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

Excipients (core): lactose monohydrate 100.00 mg / 300.00 mg, corn starch 24.00 mg / 72.00 mg, sodium lauryl sulfate 5.67 mg / 17.00 mg. povidone K-30 13.33 mg / 40.00 mg, croscarmellose sodium 20.33 mg / 60.00 mg, crospovidone XL-10 18.67 mg / 56.00 mg, magnesium stearate 4.00 mg / 12.00 mg.

Auxiliary substances (shell): Fill white (polyvinyl alcohol 38.6%, gitanic dioxide 30.0%, talc 17.5%, macrogol 10.9%, lecithin 3.0%) 10.66 mg / 19.00 mg: macrogol 4000 0.08 mg / 0.04 mg, polysorbate-80 0.48 mg / 0.70 mg, hypromellose 1.00 mg / 1.20 mg, titanium dioxide 0.64 mg / 0.66 mg, quinoline yellow dye 1.14 mg / 1.40 mg.

Description:

Dosage 200 mg

Round biconvex tablets, covered with a film coating of yellow color. On the cross section, the core of the tablet is white or almost white in color.

Dosage 600 mg

Oblong biconvex tablets, coated with a film coat from yellow to brownish-yellow, with a risk on one side. On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:An 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 selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus tin 1 (HIV-1). It is a noncompetitive inhibitor of HIV-1 reverse transcriptase, does not inhibit HIV-2 reverse transcriptase and DNA polymerase (α, β, γ and δ) of human cells.

Sensitivity of HIV in vitro: the clinical significance of data on the sensitivity of HIV-1 to efavirenz in vitro has not been established. The antiviral efficacy of efavirenz in vitro was evaluated on the lines of lymphoblastic cells, peripheral blood mononuclear cells, and macrophage / monocyte cultures. The concentration of efavirenz needed for 90-95% of the inhibition of laboratory-adapted wild-type strains and clinical isolates is between 0.46 and 6.8 nmol / L. Efavirenz demonstrated synergistic activity in the cell culture in combination with nucleoside analogues - reverse transcriptase inhibitors (NRTIs), zidovudine, didanosine, and indinavir protease inhibitors.

Stability. The activity of efavirenz with respect to varieties of the virus with amino acid substitutions in reverse transcriptase at positions 48, 108, 179, 181 or 236, as well as for varieties with amino acid substitutions in the protease was the same as for wild type virus strains. The only substitutions resulting in the highest resistance to efavirenz in cell culture are the replacement of leucine with isoleucine at position 100 (L100I, 17-22 fold stability) and lysine for asparagine at position 103 (K103N, 18-33 fold stability). A more than 100-fold decrease in the susceptibility of viruses to the drug was observed for varieties of HIV. which, in addition to other amino acid substitutions in the reverse transcriptase, expressed K103N.

K103N is the most frequently observed substitution in reverse transcriptase in viral isolates from patients who have experienced a marked increase in viral load during clinical studies of efavirenz in combination with indinavir or a combination of zidovudine with lamivudine.This mutation was observed in 90% of patients with ineffective efavirenzem therapy. Substitutions in reverse transcriptase at positions 98, 100, 101, 108, 138, 188, 190 and 225 were also observed, but less frequently and often only in combination with K103N. The type of amino acid substitution in reverse transcriptase associated with resistance to efavirenz was independent of other antiviral drugs used in combination with efavirenz.

Cross-resistance. A study of cross-resistance profiles of efavirenz, nevirapine and delavirdine on cell cultures showed that replacing K.103N leads to a loss of susceptibility to all three NNRTIs. Two of the three examined delavirdine-resistant clinical isolates had cross-resistance to efavirenz and contained a replacement for K103N. Third isolate. having a substitution in reverse transcriptase at position 236, did not have a 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 (increase in the number of viral particles) 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 the replacement of K103N or the replacement of valine by isoleucine at position 108 (VI081) in reverse transcriptase. Among the tested isolates after ineffective efavirenz therapy, three isolates remained sensitive to efavirenz on cell cultures, and also had sensitivity to nevirapine and delavirdine.

The likelihood of cross-resistance between efavirenz and protease inhibitors is low due to various binding sites to the target and various mechanisms of action.

Pharmacokinetics:

Suction. After oral administration of a single dose from 100 to 1600 mg, the maximum concentration (C_max) efavirenz in plasma was achieved in 3-5 hours and was 1.6-9.1 μmol / l. Dose-dependent increase in C_max and the area under the concentration-time curve (AUC) is observed when the drug is taken in doses up to 1600 mg; this increase is less than proportional, indicating a reduction in absorption at higher doses.Time to reach C_max does not change after repeated administration, and the equilibrium concentration in plasma is reached after 6-7 days. In HIV-infected patients during the period of stable condition, the average C_max, (minimum concentration) C_min and AUC have a linear character when applied at a daily dose of 200, 400 and 600 mg.

Effect of food on absorption. Bioavailability of a single dose of efavirenz 600 mg when taken together with high-fat foods (about 1000 kcal, 50-60% of calories due to fat) increases by an average of 28% compared with taking the same dose of the drug on an empty stomach.

Distribution. The connection with blood plasma proteins is 99.5-99.75% (mainly with albumin). The concentration in the cerebrospinal fluid is 0.26-1.19% (on average 0.69%) of that in the plasma, which is approximately 3 times higher than the unbound protein fraction in the plasma.

Metabolism. Metabolized mainly by the cytochrome P450 system (mainly CYP3A4 and CYP2B6) to hydroxylated metabolites followed by their glucuronation. Metabolites are pharmacologically inactive. Efavirenz induces enzymes of the cytochrome P450 system, which leads to stimulation of its own metabolism.Repeated administration of 200-400 mg doses for 10 days causes its cumulation to be less than the expected degree (by 22-42% less), and with a shorter terminal half-life of OV2) - 40-55 h after multiple doses ( T1 / 2 single dose - 52-76 hours). The degree of induction of CYP3A4 is similar in the administration of doses of efavirenz 400 mg and 600 mg.

Efavirenz inhibits the isoenzymes CYP2C9, CYP2C19 and CYP3A4 in the range of concentrations observed in plasma. Does not inhibit CYP2F.1; CYP2D6 and CYP1A2 inhibit only in concentrations significantly exceeding those used in the clinic. Exposure of efavirenz in the blood plasma may increase in patients homozygous for polymorphism of the G516T gene of the CYP2B6 isoenzyme. It was also shown that efavirenz induces isoform 1A1 uridine-diphosphate-glucononyltransferase (UDF-GT1A1), therefore the concentration of raltegravir, which is the substrate of UDF-GT1A1, in blood plasma decreases with simultaneous use with efavirenzem.

Excretion. About 14-34% of efavirenz is excreted in the urine, less than 1% of the dose is excreted through the kidneys unchanged.

Pharmacokinetics in special groups of patients.

Liver failure. In patients with mild liver failure (class A according to the Child-Pugh classification), there were no significant differences in the pharmacokinetics of efavirenz.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.

Renal failure. The pharmacokinetics of efavirenz in patients with renal insufficiency has not been studied, however, given that less than 1% of efavirenz is excreted unchanged in urine, renal dysfunction should not have a significant effect on its excretion.

Sex, race and advanced age.

There were no significant differences in the pharmacokinetics of efavirenz in men and women, as well as in patients of different race. There are no pharmacokinetic differences in patients older than 65 years. although clinical studies of efavirenz did not include a sufficient number of patients 65 years of age or older.

Children. In children under 3 years of age or a body weight of less than 13 kg, the effect of efavirenz has not been studied. The pharmacokinetic parameters of efavirenz in children and adults were similar.

Indications:

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

Contraindications:

- Hypersensitivity to any other component of the drug.

- Simultaneous reception of terfenadine, astemizole, cisapride, midazolam. triazolam, pimozide, bepridil, ergot alkaloids (ergotamine, dihydroergotamine, ergonovine, metilergonovin) (efavirenz competitive interaction with CYP3A4 isoenzyme may lead to the suppression of metabolism of these drugs and create the potential for serious and / or life-threatening adverse events, including arrhythmias , prolonged sedation or respiratory depression).

- Simultaneous reception with preparations containing St. John's Wort (Hypericum perforatum), since it is possible to reduce the concentration of efavirenz in the blood plasma and reduce its clinical effect.

- Simultaneous treatment with saquinavir as the sole protease inhibitor, other non-nucleoside reverse transcriptase inhibitors (see. The section "Interaction with other drugs").

- Body weight less than 32.5 kg (for a dosage of 200 mg), body weight less than 40 kg (for a dosage of 600 mg).

- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption (formulation contains lactose).

- Hepatic insufficiency of severe severity (class C according to Child-Pugh classification).

Carefully:

- Patients with a history of psychiatric disorders are at increased risk of developing serious adverse reactions from the psyche.

- Patients with hepatic insufficiency of mild and moderate severity (class A and B according to the Child-Pugh classification).

- Patients who have convulsions (including anamnesis).

- Patients receiving concomitant anticonvulsants with a predominant metabolism in the liver, such as phenytoin, carbamazepine, phenobarbital, valproic acid, vigabartine (periodic monitoring of blood concentration is necessary).

- Simultaneous use with darunavir, artemether / lumefantrine.

Pregnancy and lactation:

Adequate and well-controlled studies in pregnant women have not been conducted. Efavirenz should not be used during pregnancy, except when it is necessary to use it (the potential benefit to the mother exceeds the risk to the fetus, and there are no other appropriate treatment options). Women receiving efavirenz, pregnancy should be avoided.In addition to oral or other hormonal contraceptives, other reliable contraceptive methods should be used, including for 12 weeks after discontinuing efavirenz treatment.

It is not known whether efavirenz with human breast milk. Because these animal studies suggest that. that the drug can penetrate into breast milk, women taking efavirenz during lactation, breast-feeding is not recommended. Under all circumstances, HIV-infected mothers are not recommended to breast-feed to avoid HIV transmission.

Dosing and Administration:

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

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

To improve the tolerability of side effects from the nervous system, the first 2-4 weeks of treatment, as well as in patients who have these effects persist, it is recommended to take the drug at bedtime.

Adults and children weighing more than 40 kg

- 600 mg once in a combination therapy with protease inhibitors and / or nucleoside reverse transcriptase inhibitors (NRTIs).

Children weighing over 32.5 kg: in combination with protease inhibitors and / or NRTI for children weighing from 32.5 kg doses are selected depending on body weight (see Table 1).

Efavirenz can be given only to those children who can swallow tablets.

Table 1. Doses for children with Efavirenz once a day

Weight, kg)	Dose of Efavirenz (mg)
32.5 to <40	400
From 40 and more	600

Correction of the dose.

When applied simultaneously with rifampicin in patients with a body weight of 50 kg or more, the dose of efavirenz should be increased to 800 mg / day. When appointing simultaneously with efavirenzem dose adjustment rifampicin is not required (see section "Interaction").

With simultaneous use of efavirenz with voriconazole, the maintenance dose of voriconazole should be increased to 400 mg every 12 hours, and the dose of efavirenz should be reduced by 50%. those. up to 300 mg once a day. When discontinuing voriconazole therapy, the dose of efavirenz should be restored.

Patients with renal insufficiency.

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

Patients with hepatic insufficiency.

In patients with mild liver function disorders, dose adjustment for efavirenz is not required. Thus patients should be under supervision for timely revealing dose-dependent undesirable reactions, especially from nervous system (see section "Special instructions").

In patients with violations of the liver function of moderate severity, the use of the drug is not recommended, since at the moment there is not enough data to determine whether correction of the dose is necessary in such cases.

Side effects:

Side effects are classified according to the frequency of development: very often (> 10%). often (> 1% and <10%), infrequently (> 0.1% and <1%), rarely (> 0.01% and <0.1%), very rarely (<0.01%).

From the nervous system: often - attention disorder, dizziness, headache, drowsiness, impaired cerebellar coordination and balance: infrequent - excitation, amnesia, ataxia, impaired coordination of movements, tremor, convulsions, pathological thinking. Usually the symptoms disappear after 2-4 weeks from the beginning of the drug intake

From the side of the psyche: often - pathological dreams,anxiety, anxiety, depression, insomnia, lability; infrequently, a tendency to affect, aggressiveness, confusion, euphoria, hallucinations, paranoid behavior, psychosis, suicidal attempts, suicidal intentions: rarely: completed suicides, delusions, mania, paranoia, neurosis.

From the immune system: infrequently, hypersensitivity reactions.

From the side of the organ of vision: infrequently - indistinctness of visual perception.

Co the sides of the hearing organ and labyrinthine disorders: infrequently - vertigo, noise in the ears.

From the digestive system: often - abdominal pain, diarrhea, nausea, vomiting; infrequently - pancreatitis.

Co side of the liver and bile ducts: infrequently acute hepatitis; rarely - liver failure.

From the respiratory system: rarely - shortness of breath.

From the cardiovascular system: rarely - a feeling of palpitations.

From the skin and subcutaneous tissues: very often - a rash; often - itchy skin; infrequently - multiforme exudative erythema, Stevens-Johnson syndrome, rarely - photoallergic dermatitis.

Co the sides of the genitals and the breast: infrequently - gynecomastia.

Laboratory parameters: hepatic enzymes: often - increased activity of "hepatic" transaminases: increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), amylases.

Lipids: in some cases an increase in the content of total cholesterol and high-density lipoproteins by 10-20% was observed.

Common violations: often - increased fatigue, vascular disorders, osteonecrosis; infrequently - asthenia, "tides" of blood to the skin of the face.

Description of individual adverse events.

Skin rash, usually a mild to moderate degree usually occurs while continuing treatment. Less than 1% of patients receiving the drug, there is a severe rash, including. Bullous, with wetness, desquamation or ulcers. In patients with severe rash, accompanied by the formation of blisters, desquamation, involvement of mucous membranes or fever, the drug must be discarded. A rash was observed in 26 children from 57 (46%) who received efavirenz for 48 weeks, three patients experienced a severe form of rash. Multiple exudative erythema or Stevens-Johnson syndrome occurred in 0.1% of patients (for details, see "Specific guidance").

Symptoms from the side of the psyche. Serious psychiatric adverse reactions were reported in patients who received efavirenz: severe depression, suicidal thoughts and attempts, aggressive behavior, paranoid behavior, mania. Patients who have experienced a history of mental illness are at greater risk of serious psychiatric adverse reactions. There were post-marketing reports of severe depression, death from suicide, delirium and psychotic behaviors (for a detailed description, see "Special instructions").

Symptoms from the nervous system. Symptoms, including dizziness, insomnia, drowsiness, impaired concentration and pathological dreams, were observed in patients who received efavirenz in a dose of 600 mg daily. These symptoms usually started within the first two days of therapy and usually disappeared after the first 2-4 weeks. Patients should be informed that if these symptoms occur, they will probably improve with continued therapy. Symptoms from the nervous system may occur more often when efavirenz take with food at the same time; use of the drug at night,will improve the tolerability of these symptoms and may be recommended during the first weeks of use.

Liver failure. There are post-marketing reports on the development of hepatic insufficiency (in patients who did not previously have a violation of liver function or other risk factors), which was characterized by fulminant course, in some cases leading to transplantation or lethal outcome (for details, see "Special instructions").

Osteonecrosis, cases of osteonecrosis were observed, mainly in patients with known risk factors, with long-term HIV infection, as well as in patients who took long-term combined LTVT. However, the frequency of this complication is not established.

Lipodystrophy and metabolic disorders. Combined antiretroviral therapy is associated with the redistribution of adipose tissue (lipodystrophy) in HIV-infected patients, including loss of peripheral and facial subcutaneous fat, increased intraperitoneal and internal fat, breast hypertrophy and fat accumulation in the back of the neck (buffalo buffalo).Combined antiretroviral therapy can cause metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia (for details, see "Specific guidance").

Immunodeficiency Syndrome was observed in patients taking a combination of antiretroviral drugs, including efavirenz. At the beginning of treatment, increasing the immune response due to therapy can lead to an inflammatory response to negative or residual opportunistic infections that need further evaluation and treatment. It was reported about the possible development autoimmune diseases (eg, Graves' disease), but the timing of their occurrence may be more diverse and these events may occur several months after the initiation of treatment (for a detailed description, see "Special instructions").

Children and adolescents: type and frequency of adverse events in children in general is similar to that in adults, with the exception of rash, which in children is more common than in adults and more pronounced. The appointment of appropriate antihistamines to children before initiation of efavirenz therapy for the purpose of preventing rash may be appropriate.

Overdose:

It was reported that the symptoms of the nervous system increased in patients with a random dose of 600 mg 2 times a day. One patient had involuntary muscle contractions.

Treatment: general supportive measures, including monitoring vital signs and monitoring the clinical condition of the patient. To accelerate the removal of a nonabsorbed drug, Activated carbon. There is no specific antidote. The effectiveness of dialysis is unlikely, because efavirenz actively binds to proteins.

Interaction:

Efavirenz is an inducer of isoenzymes CYP3A4, CYP2B6 and UGT1A1, therefore it can reduce the concentration in the plasma of drugs that are substrates of these isoenzymes. Efavirenz can be an inducer of CYP2C9 and CYP2C19 isoenzymes, however in in vitro studies efavirenz had an inhibitory effect on them. The concentration of efavirenz can be increased when combined with drugs (for example, ritonavir) or with food (for example, grapefruit juice) that inhibit the isoenzymes CYP3A4 or CYP2I36. Drugs that induce these enzymes can lead to a decrease in plasma concentrations of efavirenz.

Efavirenz should not be used concomitantly with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil and ergot alkaloids (eg, ergotamine, dihydroergotamine, ergometrine, methylergometrin), since inhibition of their metabolism by efavirenz can cause serious life-threatening adverse events.

St. John's Wort: the simultaneous administration of efavirenz and preparations containing St. John's wort is contraindicated, since this can lead to a decrease in the concentration of efavirenz in plasma. This effect is due to the induction of the CYP3A4 isoenzyme and can lead to loss of therapeutic effectiveness and development of resistance. The patient was already taking drugs / products containing St. John's wort, then the application of the latter should be canceled, the concentration of the virus in the blood checked and, if possible, the concentration of efavirenz in the blood. After withdrawal of preparations / 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, connected with the induction of enzymes,may persist for at least 2 weeks after its cancellation.

Concomitant antiretroviral drugs.

HIV protease inhibitors.

Atazanavir: simultaneous use with atazanavir / ritonavir is not recommended. If joint use of atazanavir with NNRTI is required, then it is necessary to increase the doses of both drugs (atazanavir and ritonavir) to 400 mg and 200 mg, respectively, therapeutic monitoring is necessary.

Darunavir: simultaneous use with darunavir / ritonavir at a dose of 800/100 mg once a day can lead to a decrease in C_min darunavir. The use of efavirenz in combination with darunavir / ritonavir in a dose of 600/100 mg is possible two times a day. This combination should be used with caution.

Indinavir: with simultaneous use with indinavir (800 mg every 8 hours) AUC and C_min indinavir decreased by 31 and 40%, respectively, as a result of the induction of CYP3A4.

When efavirenz is prescribed, 600 mg once daily with indinavir / ritonavir 800/100 mg twice daily AUC, C_max and C_min Indinavir declined by about 25%, 17% and 50%, respectively. The pharmacokinetic parameters of efavirenz taken in combination with indinavir / ritonavir are comparable to those given by single efavirenz (600 mg once daily).

It is not necessary to select a special dose for the administration of efavirenz with indinavir or indinavir / ritonavir.

Lopinavir / ritonavir: when this combination with efavirenz is used, the plasma concentration of lopinavir is reduced by 30-40%. When concomitant administration with efavirenz (600 mg once a day) should consider the increase in doses of lopinavir / ritonavir in soft capsules or oral solution by 33% (but 4 capsules / -6.5 ml 2 times a day instead of 3 capsules / 5 ml 2 times). However, care should be taken because such dose adjustment may not be sufficient for some patients. The dose of lopinavir / ritonavir in tablets should be increased to 500/125 mg twice a day with simultaneous use with efavirenzem 600 mg once a day.

Nelfinavir: while taking nelfinavir (750 mg 3 times a day) AUC and C_max Nelfinavir increases by 20% and 21%, respectively. When appointing efavirenz in combination with nelfinavir, dose adjustment is not required.

Ritonavir: simultaneous administration of efavirenz 600 mg once a day before bedtime and ritonavir 500 mg every 12 h resulted in an increase in the incidence of side effects (incl.dizziness, nausea, paresthesia) and the deviation of laboratory indicators (increased activity of "liver" enzymes). When appointing efavirenz together with ritonavir, it is recommended to keep a constant watch on the activity of liver enzymes.

Saquinavir: with the simultaneous administration of saquinavir (1200 mg 3 times a day) AUC and C_max saquinavir decreased by 62% and 50%, respectively. The administration of efavirenz in combination with saquinavir as the sole inhibitor of proteases is not recommended.

Saquinavir /ritonavir: there is no evidence of a possible interaction between efavirenz and combination saquinavir ritonavir.

Fosamprenavir: although efavirenz reduces C_max, C_min and AUC of amprenavir by approximately 40%, the effect of efavirenz is compensated by the pharmacokinetic booster effect of ritonavir. Thus, if efavirenz is prescribed in combination with fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily), no special dose selection is required.

In addition, when efavirenz is prescribed in combination with fosamprenavir / nelfinavir, there is no need to adjust the dose of any of these drugs.Treatment with efavirenz in combination with fosamprenavir / saquinavir is not recommended, since this combination causes a mutual weakening of the effect.

NNRTI: studies evaluating the use of efavirenz in combination with other NNRTIs have not been conducted, so there is no data on possible pharmacokinetic or pharmacodynamic interactions.

Antagonists CCR5. Maraviroc. With simultaneous use with maraviroc, efavirenz concentrations were not measured, interaction is not expected. See the instructions for medical use of medicines, which include maraviroc.

HIV integrase inhibitors. Raltegravir. With simultaneous use with raltegravir, dose adjustment is not required.

NRTI: studies of the interactions of efavirenz and drugs from the NRTI group have not been carried out, except for interactions with lamivudine, zidovudine, and tenofovir with disoproxil 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.

Hepatitis C protease inhibitors: Boceprevir. With the simultaneous use of boceprevir with efavirenzem, there was a decrease in plasma concentrations of bocepreviir. This condition has no clinical significance.

Telaprevir. With simultaneous use of efavirenz and telaprevir, the latter should be applied at a dose of 1125 mg every 8 hours.

Simeprevir. As a result of a significant decrease in the concentration in the plasma of simeprevir due to the induction of isoenzymes CYP3A4 by efavirenzem, a decrease in the therapeutic effect of simeprevir is possible. Simultaneous application of simeprevir and efavirenz is not recommended.

Antimicrobials:

Clarithromycin: simultaneous administration of efavirenz 400 mg once a day with clarithromycin 500 mg every 12 hours for 7 days leads to a decrease in AUC and C_max clarithromycin by 39 and 26%, respectively, is thin as AUC and C_max of active hydroxy metabolite of clarithromycin increased by 34% and 49%, respectively. The clinical significance of the change in the concentration of clarithromycin in plasma is unknown. In 46% of patients with efavirenz and clarithromycin, skin rashes are noted. When prescribed together with clarithromycin, dose adjustment for efavirenz is not required.Instead of clarithromycin, one should consider the possibility of using another antibiotic, for example, azithromycin.

Azithromycin: clinically significant pharmacokinetic interactions were not detected. When prescribing azithromycin in combination with efavirenz, dose adjustments are not required.

Other antibiotics from the macrolide group (eg, erythromycin) / efavirenz. There are no data to develop recommendations for the dosing regimen.

Rifampicin: when applied simultaneously with rifampicin in patients with a body weight of 50 kg or more, the dose of efavirenz should be increased to 800 mg / day. When appointing simultaneously with efavirenzem dose adjustment, rifampicin is not required. When adjusting the dose, individual tolerability and a virologic response should be considered. Rifabutin: has no significant effect on the pharmacokinetics of efavirenz. However, with simultaneous use with efavirenz, the daily dose of rifabutin should be increased by 50%. For therapeutic regimens in which rifabutin is taken two or three times a week, the dose of rifabutin should be doubled.

Antifungal preparations: Since it is impossible to give recommendations on changing the dosing regimen itraconazole, should consider the use of alternative antifungal drugs.

The simultaneous use of pose and efavirenz, unless the expected benefit to the patient does not exceed the possible risk.

With the simultaneous use of efavirenz with voriconazole, the maintenance dose of voriconazole should be increased to 400 mg every 12 hours, and the dose of efavirenz should be reduced by 50%, i.e. up to 300 mg once a day. When discontinuing voriconazole therapy, the dose of efavirenz should be restored.

With simultaneous appointment fluconazole and efavirenz of any clinically significant pharmacokinetic interaction is not observed.

There are no data to develop recommendations for the dosing regimen ketoconazole and other antifungal agents - imidazole derivatives.

Anti-malarial.

Artemether / lumefantrine. It is possible to reduce the antimalarial effect due to a decrease in the concentration of artemether and lumefantrine with simultaneous use with efavirenzem.Care should be taken when using this combination.

Atavahon / proguanil. If possible, simultaneous use should be avoided.

Antacids / famotidine: antacids containing aluminum or magnesium hydroxide; and famotidine, do not affect the absorption of efavirenz. Based on these data, it can be assumed that a change in the gastric pH due to the intake of other drugs is unlikely to affect the absorption of efavirenz.

Anticoagulants: efavirenz may increase or decrease the plasma concentration and effect of warfarin or acenocoumarol.

Anticonvulsants: with the simultaneous use of phenytoin and phenobarbital with efavirenz it is possible to reduce or increase the concentrations of these drugs in the blood plasma, therefore, periodic monitoring of their concentrations in the plasma should be carried out.

With the simultaneous use of carbamazepine, valproic acid, vigabartine and gabapeptin with efavirenzem, there is no need for correction of their dosing regimen, however, periodic monitoring of plasma concentrations of drugs should be performed. It is recommended the use of alternative anticonvulsants.

Care should be taken when prescribing the drug Efavirenz patients who have a history of cramps.

Antidepressants: with the simultaneous use of paroxetine and efavirenza no clinically significant changes in pharmacokinetic parameters are not noted. When using paroxetine and fluoxetine in combination with efavirenz, dose adjustments for these drugs are not required. Sertraline has no significant effect on the pharmacokinetics of efavirenz, efavirenz reduces C_max and AUC sertraline by 29 and 39%, respectively. An increase in the dose of sertraline when given in combination with efavirenz should be monitored by a clinical response.

Lorazepam: efavirenz increases C_max and AUC of lorazepam at 16 and 7%, respectively. With the simultaneous administration of efavirenz and lorazepam, dosage adjustment is not required.

Cetirizine: does not have a clinically significant effect on the pharmacokinetic parameters of efavirenz. Efavirenz reduces C_max cetirizine by 24%, but does not change the AUC. With the simultaneous administration of efavirenz and cetirizine, no dosage adjustment is required.

Inhibitors of reuptake of noradrenaline and dopamine. Bupropion. A clinical response should be used to increase the dose of bupropion, but not above the maximum allowable dose. Correction of the dose of efavirenz is not required.

Oral contraceptives: after a single administration of ethinyl estradiol AUC by efavirenz increases by 37%, while a significant change in C_max ethinyl estradiol is not noted. The clinical significance of these effects is unknown. Effects of a single dose of ethinylestradiol on C_max or AUC of efavirenz is not observed. Since the results of the possible interaction of efavirenz with oral contraceptives are not fully understood, barrier barrier methods should be used in addition to them. With the simultaneous use of efavirenz and depot-medroxyprogesterone acetate, etonogestrel, in addition to hormonal contraceptives, a reliable method of barrier contraception should be used.

Methadone: efavirenz reduces the level of C_max and methadone AUC at 45 and 52%, respectively; should gradually increase the dose of methadone to prevent the development of opiate withdrawal syndrome.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.

Inhibitors of HMG-CoA reductase: atorvastatin, pravastatin and simvastatin do not have a clinically significant effect on the pharmacokinetic parameters of efavirenz, efavirenz reduces their concentration in the plasma, which may require correction of the doses of atorvastatin, pravastatin and simvastatin. With simultaneous application with rosuvostatin, dose adjustment is not required. Periodic monitoring of cholesterol concentration in the blood should be performed.

Hormonal contraceptives. DepoMedroxyprogesterone acetate. because of a limited amount of available information, in addition to hormonal contraceptives, reliable methods of barrier contraception should be used.

Immunosuppressive drugs (eg, ciclosporin, tacrolimus, sirolimus). You may need to adjust the dose of immunosuppressants. When starting and / or stopping efavirenz therapy, it is necessary to monitor the concentration of immunosuppressants (until stable concentration is reached, at least 2 weeks).

Buprenorphine. With simultaneous application with buprenorphine, correction of the dose of buprenorphine or efavirenz is not required.

Calcium channel blockers: efavirenz lowers C_max and AUC of diltiazem and its metabolites. The increase in pharmacokinetic parameters of efavirenz with simultaneous application with diltiazem is clinically insignificant and does not require correction of the dose of efavirenz. Efavirenz when used concomitantly with felodipine, nicardipine, nifedipine, verapamil (substrates CYP3A) can reduce their plasma concentrations. The question of the necessity of correction of doses of blockers of "slow" calcium channels is solved taking into account the clinical response.

Extracts of Gingo Biloba. The use of efavirenz with extracts of Gingo Biloba is not recommended.

Interaction with the test for cannabinoids: Efavirenz does not bind to cannabinoid receptors. False positive results of urine analysis for cannabinoids were noted only when using the analysis of CED1A DAU Multi-Level TNS. which is used for screening, but not using other methods for cannabinoid assays, including tests that are used to confirm positive results.

Special instructions:

Efavirenz is not used as a monotherapy (rapid cross-resistance of the virus) for the treatment of HIV or as the only drug added to unsuccessful treatment.

Treatment with the drug should always begin in combination with one or more antiretroviral drugs that the patient has not previously received. When choosing new antiretroviral drugs for use in combination, one should consider the possibility of cross-resistance of the virus. When appointing drugs that should be used concomitantly with efavirenz, the doctor should refer to the appropriate "Instructions for the medical use" of these drugs.

Patients should be advised that antiretroviral therapy, including efavirenzem, does not protect against transmission of the HIV virus through sexual contact or through blood, therefore appropriate precautions should be taken. Joint use of efavirenz with combined preparations containing efavirenz, emtricitabine and tenofovir disoproxyl fumarate is not recommended.Women of fertile age should be avoided during pregnancy. It is necessary to use reliable methods of barrier contraception in combination with other methods (including oral or other hormonal contraceptives).

If, due to the development of unwanted drug reactions, discontinuation of therapy with the drug is necessary efavirenz, all antiretroviral drugs should be canceled at the same time.

Skin rash usually occurs while continuing treatment. Antihistamines and / or glucocorticosteroids can improve the tolerability of therapy and accelerate the disappearance of the rash. Less than 1% of patients receiving the drug, there is a severe rash, including. Bullous, with wetness, desquamation or ulcers. In patients with severe rash, accompanied by the formation of blisters, desquamation. involving mucous membranes or fever, the drug should be discarded. To avoid the emergence of resistant viruses when drug is withdrawn, it should also consider the possibility of abolishing other antiretroviral drugs.

A rash was observed in 26 children from 57 (46%) who received efavirenz within 48 weeks, the sin of the patients had a severe form of rash. The appointment of antihistamines before the initiation of efavirenzem in children for the prevention of rash can be advisable.

Multiple exudative erythema or Stevens-Johnson syndrome occurred in 0.1% of patients. Efavirenz It is not recommended for patients who previously had other life-threatening skin reactions (for example, Stevens-Johnson syndrome) on the background of taking other NNRTIs.

Psychiatric symptoms. Psychiatric adverse reactions were reported in patients who received efavirenz. Patients with a history of psychiatric disorders are at greater risk of serious psychiatric adverse reactions, for example, severe depression was more common in patients with a history of depression. There were postmarketing reports of severe depression, death from suicide, delirium and psychotic behavior. Patients should be informed that if they develop such symptoms (severe depression, psychosis or suicidal thoughts), they should consult a doctor to assess the possible association of these symptoms with the use of efavirenz.When it is established, it is necessary to determine whether the potential benefit of the drug is greater than the potential risk of psychiatric side effects.

Symptoms from the side of the system. Symptoms, including dizziness, insomnia, drowsiness, impaired concentration and pathological dreams, were observed in patients who received efavirenz in a dose of 600 mg daily. These symptoms usually started within the first two days of therapy and usually disappeared after the first 2-4 weeks. Patients should be informed that if these symptoms occur, they will probably improve with continued therapy.

Syndrome of restoration of immunity. In HIV-infected patients with severe immunodeficiency during the use of a combination of antiretroviral therapy, an inflammatory response to asymptomatic opportunistic infections that can lead to serious clinical symptoms is possible. Typically, such reactions are observed during the first few weeks or months of onset of therapy. Possible development: cytomegalovirus retinitis, generalized and / or local mycobacterial infection, pneumonia,caused by Pneumocystis jiroveci.

Any inflammatory response should be evaluated and, if necessary, prescribed treatment.

It was reported about the possible development autoimmune diseases (eg, Graves' disease), but the timing of their occurrence may be more diverse and these events may occur several months after the start of treatment.

Lipodystrophy and metabolic disorders. Combined antiretroviral therapy caused a redistribution of subcutaneous fat in the body (lipodystrophy) in patients with HIV infection. The high risk of lipodystrophy was associated with individual factors, such as advanced age, and also with longer duration of antiretroviral therapy. Combined antiretroviral therapy can induce metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia. Clinical examination should include a physical assessment of the signs of fat redistribution, measurement of serum lipids and glucose in the blood. During the treatment it is necessary to control the concentration of cholesterol in the blood plasma.

Osteonecrosis. The etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, severe immunodeficiency, high body mass index). Cases of osteonecrosis have been reported in patients with HIV infection and / or a prolonged use of a combination of antiretroviral therapy. Patients should be advised to see a doctor if they experience pain and joint stiffness or difficulty in movement.

Special groups of patients.

Violation of the function of the liver. Efavirenz is contraindicated in patients with severe hepatic impairment (Child-Pugh class C). In patients with mild liver failure (class A Child-Pugh classification), there were no significant differences in the pharmacokinetics of efavirenz. Patients should carefully monitor dose-related adverse reactions, especially from the nervous system. During the treatment period, it is necessary to monitor the activity of "hepatic" enzymes in patients with known or suspected hepatitis B or C in the history, as well as in patients receiving other hepatotoxic drugs.In patients with a history of liver failure, including chronic active hepatitis, the incidence of liver function abnormalities increases with combined antiretroviral therapy, so these patients should be monitored in accordance with the standard regimen.

In the case of a persistent increase in serum transaminase activity, which is more than 5 times higher than the upper limit of the norm, one should compare the benefits of continuing treatment with the risk of a significant hepatotoxic effect. There are post-marketing reports on the development of hepatic insufficiency in patients who have not previously had a violation of liver function. It is necessary to monitor the activity of "hepatic" enzymes in patients, including without compromising liver function or other risk factors.

Impaired renal function. The pharmacokinetics of efavirenz in patients with renal insufficiency has not been studied, however, given that less than 1% of efavirenz is excreted in the urine in an unmodified form, renal function should not have a material impact on its excretion.There is a significant experience in the use of the drug in patients with severe renal failure, therefore, monitoring of safety in this group of patients is recommended.

Patients of advanced age. Clinical studies of efavirenz did not include a sufficient number of patients 65 years of age or older.

Children. In children under 3 years of age or a body weight of less than 13 kg, the effect of efavirenz has not been studied.

Convulsions. Seizures were observed in patients taking efavirenz. Patients who receive concomitant anticonvulsants metabolized by the liver, such as phenytoin, carbamazepine and phenobarbital, periodic monitoring of plasma concentrations may be required. When carbamazepine was used together with efavirenz, a decrease in the concentration of carbamazepine was noted. It is necessary to warn patients about a possible reduction in the concentration of anticonvulsant drugs and apply this combination with caution. Patients with seizures in the anamnesis should be under special supervision.

During the treatment period it is necessary to control activity of "liver" enzymes in patients with known or suspected hepatitis B or C in the anamnesis, as well as in patients receiving other hepatotoxic drugs. In the case of a persistent increase in serum transaminase activity, which is more than 5 times higher than the upper limit of the norm, one should compare the benefits of continuing treatment with the risk of a significant hepatotoxic effect.

During the treatment period it is necessary to control cholesterol concentration in the blood plasma. Patients should be informed about possible neurological and psychiatric reactions, as well as the potential additive effect on the central nervous system while taking with alcohol or psychotropic drugs.

Effect of food. The use of efavirenz with food can lead to an increase in its absorption and an increase in the frequency of adverse reactions. It is recommended that efavirenz on an empty stomach, preferably at bedtime.

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:

For 30 tablets in a can of high-density polyethylene, sealed with aluminum foil, with a screw cap with a gasket and having a device that prevents children from opening the can.

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

For 10 tablets in a blister of PVC / aluminum foil. 10 blisters together with instructions for use are placed in a pack of cardboard.

Storage conditions:

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 printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002993

Date of registration:12.05.2015

The owner of the registration certificate:ARS, LLC ARS, LLC Russia

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Efavirenz (Efavirenz)