Regast - instructions for use, doses, side effects, contraindications

Core: betadex (beta-cyclodextrin) 2.0 mg / 6.0 mg / 8.0 mg / 12.0 mg; calcium stearate 1.0 mg / 3, 0 mg / 4.0 mg / 6.0 mg; crospovidone - 12.0 mg / 36.0 mg / 48.0 mg / 72.0 mg; sodium lauryl sulfate 3.5 mg / 10.5 mg / 14.0 mg / 21.0 mg; lactose monohydrate - 62.0 mg / 186.0 mg / 248.0 mg / 372.0 mg; Povidone To 25 - 4.0 mg / 12.0 mg / 16.0 mg / 24.0 mg; polysorbate-80 (Tvin- 80) - 1.5 mg / 4.5 mg / 6.0 mg / 9.0 mg Microcrystalline cellulose - 9.0 mg / 27.0 mg / 36.0 mg / 54.0 mg.

Film Sheath: Ready-soluble film coating - 5.0 mg / 15.0 mg / 20.0 mg / 30.0 mg (shell composition: hydroxypropylmethylcellulose (hypromellose) - 74.2%, polyethylene glycol 6000 (Macrogol 6000) - 14.3% , titanium dioxide 3.5%, talc-2.3%, iron dye red oxide-1.4%, iron dye oxide yellow-4.3%).

Description:

For the dosage of 100 mg: film-coated tablets, round, biconvex, with a risk on the one hand, from light brown to brown.

For dosages of 300 mg, 400 mg, 600 mg: film-coated tablets, oval, biconvex, from light brown to brown.

On a cross-section a tablet of white or white with a yellowish shade of 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:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV-1. Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase and does not significantly inhibit HIV-2 reverse transcriptase and human cellular DNA polymerases (alpha, beta, gamma and delta).

Sensitivity of HIV in vitro. Clinical significance of HIV-1 sensitivity to efavirenz in vitro not installed. Antiviral efficacy of efavirenz in vitro was evaluated on lymphoblastic cell lines, mononuclear cells of peripheral blood, and macrophage / monocyte cultures.The concentration of efavirenz needed for 90 to 95% inhibition (IC90-95) of laboratory-adapted wild-type strains and clinical isolates resistant to zidovudine ranges from 0.46 to 6.8 nmol / L.

Efavirenz demonstrated synergistic activity in cell culture in combination with nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and didanosine and a protease inhibitor indinavir.

Stability. 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, as well as for varieties with amino acid substitutions in the protease was similar to that for wild-type viral strains. The only substitutions that led to the highest resistance to efavirenz in cell culture are the replacement of leucine with isoleucine at position 100 (L100I, 17-22-fold resistance) and lysine for asparagine at position 103 (K103N, 18-33-fold 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.

K103N is the most frequently observed reverse transcriptase substitution in viral isolates obtained from patients who experienced a significant increase in the number of viral particles after treatment withdrawal in clinical studies of efavirenz in combination with indinavir or in combination of zidovudine with lamivudine. Replacement in reverse transcriptase at positions 98, 100, 101, 108, 138, 188, 190 and 225 was also observed, but less frequently and often only in combination with K103N. The type of amino acid substitutions in reverse transcriptase associated with resistance to efavirenz did not depend on other antiviral drugs used in combination with efavirenz.

Cross-resistance. A study of cross-resistance profiles of efavirenz, nevirapine, and delavirdine on cell cultures showed that the replacement of K103N leads to a loss of susceptibility to all three non-nucleoside reverse transcriptase inhibitors. 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 (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 a replacement for K103N or a replacement of valine by isoleucine at position 108 (V1081) 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 the presence of different target enzymes. The presence of cross-resistance between efavirenz and nucleoside reverse transcriptase inhibitors is also unlikely due to different binding sites to the target and various mechanisms of action.

Pharmacokinetics:

Suction

In healthy volunteers, the maximum concentration (C_max) efavirenz in the blood plasma 1,6 - 9,1 μM was achieved 5 hours after a single oral intake of the drug in doses from 100 mg to 1600 mg. Dose-dependent increase in maximum concentration (C_max) and the area under the curve "concentration-time" was noted when taking the drug in doses up to 1600 mg; while the proportional dependence of the degree of increase in these parameters on the dose was not achieved, from which it can be assumed that at higher doses, the absorption decreases. Time to reach C_max in plasma (3-5 hours) did not change after repeated administration of the drug, and the equilibrium concentration in 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_m_in) and the area under the "concentration-time" curve have a linear dependence on the daily dose. In 35 patients who received efavirenz in a dose of 600 mg once a day, C_max when the equilibrium concentration reached 12.9 ± 3.7 μM, C_m_in - 5.6 ± 3.2 μM, the area under the concentration-time curve is 184 ± 73 μM per hour.

Effect of food on absorption

Efavirenz can be taken regardless of food intake.Taking efavirenz with food can increase its effect and lead to an increase in the frequency of adverse reactions. Bioavailability of a single dose of efavirenz 600 mg in healthy volunteers increased with the intake of tablets along with food with normal or high fat content by 22% and 17% respectively, compared with taking the same dose of the drug on an empty stomach. Efavirenz it is recommended to be taken before bedtime on an empty stomach. Distribution

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

Metabolism

Clinical studies and research in vitro using human liver microsomes showed that efavirenz is metabolized mainly by the cytochrome P450 system to hydroxylated derivatives,which are then bound to glucuronic acid to form glucuronides. In general, these metabolites are inactive in relation to HIV-1. Research in vitro suggest that the isoenzymes CYP3A4 and CYP2B6 are the main isoenzymes that metabolize efavirenz. Research in vitro showed that efavirenz in concentrations corresponding to those in plasma, inhibits the CYP2C9, CYP2C19 and CYP3A4 isoenzymes of the cytochrome P450 system. In studies in vitro efavirenz did not inhibit the CYP2E1 isoenzyme and inhibited the CYP206 and CYP1A2 isoenzymes only at concentrations much higher than those in clinical practice.

It was shown that efavirenz induces enzymes of the cytochrome P450 system, which leads to the induction of its own metabolism. With repeated administration of 200-400 mg per day for 10 days, a lower degree of cumulation of the drug was observed than anticipated (22-42% lower) and a shorter final half-life period of 40-55 hours (the half-life of a single dose is 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. Pharmacokinetic interactive studies have shown,that the daily intake of 400 mg or 600 mg of efavirenz in combination with indinavir is not the reason for further reduction of the area under the concentration-time curve of indinavir in comparison with the cases when a dose of efavirenz 200 mg was prescribed.

Excretion

Efavirenz has a relatively long half-life, which ranges from 52 to 76 hours after taking a single dose and 40 to 55 hours after prolonged use. In urine, approximately 14 to 34% of the isotope-labeled dose of efavirenz is detected, less than 1% of the dose of efavirenz is excreted by the kidneys unchanged.

Pharmacokinetics in specific patient groups

Liver failure

With a single administration of efavirenz, there was a twofold increase in its half-life 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 efavirenz, 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.At present, there is insufficient data to conclude whether the average and severe degree of hepatic insufficiency (class B and C according to the Child-Pugh classification) affect the pharmacokinetics of efavirenz (see "Contraindications", "With caution").

Renal insufficiency

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

Sex and race

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

Age

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

Children

The use of efavirenz in children under 3 years of age and patients weighing less than 13 kg has not been studied. The pharmacokinetic parameters of efavirenz in children and adults were similar.In 49 children who received a dose of efavirenz, equivalent to 600 mg (the dose was calculated based on body weight), C_max was 14.2 μM, C_m_i_n - 5.6 μM and the area under the concentration-time curve is 218 μM per hour.

Indications:

As part of combined antiviral therapy for the treatment of adults, adolescents and children over 3 years old, infected with the human immunodeficiency virus (HIV-1).

Contraindications:

- hypersensitivity to any of the components of the drug;

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

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

- Children under the age of 3 years or with a body weight of less than 13 kg;

- simultaneous administration with terfenadine, astemizole, cisapride, pimozide, bepridilum, midazolam, triazolam and ergot alkaloids, since the competitive interaction of efavirenz with the CYP3A4 isozyme may lead to suppression of the metabolism of these drugs and the appearance of prerequisites for the occurrence of serious and / or life-threatening adverse events (for example, cardiac arrhythmia, prolonged sedation or respiratory depression);

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

- 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.

Carefully:

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

- when efavirenz is prescribed for patients with mild to moderate liver function disorders (Child-Pugh class A and B);

- when efavirenz is prescribed for patients with convulsions (including in anamnesis) (see section "Special instructions");

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

Pregnancy and lactation:

Adequate and well-controlled studies of efavirenz 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 12 weeks after the cessation of treatment with efavirenz.

It is not known whether efavirenz with human breast milk. Because these animal studies indicate 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.

Adults: 600 mg once a day as part of a combination therapy with protease inhibitors and / or nucleoside reverse transcriptase inhibitors (NRTIs) (see "Interactions with Other Drugs").

Combination therapy:

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 efavirenzom dose adjustment rifampicin is not required (see the section "Interaction with other medicinal products").

With the simultaneous use of efavirenz and voriconazole, you should increase the maintenance dose of voriconazole to 400 mg every 12 hours and reduce the dose of efavirenz to 300 mg once a day (see section "Interaction with other medicines"). After discontinuation of therapy with voriconazole, the initial dose of efavirenz (600 mg) should be used.

Concomitant antiretroviral therapy: efavirenz should be used as part of combination therapy with other antiretroviral drugs (see section "Interaction with other drugs").

Adolescents and children weighing 40 kg or more: 600 mg once a day as part of a combination therapy with a protease inhibitor and / or NRTI.

Children aged 3 years and over with a body weight of 13 to 40 kg: Recommendations for the use of efavirenz with a protease inhibitor and / or NRTI are given in Table 1.

Table 1. Doses for children with efavirenz once a day

Body weight (kg)	Dose (mg)
from 13 to <15	200
from 15 to <20	250
from 20 to <25	300
from 25 to <32.5	350
from 32.5 to <40	400

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

Patients with renal insufficiency

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 impaired 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:

Generally efavirenz well tolerated. Side effects possibly caused by the use of the drug are presented below. The frequency of the phenomena is determined by the following assumption: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1 000); very rarely (<1/10000).

Immune system disorders

Infrequent: hypersensitivity reactions.

Disorders of the psyche

Often: pathological dreams, anxiety, depression, insomnia. Infrequently: a tendency to affect, aggressiveness, confusion, euphoria, hallucinations, mania, paranoid behavior, psychosis, suicidal intent, suicidal attempt. Rarely: delirium, neurosis, death due to suicide.

Disturbances from the nervous system

Often: disorders of cerebellar coordination and balance, attention disorder, dizziness, headaches, drowsiness. Infrequent: anxiety, amnesia, ataxia, impaired coordination of movements, convulsions, impaired thinking, tremor.

Disorders from the endocrine system

Infrequently: gynecomastia.

Metabolic disorders

Often: hypertriglyceridemia. Infrequently: hypercholesterolemia.

Disturbances on the part of the organ of sight

Infrequent: blurred vision.

Hearing disorders and labyrinthine disorders

Infrequently: vertigo, noise in the ears.

From the respiratory system

Rarely - shortness of breath.

From the side of the cardiovascular system

Rarely, a feeling of palpitations.

Disorders from the gastrointestinal tract

Often: abdominal pain, diarrhea, nausea, vomiting. Infrequent: pancreatitis, an asymptomatic increase in serum amylase activity.

Disturbances from the liver and bile ducts

Often: increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT). Infrequently: acute hepatitis. Rarely: hepatic insufficiency.

From the side of the musculoskeletal system

Infrequently: myalgia, arthralgia, myopathy, osteonecrosis.

Disturbances from the skin and subcutaneous tissues

Very often: rash. Often: itchy skin. Infrequently: multimorphic exudative erythema, Stevens-Johnson syndrome.Rarely: photoallergic dermatitis.

General disorders

Often: increased fatigue. Infrequently: asthenia, "tides" of blood to the skin of the face.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, the onset of combined antiretroviral therapy may increase the risk of inflammatory reactions to asymptomatic or residual opportunistic infections. Autoimmune diseases (for example, Graves' disease) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could arise many months after the initiation of therapy (see section "Special instructions").

Lipodystrophy and metabolic disorders

Combined antiretroviral therapy is associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including depletion of peripheral and facial subcutaneous fat, its accumulation in the intraperitoneal space, internal organs, posterior neck ("bison hump") and mammary hypertrophy. Combined antiretroviral therapy can cause metabolic disorders,such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

Children and teens

The type and frequency of adverse events in children as a whole is similar to that in adults, with the exception of rash, which is more common in children than in adults, and is more pronounced. The appointment of appropriate blockers of H1-histamine receptors to children before initiation of efavirenz therapy for the purpose of preventing rash may be appropriate.

Overdose:

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

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

Interaction:

Efavirenz in vivo is the inducer of the isoenzymes CYP3A4, CYP2B6 and UDF-GT1A1. Concentration in the blood plasma of compounds that are substrates for these isoenzymes may decrease with simultaneous use with efavirenz. Efavirenz can be an inducer of the isoenzymes CYP2C19 and CYP2C9, however, in vitro inhibition of these isoenzymes was also observed. Until the end, the effect of simultaneous use of efavirenz with compounds that are substrates for these isoenzymes is not clear.

Exposure to efavirenz may decrease with the use of the drug concomitantly with certain medications (eg, ritonavir) or foods (eg, grapefruit juice) that inhibit the isoenzymes CYP3A4 or CYP2B6. Compounds or herbal preparations (for example, containing the extract of Gingo Biloba, as well as St. John's wort), which induce these isozymes, can lead to a decrease in the concentration of efavirenz in the blood plasma. Simultaneous reception with drugs containing St. John's wort is contraindicated. Simultaneous reception with extracts of Gingo Biloba is not recommended.

Contraindicated combination therapy

Concomitant use of efavirenz with terfenadine, astemizole, cisapride, pimozide, bepridilom, midazolam, triazolam and ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, or metilergonovin), because inhibition of their metabolism efavirenz can cause serious, life-threatening consequences (cm. "Contra ").

St. John's Wort (Hypericum perforatum): application of preparations / products containing St. John's wort to the patients receiving efavirenz it is contraindicated. The concentration of efavirenz in the blood plasma can decrease with simultaneous application to St. John's Wort, as it causes the induction of enzymes and / or transport proteins responsible for the metabolism of drugs. If the patient is already taking drugs / products containing St. John's Wort, the application of the latter should be discarded, the concentration of the virus in the blood checked and, if possible, the concentration of efavirenz in the blood. After withdrawal of drugs / products containing St. John's wort, the concentration of efavirenz may increase and then a dose adjustment of efavirenz will be required.The effect of St. John's wort, associated with the induction of enzymes, can persist for at least 2 weeks after it is discontinued (see "Contraindications"),

Other interactions

The interactions between efavirenz and HIV protease inhibitors, other antiretroviral drugs, in addition to HIV protease inhibitors, as well as between efavirenz and non-ARV drugs, are shown in Table 2 below. An increase in the indicator value is indicated by the arrow (, - with the arrow "|", if the indicator remains unchanged by the arrow "<->". If necessary, 90% and 95% confidence intervals are presented in brackets. or volunteers, unless otherwise specified.

Table 2. Interactions between efavirenz and other drugs

Special instructions:

Efavirenz should not be used as a single drug for the treatment of HIV infection, nor should it be added as a single remedy to an ineffective therapy regimen.

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

The simultaneous use of efavirenz with fixed combinations containing efavirenz, emtricitabine and tenofovir, disoproxil fumarate is not recommended unless dosage adjustment is required (eg, with simultaneous use with rifampicin). When appointing drugs that should be taken concomitantly with efavirenz, the doctor should refer to the appropriate "Instructions for medical use" for these medications. 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 increased likelihoodselection of mutagenic viruses resistant to therapy.

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

Taking efavirenz with food can increase its effect and lead to an increase in the frequency of adverse reactions. Therefore, the drug is recommended to be used before bedtime on an empty stomach.

Skin rash: in clinical studies of efavirenz, it is reported that mild and moderate rashes, which usually disappear when the therapy is continued. Admission of appropriate blockers of H1-histamine receptors and / or glucocorticosteroid preparations can improve tolerance and contribute to the early disappearance of the rash. The severe form of the rash, accompanied by blistering, desquamation or ulceration, was observed in less than 1% of patients taking efavirenz. Multimorphic exudative erythema or Stevens-Johnson syndrome occurred in 0.14% of cases. If patients develop a severe form of rash, accompanied by the appearance of blisters, desquamation involving the mucous membranes or fever, it is necessary to immediately stop taking efavirenz. In the event of discontinuation of efavirenz therapy, consideration should be given to discontinuingother antiretroviral agents to avoid the emergence of a resistant to therapy virus

A rash was observed in 26 children from 57 (46%) who received efavirenz for 48 weeks, three patients experienced a severe form of rash. The appointment of H1-histamine receptor blockers before initiating efavirenz therapy in children with the goal of preventing the onset of rash may be appropriate.

Symptoms from the side of the psyche:

there are data on the occurrence of undesirable phenomena on the part of the psyche in patients who received efavirenz. Patients with a history of mental disorders are at increased risk for developing serious adverse events from the psyche. Also there are post-registration data on cases of suicide, delusions and psychosocial behavior. Patients should be warned that if they develop these symptoms, they should immediately contact their doctor. The physician should determine the possible association of these symptoms with the use of efavirenz, and if this relationship is confirmed, assess the risk ratio for the patient when continuing therapy and the potential benefits of taking the drug (see.see "With caution").

Symptoms from the nervous system:

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

Immunodeficiency Syndrome:

In HIV-infected patients with severe immunodeficiency during the onset of antiretroviral therapy, it is possible to develop an inflammatory response to asymptomatic or residual opportunistic infections, which can lead to serious deterioration or worsening of symptoms. As a rule, similar reactions are observed in the first weeks or months after the onset of antiretroviral therapy.The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumonia caused by Pneumocystis jiroveci (formerly called Pneumocystis carinii). Any symptoms of inflammation should be identified and, if necessary, prescribed treatment. Autoimmune diseases (for example, 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. Lipodystrophy and metabolic disorders

Combined antiretroviral therapy is associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including depletion of peripheral and facial subcutaneous fat, its accumulation in the intraperitoneal space, internal organs, posterior neck ("bison hump") and mammary hypertrophy. Combined antiretroviral therapy can induce metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia. Osteonecrosis

There were cases of osteonecrosis,especially in patients with common risk factors (taking corticosteroids, drinking alcohol, acute immunosuppression, increased weight index), HIV infection at a late stage, or on long-term combined antiretroviral therapy. Patients should be advised to consult a doctor if joint pain occurs, joint stiffness, or difficulty in moving.

Special patient groups

Diseases of the liver: efavirenz is contraindicated in patients with severe hepatic insufficiency (class C according to Child-Pugh classification) (see the section "Contraindications") and is not recommended for patients with impaired liver function of moderate severity, because at the moment there is not enough data to establish whether such cases, dose adjustment. Due to the intensive metabolism of efavirenz under the influence of the cytochrome P450 system and the limited clinical experience of the use of efavirenz in patients with chronic liver diseases, the drug should be administered with caution to patients with mild liver function disorders (see "With caution").Thus patients should be under supervision for timely revealing dose-dependent undesirable reactions, especially from nervous system. Also, at certain intervals, laboratory tests should be performed to assess the liver condition.

The safety and efficacy of efavirenz has not been confirmed in patients with significant liver disorders in the anamnesis. Patients with chronic hepatitis B and C who are taking combined antiretroviral therapy (ARVT) are at risk for developing severe adverse liver reactions that can lead to death. In patients with a history of hepatic dysfunction, including chronic active hepatitis, the incidence of liver function abnormalities increases with combined ARVT, so these patients should be monitored in accordance with the standard regimen. In patients with worsening of liver disease or with a steady increase in serum transaminase activity exceeding the upper limit of the norm by more than 5 times, the benefit of continuing efavirenz therapy should be compared with the possible risk of developinghepatotoxicity. For such patients, consideration should be given to the feasibility of discontinuing or canceling ARVs.

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

Renal insufficiency: the pharmacokinetics of efavirenz in patients with renal insufficiency has not been studied, however, due to the fact that in unchanged kidneys less than 1% of the amount of efavirenz is excreted, renal dysfunction should not have a significant effect on efavirenz excretion.

Experience in patients with severe renal failure is not available, therefore, in this group of patients, monitoring is recommended in order to evaluate the safety of therapy.

Older patients: Since a small number of elderly patients were included in clinical studies,that the effect of the drug on elderly patients is different from that in young patients, it is not possible (see Pharmacokinetics).

Children: The use of efavirenz in children less than 3 years old or weighing less than 13 kg has not been investigated. There is evidence that in very young children the pharmacokinetics of efavirenz can be altered.

Convulsions: in patients who received efavirenz, convulsions were extremely rare, including patients with a history of seizures. In patients receiving concomitant anticonvulsant drugs with a predominant metabolism in the liver, such as phenytoin, carbamazepine and phenobarbital, it is necessary to carry out periodic monitoring of their concentrations in the blood plasma. Caution should be exercised when prescribing patients who have a history of seizures (see the sections "With caution" and "Side effect").

"Hepatic" enzymes: in patients with diagnosed or suspected hepatitis B and C in the anamnesis and patients taking drugs associated with toxic effects on the liver, it is recommended to conduct regular monitoring of the activity of "liver" enzymes.In patients with a steady increase in the activity of serum transaminases exceeding 5 times the upper limit of normal, the benefits of continued therapy with efavirenz needs to be weighed against the possible risk for the occurrence of hepatotoxicity (see. Section "Side effects").

Cholesterol: in patients taking efavirenz the concentration of cholesterol in the blood should be monitored (see the "Side effect" section).

Interaction with the test for cannabinoids: efavirenz It does not bind to cannabinoid receptors, but there are reports of false positive results of urine tests on cannabinoids in uninfected volunteers who received efavirenz. False positive test results have been observed only in the analysis CEDIA DAU Multi-Level TIS, which is used for screening, and have not been observed during other tests for cannabinoids, including tests used for confirmation of positive results.

Effect on the ability to drive transp. cf. and fur:There have been no studies aimed at studying the impact on the ability to drive a car and work with devices. Efavirenz may cause dizziness, impaired attention, and / or insomnia. Patients should be warned that if they have any of these symptoms, they should avoid driving the car and controlling the devices.

Form release / dosage:Tablets, film-coated, 100.0 mg, 300.0 mg, 400.0 mg, 600 mg.

Packaging:

10 tablets per contour cell packaging made of polyvinylchloride film and aluminum foil.

By 2, 3, 6 or 9 contour mesh packages together with the instructions for use are placed in a pack of cardboard.

For 30, 60 or 90 tablets in a polymer jar with a cover pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive. On 1 bank together with instructions on application place in a pack from a cardboard.

Storage conditions:

In the original packaging of the manufacturer at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002554

Date of registration:31.07.2014

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Registan (Regast)