Efavirenz Canon - instructions for use, dose, side effects, contraindications

Excipients: giprolose low-substituted (hydroxypropylcellulose) 10 mg, silicon colloidal 4 mg, croscarmellose sodium 16 mg, lactose monohydrate 73 mg, magnesium stearate 4 mg, sodium lauryl sulfate 4 mg, povidone K-30 18 mg, microcrystalline cellulose 71 mg;

composition of film shell: Fill yellow with 12 mg, including: [giprolose (hydroxypropyl cellulose) 4.2 mg, hypromellose (hydroxypropylmethylcellulose) 4.08 mg, titanium dioxide 3.222 mg, iron oxide oxide yellow 0.4956 mg, sunset sunset yellow 0.0024 mg ].

1 tablet, film-coated 600 mg, contains:

active substance: efavirenz 600 mg;

Excipients: giprolose low-substituted (hydroxypropylcellulose) 30 mg, silicon dioxide colloid 12 mg, croscarmellose sodium 48 mg, lactose monohydrate 219 mg, magnesium stearate 12 mg, sodium lauryl sulfate 12 mg, povidone K-30 54 mg, microcrystalline cellulose 213 mg;

composition of film shell: Fill yellow 36 mg, including: [giprolose (hydroxypropyl cellulose) 12.6 mg, hypromellose (hydroxypropylmethylcellulose) 12.24 mg, titanium dioxide 9.666 mg, iron oxide dye yellow 1,4868 mg, dye sunset yellow 0.0072 mg ].

Description:

Tablets are round biconvex (dosage 200 mg) or oval biconvex (600 mg dosage), covered with a film coat of brownish-yellow color. On the cross-section - almost white.

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 (RT) and does not significantly inhibit HIV-2 RT and DNA polymerase (α, β, γ, δ) of human cells.

Antiviral activity. Antiviral efficacy of efavirenz in vitro was evaluated on lymphoblastic cell lines, mononuclear cells of peripheral blood, and macrophage / monocyte cultures. The inhibitory concentration (IR) of efavirenz, necessary for 90-95% inhibition (IR_90-95) of wild-type strains or laboratory 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 RT in positions 48, 108, 179, 181 or 236, as well as for varieties 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 (L1001, 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 viremia) 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 isolates resistant to ISPI contained a replacement K103N or the replacement of valine by isoleucine at position 108 (VI081) 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 (C_m_Oh) of efavirenz in the blood plasma of 1.6-9.1 μmol / l was achieved 5 hours after a single oral intake of the drug in doses from 100 to 1600 mg. Dose-dependent increase in C_m_Oh and the area under the "concentration-time" curve (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. Time to reach C_m_Oh 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 an equilibrium concentration of the drug in the blood plasma mean C_m_Oh, the minimum concentration (C_min) and AUC were linear with the admission of 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 once a day, C_m_Oh 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 / Lh.

Influence of food intake or absorption. With a single admission of healthy volunteers, efavirenz in a dose of 600 mg in the form of tablets coated with a film coat, along with food with a high fat content, there was an increase AUC na 28% and C_m_Oh on 79% in comparison with the given parameters at reception of a preparation on an empty stomach.

Distribution. Efavirenz is highly associated with plasma proteins (approximately 99.5-99.75%), mainly with albumin. In HIV-1 infected patients (n = 9) who took efavirenz in doses of 200 to 600 mg once a day for at least 1 month, the concentration of efavirenz in cerebrospinal fluid was from 0.26 to 1.19% (averaging 0.69%) from 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.

Metabolite. 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 the main 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 can be clinically 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 isoform 1A1 of uridine-diphosphate-glucuronyltransferase (UDF-GT1A1), therefore the concentration of raltegravir, which is the substrate of UDF-GT1A1,in blood plasma decreases 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 Efavirenz is excreted by the kidneys unchanged.

Pharmacokinetics in specific patient groups

Violation of the function of the liver. 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 Caution).

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

Sex and race. In men and women, as well as in patients of different racial affinities, there were similar pharmacokinetic parameters of efavirenz.

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 a sufficient number of patients 65 years of age or older.

Children. Efavirenz It has not been studied in children under 3 months of age or weighing less than 3.5 kg. Pharmacokinetic parameters of efavirenz in children and adults were similar. In 49 children who took efavirenz in a dose equivalent to 600 mg (the dose was calculated based on body weight), the value of C_m_Oh 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 the human immunodeficiency virus (HIV-1).

Contraindications:

- Hypersensitivity to any of the components of the drug;

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

- hepatic insufficiency of severe degree (class C according to the Child-Pugh classification);

- children under the age of 3 years or with a body weight of less than 13 kg (for a dose of 200 mg), children weighing less than 40 kg (for a dose of 600 mg);

- simultaneous administration with terfenadine, astemizole, cisapride, pimozide, bepridil, midazolam, triazolam and ergot alkaloids (eg, 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, cardiac arrhythmias, prolonged sedation or respiratory depression);

- simultaneous administration with saquinavir as the only protease inhibitor, other non-nucleoside reverse transcriptase inhibitors (see section "Interaction with other drugs");

- simultaneous reception with preparations containing St. John's wort perfumed (Hypericum perforatum), since it is possible to reduce the concentration of efavirenz in the blood plasma and reduce its clinical effect (see section "Interaction with other drugs").

Carefully:

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

- patients with violations of liver function of mild and moderate severity (class A and B according to the Child-Pugh classification);

- with the appointment of efavirenz to patients who have convulsions (including in history);

- Patients receiving concomitant anticonvulsants with a predominant metabolism in the liver, such as phenytoin, carbamazepine and phenobarbital (it is necessary to carry out periodic monitoring of blood concentrations) (see section "Special instructions";

- 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 is not 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:

Inside, the drug is recommended to be taken before going to bed on an empty stomach.

Efavirenz intake during meals can increase the exposure of efavirenz and lead to an increase in the incidence of adverse reactions. Efavirenz therapy should be prescribed by a doctor who has experience in the treatment of HIV infection.

Efavirenz should be given in combination with other antiretroviral drugs and drugs.

Adults

Efavirenz is prescribed in combination with NRTIs with or without an HIV protease inhibitor at 600 mg once daily.

Dose correction

If efavirenz is applied simultaneously with voriconazole, the dose of voriconazole should be increased to 400 mg twice a day, and the dose of efavirenz should be reduced to 300 mg * once a day. After cessation of therapy with voriconazole, the initial dose of efavirenz (600 mg) should be used (see Interaction with other drugs).

If efavirenz is used concomitantly with rifampicin in patients with a body weight of 50 kg or more, an increase in the dose of efavirenz to 800 mg 1 time per day may be required (see Interactions with Other Drugs).

* with the simultaneous use of the drug Efavirenz Canon and voriconazole, one should bear in mind that tablets with a low dose of efavirenz in the Russian Federation are not registered.

Children from 3 years old

Efavirenz 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). Efavirenz may be prescribed only to those children who can swallow tablets. The safety and effectiveness of efavirenz in children under 3 years of age or body weight less than 13 kg are not established.

Table 1. Doses for children with Efavirenz Canon once a day *

Body weight, kg	Dose of the drug Efavirenz Canon, 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 weighing less than 40 kg are given for information only and are not applicable for tablets at 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 unchanged kidneys less than 1% of the dose of efavirenz is withdrawn, renal dysfunction should not have a significant effect on the excretion of efavirenz (see Special instructions).

Patients with hepatic insufficiency

Have patients with liver diseases of mild severity, correction of the dose of efavirenz is not required. In this case, patients should be carefully observed for the development of unwanted reactions, especially from the nervous system (see Contraindications and Special instructions).

It is not recommended to use efavirenz in patients with moderate hepatic insufficiency, since at the moment there is not enough data to establish whether dose correction is necessary in such cases.

Side effects:

General security profile

Generally efavirenz well tolerated in clinical studies. In the subgroup of patients who took efavirenz in a dose of 600 mg once a day in combination with HIV protease inhibitors and / or NRTIs, the most frequent (at least 5% of patients) adverse reactions at least (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%) were of average severity.

The most noticeable adverse events associated with taking efavirenz were a skin rash and symptoms from the nervous system. Symptoms from the nervous system usually appeared shortly after the initiation of therapy and, as a rule, disappeared after the first 2-4 weeks of therapy. Also in patients who took efavirenzsevere skin reactions, such as Stevens-Johnson syndrome and multiform erythema exudative, have been observed; mental disorders, including severe depression, death due to suicide and psychotic behavior, as well as convulsive seizures.When efavirenz is used simultaneously with food, the systemic exposure of efavirenz may increase, which can lead to an increase in the frequency of undesired reactions (see Special instructions). Safety profile for long-term therapy, including efavirenzwere evaluated in a controlled trial in which patients took either efavirenz + zidovudine + 3TC for 180 weeks, or efavirenz + indinavir for 102 weeks, or indinavir + zidovudine + 3TC for 76 weeks. Long-term use of efavirenz in this study was not accompanied by the appearance of any new safety data.

The following are moderate and severe adverse reactions, for which a possible causal relationship was established with the treatment regimen used (according to the researchers) and which were observed during clinical trials of efavirenz used in the recommended dose in combination ARVT. Italic events are identified that were registered during the post-registration period of the use of efavirenz in combination therapy.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

Infrequently: hypersensitivity.

Disorders from the metabolism and nutrition

Often: hypertriglyceridemia¹; infrequently: hypercholesterolemia¹.

Disorders of the psyche

Often: pathological dreams, anxiety, depression, insomnia¹; infrequently: propensity to affect, aggressiveness, confusion, mood with a penchant for euphoria, hallucinations, mania, paranoid behavior, psychosis², suicidal attempt, suicidal intentions; rarely: rave³, neurosis³, death due to suicide^3,1.

Disturbances from the nervous system

Often: disorders of cerebellar coordination and balance², attention deficit (3.6%), dizziness (8.5%), headaches (5.7%), drowsiness (2.0%)¹; infrequently: anxiety, amnesia, ataxia, impaired coordination of movements, convulsions, impaired thinking, tremor².

Disturbances on the part of the organ of sight

Infrequently: blurred vision.

Hearing disorders and labyrinthine disorders

Infrequently: noise in ears², vertigo.

Violation of the vessels

Infrequently: "tides" of blood to the skin of the face².

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 (ACT)¹, alanine aminotransferase (ALT)¹ and gamma-glutamyl transferase (GGT)¹; infrequently: acute hepatitis; rarely: hepatic failure^3,1.

Disturbances from the skin and subcutaneous tissues

Often: skin rash (11.6%)¹; often: itching; infrequently: exudative erythema multiforme, syndrome Stevens-Johnson¹; rarely: photo allergic dermatitis².

Violations of the genitals and mammary gland

Infrequently: gynecomastia.

General disorders

Often: increased fatigue.

¹For a more detailed description, see below.

²These undesirable reactions were recorded in the post-registration period of observation; the frequency of these reactions was determined using data from 16 clinical trials (3969 patients).

³These undesirable reactions were recorded during the post-registration period of observation, however, in patients taking efavirenz in 16 clinical trials, they were not reported as phenomena associated with the use of the drug. According to the frequency classification, these side effects were regarded as observed "rarely" (based on an upper bound estimate of 95% confidence interval for 0 events, based on the number of patients taking efavirenz in the course of these clinical studies (n = 3969)).

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, compared with 17% of patients in control groups. In 18% of patients, the skin rash was associated with efavirenz, while 1.7% of patients were discontinued due to 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. In 6 children, the 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 rashes develop, which appear during the first two pellets after the 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 recommending 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 taking combined ARVT with efavirenz and 0.6% in the control group of patients, suicidal intentions of 0.6% and 0, 3%, suicide attempts without lethal outcome 0.4% and 0%, aggressive behavior 0.4% and 0.3%, paranoid reactions 0.4% and 0.3%, manic reactions 0.1% and 0% respectively .

Patients with a history of mental disorders are at increased risk for 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 Post-registration period reports of deaths as a result of suicide, delusional disorders and psychosocial behavior were received.

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 - 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 1 hour 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 p.Method of administration and dose). 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.

Syndrome of restoration of immunity. 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, posterior neck ("buffalo buffalo") and mammary hypertrophy.

Combined ARVT can induce metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia (see Specific guidance).

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

Laboratory indicators

"Hepatic" enzymes: increased activity ACT and ALT more than 5 times higher than the upper limit of the norm (VGN) was observed in 3% of patients from 1008 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 in 1,5-2% of patients from the control group (7% with prolonged ARVT with efavirenz and 3% with prolonged ARVT 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 in 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 studies of the use of different combination ARVT with efavirenz in patients who had not previously received ARVT, an increase in the concentration of OCC by 21-31%, high-density lipoprotein cholesterol (HDL-C) by 23-34%, and triglycerides by 23- 49%.The proportion of patients who had a ratio of OXC / HDL cholesterol greater than 5 did not change. The magnitude of changes in lipid concentrations can be due to factors such as the duration of therapy and the intake of other drugs in combination ARVT.

Interaction during the test for cannabinoids: 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 have been taking 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 efavirenz therapy. Although symptoms from the nervous system in young children are difficult to identify, it is believed that such symptoms in children are less common 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, increased activity ACT more than 5 times higher than ULN observed in 13% of patients who took 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 liver dysfunction (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 control of the basic indicators of vital activity of the body and monitoring the 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 it binds to proteins, it is unlikely that with a significant removal of the drug from the blood.

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 selecting new antiretroviral drugs for use in combination with efavirenz, the possibility of developing cross-resistance of the virus should be considered (see Pharmacodynamics).

It is not recommended to use efavirenz concomitantly with tableted medicines with fixed combinations of efavirenz,emtricitabine and tenofovir disoproxil fumarate, unless dose adjustment is required (eg, with rifampicin).

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

When prescribing drugs for simultaneous use with efavirenz, the doctor 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, which usually disappeared with the continuation of therapy. Reception of the corresponding blockers H₁histamine 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, desquamation of the epithelium or the formation of ulcers, was observed in less than 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 involvement of mucous membranes or fever, it is necessary to immediately stop taking efavirenz.Efavirenz 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 the therapy virus (see Adverse Effect).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. In 6 children, the 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 Adverse Effect). Efavirenz It is not recommended for patients who previously had other life-threatening skin reactions (such as Stevens-Johnson syndrome) in the presence of other NNRTIs.

Symptoms from the side of the psyche: there are data on the origin of adverse effects 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 symptoms such as severe depression, psychosis or suicidal ideation, they should immediately notify their doctor. The doctor should determine the possible connection of these symptoms with the use of efavirenz, and if this relationship is confirmed, assess the risk ratio for the patient while continuing therapy and the potential benefits of taking the drug (see Adverse Effect).

Symptoms from the nervous system: in patients taking efavirenz in a dose of 600 mg once a day as part of clinical trials, the following symptoms were often observed: dizziness, insomnia, drowsiness, decreased concentration and pathology of dreams, and other adverse events (see Side Effects). 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 occur,usually disappear when continuing therapy and are not a sign of possible violations from the psyche, which are less common.

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, it is necessary to periodically determine the concentrations of these drugs in the blood plasma. The study of drug interactions showed that when carbamazepine and efavirenz were used simultaneously, concentrations of carbamazepine in the blood plasma decreased (see 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 failure in patients without evidence of liver disease in the anamnesis, and also without other identified risk factors (see Side act).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 efavirenz is used during meals, the exposure of efavirenz may increase (see Pharmacological properties), which can lead to an increase in the frequency of undesired reactions (see Adverse Effect). In this connection it is recommended to take efavirenz 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 an increase in the 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 retinitis, 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. The connection between visceral lipomatosis and use of protease inhibitors and lipoatrophy and the use of NRTIs. The increased risk of lipodystrophy may be due to both 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 (see Adverse Effect).

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 hepatic insufficiency (class C in the Child-Pugh system) (see Contraindications; Pharmacological properties) and is not recommended for patients with moderate liver damage, because at the moment there is insufficient data to establish whether in such cases dose adjustment.

Due to the intensive metabolism of efavirenz by the cytochrome P450 system and the limited experience of clinical use of the drug in patients with chronic liver diseases should be careful when prescribing efavirenz for 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 regular intervals, laboratory tests should be performed to assess the liver condition (see Dosage and Administration).

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. In patients with a history of hepatic dysfunction, including chronic active hepatitis, the incidence of liver function abnormalities increases with combined ARVT, so these patients should be monitored in accordance with the standard regimen. In patients with worsening of the course of liver disease or with a steady increase in serum transaminase activity,exceeding more than 5 times the 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 appropriateness of interrupting or canceling ARVs (see Adverse Effect).

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, however, that in an unchanged form kidneys are taken out less than 1% of the accepted dose of efavirenz, a violation of kidney function should not have a significant effect on the excretion of efavirenz (see 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: Efavirenz in children younger than 3 months. 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:

The film-coated tablets are 200 mg and 600 mg.

Packaging:Packing at the "Canonfarm Production" CJSC, Russia.

Dosage of 200 mg: for 10 or 15 tablets in a contour mesh box made of a PVC film or PVC / PVC film and an aluminum printed lacquer foil.

For 30, 60 or 90 tablets in a can of polymer for medicinal purposes funds from polyethylene terephthalate with a lid of polypropylene.

By 3, 6, 9 contour cell packs of 10 tablets or 2, 4, 6 contiguous cell packs of 15 tablets or 1 bank of polymer for medicines, together with instructions for use are placed in a pack of cardboard.

Dosage 600 mg: 10 tablets per contour cell packaging made of polyvinylchloride film or PVC / PVDC film and aluminum foil printed lacquer.

For 30, 60 or 90 tablets in a polymer can for drugs from polyethylene terephthalate with a cap made of polypropylene.

By 3, 6, 9 contour cell packs of 10 tablets or 1 bank of polymer for medicines, together with instructions for use, are placed in a pack of cardboard.

Production and packaging at OOO "Plant named after academician VP Filatov", Russia.

Dosage of 200 mg: 30, 60 or 90 tablets in a polymer can for drugs from polyethylene terephthalate with a lid of polypropylene.

One bank of polymer for medicines, together with instructions for use, is placed in a pack of cardboard.

Dosage 600 mg: 30, 60 or 90 tablets in a polymer can for drugs from polyethylene terephthalate with a lid of polypropylene.

1 bank of polymer for medicines together with instructions for application is placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C in the manufacturer's packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004484

Date of registration:02.10.2017

Expiration Date:02.10.2022

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Plant named after academician VP Filatov, LLC Russia

Illustrated instructions

Instructions

Efavirenz Canon (Efavirenz Canon)