the possible association of these symptoms with the use of efavirenz, and if this relationship is confirmed, assess the risk ratio for the patient when continuing therapy and the potential benefits of taking the drug (see "With caution").

Symptoms from the nervous system: in patients taking efavirenz in a dose of 600 mg 1 Once a day in the clinical trials, the following symptoms were often observed: dizziness, insomnia, drowsiness, decreased concentration and pathology of dreams, and other undesirable events. Symptoms from the nervous system were usually observed during the first or second day of therapy and in most cases disappeared after the first 2-4 weeks.Patients should be informed that such symptoms, if they appear, usually disappear when continuing therapy and are not a sign of possible mental disorders that occur less frequently.

Convulsive seizures: reported convulsions in patients taking efavirenz, especially in patients with a history of seizures. With the simultaneous use of anticonvulsant drugs, metabolized mainly in the liver, such as phenytoin, carbamazepine and phenobarbital, should periodically conduct a determination of the concentration of these drugs in blood plasma.

Study drug interactionslo that while carbamazepine was simultaneously used with efavirenz, carbamazepine concentrations in the blood plasma decreased (see section "Interaction with other drugs").

Patients with seizures in the anamnesis should be under special supervision.

Adverse events from the liver: in the post-marketing period of observation, a small number of reports on the development of hepatic insufficiency in patients without evidence of liver disease in the anamnesis were obtained, and also without other identified risk factors (see "Side effect").In this regard, it is recommended to monitor the activity of "hepatic" enzymes even in patients without a history of hepatic dysfunction or other risk factors.

Effect of food: when Efkur-600 is used during food intake, efavirenz exposure may increase (see "Pharmacological properties"), which can lead to an increase in the frequency of undesirable reactions (see the "Side effect" section). In this regard, it is recommended to take the drug Efkur-600 on an empty stomach, preferably at night.

Immunodeficiency Syndrome: this syndrome was observed in patients with severe immunodeficiency at any time after the initiation of combined ARVT. As a result of increased immune response due to therapy for several weeks or months from the start of treatment, an inflammatory response to inactive or residual opportunistic infections such as cytomegalovirus rhinitis, generalized and / or focal mycobacterial infections, pneumonia caused by Pneumocystis jiroveci (former name Pneumocystis carinii). Such inflammatory symptoms need further evaluation and appropriate treatment.

Autoimmune disorders (such as diffuse thyrotoxic goiter) were observed against the background of restoration of immunity, but the time of initial manifestations varied greatly and the disease could occur many months after the initiation of therapy.

Lipodystrophy and metabolic disorders: combined ARVT is associated with the redistribution of subcutaneous fat body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of this phenomenon are still unknown and the mechanism of its development has not been studied sufficiently. A link between visceral lipomatosis and the use of protease inhibitors and lipoatrophy and the use of NRTIs is suggested. An increased risk of lipodystrophy may be due to as individual factors, such as old age, and factors associated with taking medications, such as prolonged ARVT and associated metabolic disorders. In this regard, a clinical examination of the patient should be a physical examination, paying attention to the redistribution of subcutaneous fat, as well as determine the concentration of lipids in the fasting serum and the concentration of glucose in the blood.Disorders of lipid metabolism should be adjusted in accordance with clinical manifestations.

Osteonecrosis: although the etiology of this disease is recognized as multifactorial (including the use of corticosteroids, alcohol abuse, severe immunosuppression, increased body mass index), cases of osteonecrosis have been observed predominantly in patients with long-term HIV infection and / or in patients receiving long-term combined ARVT. Patients should immediately consult a doctor if joint pain occurs, joint mobility is reduced, or walking difficulties occur.

Special patient groups

Patients with liver disease: efavirenz is contraindicated in patients with severe degree of hepatic insufficiency (class C in the Child-Pugh system) (see "Contraindications", "Pharmacological properties") and is not recommended for patients with moderate liver damage, since at the moment there is not enough data to establish, Do you need a dose adjustment in such cases?

Due to the intensive metabolism of efavirenz under the influence of the cytochrome P450 system and the limited experience of clinical use of the drug in patients withchronic liver diseases, caution should be exercised when prescribing the drug Efkur-600 patients with liver disease of mild severity. Thus patients should be under supervision for timely revealing dose-dependent undesirable reactions, especially from nervous system. Also, at certain intervals, laboratory tests should be performed to assess the liver condition.

The safety and effectiveness of efavirenz have not been confirmed in patients with significant violations of the liver function in history. Patients with chronic hepatitis B or C taking combined ARVT are at risk for developing severe adverse liver reactions that can lead to death. Y nacetandactors from a history of liver failure, including chronic active hepatitis, increases the incidence of liver function abnormalities in combined ARVT, so these patients should be monitored in accordance with the standard scheme. In patients with worsening of liver disease or with a steady increase in serum transaminase activity, which exceeds 5 once IGN, the benefit of continuing efavirenz therapy should be compared with the possible risk of hepatotoxicity. For such patients, consideration should be given to the feasibility of discontinuing or canceling ARVs.

With the simultaneous use of other drugs with known hepatotoxicity, it is recommended to monitor the activity of "hepatic" enzymes. Patients with hepatitis B or C with the appointment of combined antiviral therapy should also be guided by instructions for the use of prescribed drugs for the treatment of hepatitis B or C.

Patients with renal insufficiency: the pharmacokinetics of efavirenz in patients with renal insufficiency has not been studied, but due to the fact that in unchanged kidneys less 1% of the accepted dose of efavirenz, renal dysfunction should not have a significant effect on the excretion of efavirenz (see section "Pharmacological properties"). The experience of using efavirenz in patients with severe renal failure is absent, and therefore, such patients should carefully monitor the safety of the drug.

Older patients: Since a small number of elderly patients have been included in clinical trials, there is no reason to assume that the effect of the drug on elderly patients differs from that in younger patients.

Children: The use of efavirenz in children less than 3 months of age or weighing less than 3.5 kg has not been investigated.

Effect on the ability to drive transp. cf. and fur:

There have been no studies to assess the impact on the ability to drive vehicles and work with machinery. Efavirenz may cause dizziness, attention disturbance, insomnia and other unwanted medications from the CNS. Patients should be warned that if they have any of these symptoms, they should avoid driving and working with machinery.

Form release / dosage:

Film-coated tablets, 600 mg.

Packaging:

30 tablets per container of high-density polyethylene, sealed with a polymer screw cap, equipped with a mechanism for protection from children. A self-adhesive label is attached to the container.

One container, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date shown on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004056

Date of registration:29.12.2016

Expiration Date:29.12.2021

The owner of the registration certificate:Emkur Pharmaceuticals Inc. Emkur Pharmaceuticals Inc. USA

Manufacturer: & nbsp

EMCURE PHARMACEUTICALS Ltd India

Representation: & nbspEMKYUR PHARMACEUTICALS LIMITEDEMKYUR PHARMACEUTICALS LIMITEDRussia

Information update date: & nbsp27.01.2017

Illustrated instructions

Instructions

Efkur-600 (EFCURE-600)