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

Excipients: microcrystalline cellulose - 300.00 mg, giprolose - 33.75 mg, sodium lauryl sulfate - 33.75 mg, lactose monohydrate - 315.00 mg, croscarmellose sodium - 54.00 mg, magnesium stearate - 13.50 mg;

shell: hypromellose - 16.87 mg, titanium dioxide - 6.42 mg, macrogol - 1.69 mg, iron dye yellow oxide - 2.02 mg.

Description:

Double-convex capsule capsules coated with a yellow film cover, engraved "H" on one side and engraved "4" on the other 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 non-nucleoside reverse transcriptase (NNRTI) inhibitor of human immunodeficiency virus type 1 (HIV-1). It is a non-competitive inhibitor of HIV-1 reverse transcriptase, does not inhibit HIV-2 reverse transcriptase and DNA polymerase ((α, β, γ and δ) human cells.

Antiviral activity. The antiviral efficacy of efavirenz in vitro was evaluated on lymphoblastic cell lines, peripheral blood mononuclear cells, and macrophage / monocyte cultures. The inhibitory concentration (IR) of efavirenz required for 90-95% inhibition of (IC90-95) wild-type strains or laboratory clinical isolates resistant to zidovudine is in the range of 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 reverse transcriptase at positions 48, 108, 179, 181 or 236, and for species with amino acid substitutions in the protease was similar to that of wild-type virus strains. The only substitutions that led to the emergence of the greatest resistance to efavirenz in cell culture,are the replacement of leucine with isoleucine at position 100 (L100I, 17-22-fold increase in resistance) and lysine for asparagine at position 103 (K.103N, 18-33-fold increase in resistance). A more than 100-fold decrease in the susceptibility of viruses to the drug was observed for varieties of HIV expressing the replacement of K103N in addition to other amino acid substitutions in reverse transcriptase.

Replacement of K103N was the most frequently observed substitution of viral strains in reverse transcriptase from patients who experienced a significant increase in the number of viral particles in the blood plasma (recurrent viremia) in clinical studies of the use of 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 reverse transcriptase at positions 98, 100, 101, 108, 138, 188, 190 and 225 were observed. The type of amino acid substitutions in reverse transcriptase associated with resistance to efavirenz are not depended on 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 K103N leads to 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. The third isolate, which has a substitution in reverse transcriptase 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 NNRTI-resistant isolates contained the replacement of K.103N 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, and to nevirapine and delavirdine on cell cultures.

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. The presence of cross-resistance between efavirenz and nucleoside reverse transcriptase inhibitors is also unlikely due to the difference in binding sites to the target and the mechanism of action.

Pharmacokinetics:

Suction. After oral administration of a single dose from 100 to 1600 mg, the maximum concentration (C_max) of efavirenz in plasma was achieved after 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) was observed when the drug was 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 did not change after repeated administration, and the equilibrium concentration in the plasma was reached after 6-7 days. In HIV-infected patients during the period of stable condition, the average C_max, the minimum concentration (C_min) and AUC were linear in the application at a daily dose of 200, 400 and 600 mg.

Impact of poverty on absorption. With a single dose of a single dose of efavirenz 600 mg once taken with healthy volunteers, along with high-fat foods (about 1000 kcal, 50-60% of calories due to fat), there was an increase in AUC by 28% and C_max on 79% in comparison with the given parameters at reception of a preparation on an empty stomach.

Distribution. The connection with blood plasma proteins is 99.5-99.75% (mainly with albumin). Concentration in the cerebrospinal fluid - 0.26-1.19% (averaging 0.69%) from that in plasma is achieved with the reception of HIV-infected patients with efavirenz in doses of 200 to 600 mg once a day for a month, which approximately 3 times higher than the non-protein-bound (free) fraction in the plasma.

Metabolism. Metabolized mainly by the cytochrome P450 system to hydroxylated metabolites followed by their glucuronation. Metabolites are pharmacologically inactive with respect to HIV-1. In vitro studies suggest that isoenzymes CYP3A4 and CYP2B6 are the main isoenzymes that metabolize efavirenz, and that efavirenz inhibits the isozymes of 2C9, 2C19 and 3A4 of the cytochrome P450 system. In vitro studies efavirenz did not inhibit the isoenzyme CYP2E1 and inhibited the isoenzymes CYP2D6 and CYP1A2 only at concentrations much higher than those used in clinical practice.

Exposure of efavirenz in the blood plasma may increase in patients homozygous for polymorphism of the G516T gene of the CYP2B6 isoenzyme. The clinical significance of such a change is unknown, but it is impossible to exclude the possibility of an increased risk of development and an increase in the severity of unwanted reactions of efavirenz.

Efavirenz induces isoenzymes of the cytochrome P450 system, isozymes CYP3A4 and CYP2B6, which leads to stimulation of its own metabolism. Multiple doses of 200-400 mg per day for 10 days cause its cumulation to be less than expected (22-42% less), and with a shorter terminal half-life (T1 / 2) - 40-55 hours after multiple receptions (T1 / 2 single dose - 52-76 hours). The degree of induction of the isoenzyme CYP3A4 is similar in the administration of doses of efavirenz 400 mg and 600 mg. It was also shown that efavirenz induces isoform 1A1 of uridine-diphosphate-glucononyltransferase (UDF-GT1A1), therefore the concentration of raltegravir, which is the substrate of UDF-GT1A1, in the blood plasma decreases with simultaneous use with efavirenz.

In vitro studies efavirenz inhibited isoenzymes CYP2C9, CYP2C19, in vivo studies, 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 is excreted through the kidneys unchanged. Pharmacokinetics in special groups of patients.

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 according to the Child-Pugh classification), 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 Child-Pugh classification) compared with control group patients.Currently, there is insufficient data to make a conclusion whether the influence of moderate and severe hepatic impairment (class B and C according to Child-Pugh classification) on the pharmacokinetics of efavirenz.

Sex, race and advanced age. No significant differences in the pharmacokinetics of efavirenz in both men and women, as well as in patients of different race. There are no pharmacokinetic differences in patients older than 65 years have been identified, although clinical studies of efavirenz did not include sufficient numbers of patients 65 years and older.

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

Indications:

Treatment of HIV-1 infection in adults and children weighing more than 40 kg in combination antiviral therapy.

Contraindications:

Hypersensitivity to efavirenz and any other component of the drug.
Hepatic insufficiency of severe severity (Child-Pugh class C).
Weight less than 40 kg.
Simultaneous administration of terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids (ergotamine, dihydroergotamine, ergonovin, metergergonovin) (competitive interaction of efavirenz with CYP3A4 isozyme may lead to suppression of the metabolism of these drugs and create the possibility of serious and / or menacing life of undesirable phenomena, including arrhythmias, prolonged sedation or respiratory depression).
Simultaneous reception with preparations / products of vegetable origin containing Hypericum perforatum (Hypericum perforatum), as it is possible to reduce the concentration of efavirenz in the blood plasma and reduce its clinical effect.
Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption (the preparation contains lactose).

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 with a history of cramps.
Patients receiving concomitant anticonvulsants with a predominant metabolism in the liver, such as phenytoin, carbamazepine, phenobarbital, valproic acid, vigabatrin.
Simultaneous use with atazanavir, darunavir.

Pregnancy and lactation:

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

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

It is not known whether efavirenz with breast milk. Because preclinical studies in animals have shown that efavirenz may be excreted in 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:

For adults and children over 40 kg, the recommended dose of efavirenz in combination with nucleoside reverse transcriptase inhibitors (NRTIs), with or without HIV protease inhibitors (PI) is 600 mg orally once a day.Simultaneous reception of efavirenz with food can lead to an increase in the frequency of adverse reactions, it is recommended to take efavirenz on an empty stomach. 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.

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 by 50%, that is up to 300 mg * once a day (* - tablets with low dose of efavirenz in RF are not registered ). After discontinuation of therapy with voriconazole, the initial dose of efavirenz (600 mg) should be used.

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. Renal insufficiency: 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.

Liver failure: Patients with mild liver failure (Child-Pugh class A) are advised to take the usual dose of efavirenz, without correction, however, they must be carefully monitored to monitor the occurrence of dose-dependent adverse reactions, especially from the nervous system. Patients with moderate hepatic impairment (Child-Pugh class B) are not recommended to use efavirenz because there is not enough data at this time to determine if dose adjustment is necessary in such cases. Patients with hepatic insufficiency of severe severity (class C by Child-Pugh) efavirenz is contraindicated.

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 - violation of cerebellar coordination and balance, attention disorder, dizziness, headache, drowsiness, decreased concentration of attention; infrequent - excitation, amnesia, ataxia, impaired coordination of movements, convulsions, impaired thinking, tremor.Usually the symptoms disappear after 2-4 weeks from the beginning of the drug.

From the side of the psyche: often - the pathology of dreams, anxiety, depression, insomnia; infrequently - a tendency to affect, aggressiveness, confusion, euphoria, hallucinations, mania, paranoia, psychosis, suicidal ideation, suicidal attempt; rarely (the relationship of these effects with the use of efavirenz is not established) - delusions, neurosis, completed suicide.

From the immune system: infrequently - hypersensitivity.

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

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

From the side of the vessels: infrequently - "tides" of blood to the skin of the face.

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

From the liver and bile ducts: infrequently acute hepatitis; rarely - liver failure.

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

From the genitals and the breast: infrequently - gynecomastia.

From the side of metabolism and nutrition: often - hypertriglyceridemia; infrequently - hypercholesterolemia.

Laboratory indicators: often - increased activity of "hepatic" transaminases: increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), amylases. In some cases, there was an increase in the total cholesterol and high-density lipoprotein content by 10-20%.

Common violations: often - increased fatigue.

The description of individual undesirable phenomena is presented in the section "Special instructions". 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 hump). Combined antiretroviral therapy can cause metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

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.

Autoimmune diseases (such as Graves' disease) were observed against a background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

Osteonecrosis: there were cases of osteonecrosis, mainly 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.

Children and adolescents: 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 assign blockers H₁-gistaminovyh receptors to children before the beginning of therapy efavirenzem. Although the symptoms of the nervous system in young children are difficult to identify, it is believed that such symptoms are more rare in children and usually are mild. In 3.5% of patients, symptoms of moderate severity from the nervous system were observed, mainly dizziness. No child had severe symptoms and did not need to cancel therapy because of symptoms from the nervous system.

Patients with concomitant hepatitis B and C. Among patients seropositive for hepatitis B and / or C, an increase in ACT activity was more than 5 times higher than normal vaginal hypertension (upper limit of the norm) in 13% of patients taking efavirenz, and 7% of patients in the control group, and an increase in ALT activity was more than 5 times higher than ULN observed in 20% and 7% of patients, respectively. Among patients with co-infection, 3% of patients who took efavirenz, and 2% of patients from the control group discontinued therapy because of violations of the liver function.

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 in vitro 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 isoenzymes CYP2C9 and CYP2C19, 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 CYP2B6. Drugs that induce these enzymes can lead to a decrease in plasma concentrations of efavirenz.

The extract of Gingo Biloba induces isoenzymes CYP3A4 or CYP2B6 and can lead to a decrease in plasma concentrations of efavirenz.

Contraindicated combination therapy.

Contraindicated simultaneous use of efavirenz with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridilom, ergot alkaloids (ergotamine, dihydroergotamine, ergonovin, metergergonovin), as inhibition of their metabolism by efavirenz can cause serious life-threatening adverse events.

Saint 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. If the patient is already taking St. John's Wort, it is necessary to suspend his reception, check the level of viral load and the concentration of efavirenz. Concentration of efavirenz with cancellation of St. John's wort can be increased and, perhaps, dose correction is required. The induction effect of St. John's wort can persist for at least 2 weeks afterdiscontinuation of treatment.

Companion Antesiretroviral drugs.

Protease inhibitors.

Atazanavir: simultaneous use with atazanavir / ritonavir is not recommended. If simultaneous use of atazanavir with NNRTI is required, consideration should be given to increasing the dose of atazanavir to 400 mg and ritonavir to 200 mg, in combination with efavirenzem, with careful clinical monitoring.

Darunavir: simultaneous application with darunavir / ritonavir in a dose of 800/100 mg is possible once a day, while achieving 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: In the appointment of efavirenz 600 mg once a day with indinavir / ritonavir 800/100 mg twice daily AUC, C_max and C_min Indinavir declined by about 25%, 17% and 50%, respectively. Geometrically, the average value of C_minfor indinavir (0.33 mg / L) when taking ritonavir with efavirenz was higher than the baseline C_min (0.15 mg / l), when one was taken indinavir in a dose of 800 mg every 8 hours. Although the clinical significance of reducing the concentration of indinavir is not established,the observed pharmacokinetic interaction should be taken into account when choosing a therapy regimen including both efavirenz and indinavir. Correction of the dose of efavirenz is not required if it is administered with indinavir or with indinavir / ritonavir. See also information on ritonavir.

Lopinavir / ritonavir: with simultaneous appointment with efavirenz should consider the increase in doses of lopinavir and ritonavir in soft capsules or in the solution for oral administration by 33% (4 capsules / -6.5 ml 2 times a day instead of 3 capsules / 5 ml 2 times a day) . However, care should be taken because such dose adjustment may not be sufficient for some patients. The dose of lopinavir and ritonavir in tablets should be increased to 500/120 mg 2 times a day with simultaneous use with efavirenzem 600 mg once a day. See also information on ritonavir.

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 hours led to an increase in the incidence of side effects (including dizziness, nausea, paresthesia) and the deviation of laboratory indicators (increased activity of "hepatic" 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_maxsaquinavir 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 enhanced 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.

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.

NNRTI: Studies evaluating the use of efavirenz in combination with other NNRTIs have not been conducted. Since the use of two NNRTIs does not provide an advantage in terms of efficacy and safety, simultaneous use of efavirenz and other NNRTI agents is not recommended.

Chemokine receptor antagonists CCR5. Maraviroc. When used simultaneously with maraviroc, the dose of maraviroc should be increased to 600 mg 2 times a day.

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

Bocepreviir / Efavirenz (800 mg three times a day / 600 mg once a day). The concentration of boceprevir was reduced with simultaneous use with efavirenzem, but this has no clinical significance.

Telaprevir / Efavirenz (1125 mg twice daily or 750 mg every 8 hours / 600 mg once daily). When combined use of efavirenz and telaprevir, the latter should be applied at a dose of 1125 mg every 8 hours.

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, whereas AUC and C_max of active hydroxy metabolite of clarithromycin increased by 34 and 49%, respectively. The clinical significance of changes in the concentration of clarithromycin in the blood plasma is not established. Instead of clarithromycin, one should consider the possibility of using another antibiotic, for example, azithromycin. Correction of the dose of efavirenz is not required.

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

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

Rifampicin: reduces the AUC of efavirenz by 26% and the Cmax by 20%. When appointing simultaneously with rifampicin to 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, dose adjustment of rifampicin is not required.

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 drugs: itraconazole - Since it is impossible to develop recommendations on the dosage regimen of itraconazole, the possibility of using alternative antifungal agents should be considered.

Ketoconazole and other antifungal agents - imidazole derivatives: There is no data available to develop recommendations on the dosage regimen. 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 by 50%, that is, up to 300 mg * once a day (* - tablets with a low dose of efavirenz in the Russian Federation are not registered). After discontinuation of therapy with voriconazole, the initial dose of efavirenz (600 mg) should be used.

With simultaneous appointment fluconazole and efavirenz of any clinically significant pharmacokinetic interaction is not observed. The simultaneous use of efavirenz with posaconazole should be avoided, unless the potential benefit exceeds the possible risk.

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

Artemether / lumefantrine - It is possible to reduce the antimalarial effect due to a decrease in the concentration of artemether and lumefantrine while simultaneous use with efavirenz. Caution should be exercised while using efavirenz with artemether and lumefantrine.

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 medications will most likely not affect the absorption of efavirenz.

Anticoagulants: Efavirenz can increase or decrease plasma concentration and the effect of warfarin / acenocoumarol. It is possible to correct the dose of warfarin / acenocoumarol.

Anticonvulsants: carbamazepine - there is no data on the basis of which it is possible to develop recommendations on the dosage regimen. Consider using another anticonvulsant drug. It is recommended to carry out periodic monitoring of the concentration of carbamazepine in the blood plasma. If efavirenz is used concomitantly with anticonvulsants (phenytoin, phenobarbital and other anticonvulsant drugs, which are substrates of CYP450 isoenzymes), periodic monitoring of concentrations of anticonvulsants in the blood should be performed.

Valproic acid - correction of the dose of efavirenz is not required. Patients should be monitored to monitor seizures.

Vigabartin with efavirenz - dose adjustment of none of these medicines is required.

Antidepressants: with simultaneous application paroxetine and efavirenza no clinically significant changes in pharmacokinetic parameters are noted. When using paroxetine 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. When used simultaneously with fluoxetine correction of the dose is not required.

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 the reuptake of catecholamines (norepinephrine, 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.

Hormonal contraceptives: after a single administration of ethinylestradiol 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. DepoMedroxyprogesterone acetate. Because of the limited amount of information available, reliable hormonal contraceptive methods should be used in addition to hormonal contraceptives.

Implant: etonogestrel / efavirenz - the interaction was not studied, 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. 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, simvastatin, rosuvastatin 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.

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.

Blocks of "slow" calcium channels: 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 of the isoenzyme 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 (see the instruction on the use of blockers of "slow" calcium channels).

Interaction with the test for cannabinoids: Efavirenz does not bind to cannabinoid receptors. False positive urine tests for cannabinoids have been reported only when using the CEDIA DAU Multi-Level TNS analysis, 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 prescribing medications that should be taken concomitantly with efavirenz, the physician should refer to the appropriate "Instructions for Use" for these medications.

The simultaneous use of efavirenz with fixed combinations containing efavirenz, emtricitabine, tenofovir disoproxil fumarate is not recommended unless dosage adjustment is required (eg, with simultaneous administration with rifampicin).

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

In the event that the taking of any antiretroviral drug in combination therapy 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. Interrupted monotherapy with subsequent repeated administration of antiretroviral drugs is not recommended because of the emergence of resistant to therapy viruses.

Patients should be informed that treatment with antiretroviral drugs, such as efavirenz, does not prevent the risk of HIV transmission to other people during sexual intercourse or blood transfusion, so patients should take appropriate precautions.

The use of efavirenz has not been adequately studied in patients with HIV infection with a CD4 count <50 cells / mm³, and also after previous failure of therapy with HIV protease inhibitors (PIs).

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).

Skin rash. Antihistamines and / or glucocorticosteroids can improve the tolerability of therapy and accelerate the disappearance of the rash. Usually, mild or moderately expressed maculopapular skin rash develops, which appear within the first two weeks after initiation of efavirenz therapy. In most patients, a skin rash disappears when continuing with efavirenz therapy for one month. Efavirenz can be re-assigned to patients who stopped taking it because of a skin rash. Less than 1% of patients receiving the drug, there is a severe form of rash, accompanied by blisters, desquamation of the epithelium or the formation of ulcers. In patients with severe rash, accompanied by the formation of blisters, desquamation, involvement of mucous membranes or fever, the drug must be discarded. To avoid the emergence of resistant viruses when drug is withdrawn, it should also consider the possibility of abolishing other antiretroviral drugs.The use of efavirenz is not recommended for patients who previously developed life-threatening skin reactions (for example, Stevens-Johnson syndrome), including the use of other NNRTIs. Multiple exudative erythema and Stevens-Johnson syndrome occurred in 0.1% of patients.

Symptoms from the side of the psyche. The undesirable phenomena from the psyche were recorded 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 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 usually disappear when continuing therapy and are not a sign of possible mental disorders that occur less frequently.

Convulsions. Seizures were observed in patients taking efavirenz. Patients who receive concomitant anticonvulsants metabolized by the liver, such as phenytoin, carbamazepine and phenobarbital, it is necessary to periodically determine the concentrations of these drugs in the blood plasma. When carbamazepine was used together with efavirenz, a decrease in the concentration of carbamazepine was noted. Care should be taken when prescribing the drug to patients who have a history of cramps.

Adverse events from the liver. During the post-registration period, a small number of reports on the development of hepatic insufficiency in patients without evidence of liver disease in the anamnesis were obtained, and also without other identified risk factors. These cases were characterized by fulminant course, in some cases liver transplantation was required or the patient died of death. 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. 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.

Syndrome of restoration of immunity. Have HIV-infected patients with severe immunodeficiency after the onset of combined antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections that can lead to serious clinical symptoms may develop. 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.

Autoimmune diseases (such as Graves' disease) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

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. 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.Disorders of lipid metabolism should be adjusted in accordance with clinical manifestations.

Osteonecrosis. The etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, 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 (class C Child-Pugh classification) and is not recommended for patients with moderate-grade liver damage (Child-Pugh class B), as there is insufficient data at this time to determine if correction is necessary in such cases dose. In patients with mild hepatic insufficiency (class A according to the Child-Pugh classification) efavirenz should be used with caution. Patients should carefully monitor dose-related adverse reactions, especially from the nervous system.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. 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 anamnesis, as well as in patients receiving other hepatotoxic drugs. In patients with worsening of the course of the disease, or in the case of a persistent increase in serum transaminase activity, more than 5 times the upper limit of the norm, the advantages of continuing treatment with the risk of significant hepatotoxic effects should be compared. For such patients, consideration should be given to whether interruption or withdrawal of antiretroviral therapy is advisable. 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 by the kidneys unchanged, renal dysfunction should not have a significant effect on its excretion. The experience of using the drug in patients with severe renal failure is not available, therefore it is recommended to monitor the safety in this group of patients.

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.

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, impaired concentration, and / or drowsiness. During the treatment period, one should refrain from driving motor vehicles and practicing potentially dangerous speciesactivities that require increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 600 mg.

Packaging:

When manufacturing on Heterose Labs Limited

30 tablets in a bottle of high density polyethylene, sealed with aluminum foil, with a screw cap. The bottle together with instructions for use in a pack of cardboard.

In the production, packaging and packaging of OOO "MAKIZ-PHARMA" 30 tablets in a can of low pressure polyethylene (HDPE), sealed with a cover with the first opening, or in a bank imported from high density polyethylene (HDPE), sealed with a low density polyethylene (LDPE) cap with a first opening control.

Free space in the bank if necessary fill with cotton absorbent medical absorbent. 1 bank together with instructions for use 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-002511

Date of registration:26.06.2014

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

MAKIZ-PHARMA, LLC Russia

HETERO LABS, Limited India

Representation: & nbspDIALOGPARMA, LLCDIALOGPARMA, LLC

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Efavirenz (Efavirenz)