Zidolam-N - instructions for use, dose, side effects, contraindications

Active substanceZidovudine + Lamivudine + NevirapineZidovudine + Lamivudine + Nevirapine

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Zidolam-N

pills inwards

Heterose Labs Limited India

Dosage form: & nbsp

film-coated tablets

Composition:

1 tablet, film-coated, contains:

active substances: Zidovudine 300.0 mg, lamivudine 150.0 mg, nevirapine 200.0 mg;

Excipients: cellulose microcrystalline 184.0 mg, corn starch 66.0 mg, croscarmellose sodium (impellose) 18.0 mg, povidone (polyvinylpyrrolidone) 16.0 mg, magnesium stearate 15.0 mg, silicon dioxide colloid 8.0 mg, crospovidone 18 , 0 mg; shell: 20.0 mg (hypromellose 62.50%, titanium dioxide 31.25%, macrogol-400 - 6.25%).

Description:

Double-convex capsule capsules coated with a white film shell, with a risk on one side. At the break, the tablet is white or almost white.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.R.05 Zidovudine + Lamivudine + Nevirapine

Pharmacodynamics:

Zidolam-N - a combined drug, which includes lamivudine, zidovudine and nevirapine - reverse transcriptase inhibitors used in combination therapy of HIV infection.

Lamivudine and zidovudine are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Besides, lamivudine is active against hepatitis B virus. Zidovudine It is active against hepatitis B virus and Epstein-Barr virus in vitro, but in vivo, (in monotherapy), hepatitis B virus replication does not significantly suppress. Lamivudine is a synergist of zidovudine against the suppression of HIV replication in cell culture. The combined use of lamivudine with zidovudine leads to a significant reduction in the risk of progression of the disease.

Lamivudine and zidovudine belong to the group of nucleoside reverse transcriptase inhibitors (NRTIs), lamivudine is an analog of cytidine, zidovudine analogue of thymidine. Both drugs are sequentially phosphorylated with the participation of intracellular kinases (thymidine kinase, thymidylate kinase, nonspecific kinase) to 5'-triphosphates (TF). Lamivudine TF and zidovudine TF are a substrate and a competitive inhibitor of HIV reverse transcriptase. Antiviral activity is mainly due to the inclusion of their monophosphate form in the viral DNA chain, resulting in a chain break. Triphosphates of lamivudine and zidovudine have a much lower affinity for DNA polymerases of cells.

Nevirapine is a non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI).Combining with reverse transcriptase directly, blocks the activity of RNA-dependent and DNA-dependent polymerase, causing destruction of the catalytic site of the enzyme. Does not compete with matrix or nucleoside triphosphates. Does not inhibit the reverse transcriptase of HIV-2 and alpha, beta, gamma or sigma-DNA polymerase. In combination with zidovudine reduces viremia and increases the number of CD4 + cells.

Resistance

The resistant to lamivudine strains of the virus appear after 12 weeks of monotherapy; the resistance is due to the replacement in 184 of the position of the reverse transcriptase of isoleucine on valine. The 184V / I mutation provides high-level resistance tolamivudine, increases the sensitivity of the virus to zidovudine, stavudine and tenofovir, reduces the sensitivity of the virus to didanosine and abacavir, reduces the likelihood of a mutation of resistance to thymidine analogs (MPAT). In the presence of MPAT, an increase in sensitivity to zidovudine and the like is less pronounced. If the virus has only a mutation of 184V / I, a decrease in sensitivity to didanosine, etc. does not lead to clinically significant consequences. Mutations of 65R, 44D and 118I cause moderate resistance to lamivudine, while lamivudine does not contribute to the selection of strains with these mutations: MPAT infrequently combine with a 65R mutation.

With zidovudine monotherapy, the stability of viruses is fast and almost always developed. MPAT, which reduce the sensitivity of the virus to all, NRTI - 4I L, 67N, 70R, 210W, 215Y / F, 219Q / E, of which the most common are 41L, 210W and 215Y; they most significantly reduce the sensitivity of the virus to NRTI. Mutations of 67N, 70R and 219Q / E also reduce the sensitivity of the virus to NRTI, but to a lesser extent. Mutations 44D and 118I in the presence of MPAT increase the resistance to NRTIs. Combined therapy with lamivudine and zidovudine delayed the emergence of zidovudine-resistant strains in patients who had not previously received antiretroviral therapy and was effective in treating patients who had not previously received antiretroviral therapy and in patients who had strains of HIV with an M184V mutation.

Mutations affecting sensitivity to nevirapine: 100I, 103N, 106A / M, 108I,181C/I, 1880L / H, 190A. When treating nevirapine (not in combination with zidovudine), a mutation of 181 C usually appears; In the treatment of zidovudine and nevirapine, a mutation of 403N most often occurs. Mutations 103N, 106M, 188I/ C provide high level of resistance. The 188H mutation causes low level resistance.

Pharmacokinetics:

Absorption from the gastrointestinal tract of all active components of Zidolam-H is high, bioavailability of lamivudine is 80-85%, zidovudine - 60-70%, nevirapine -> 90%.

Pharmacokinetic parameters after a single oral intake of Zidolam-H by healthy volunteers are given in the table:

Parameter	Lamivudine	Zidovudine	Nevirapine
AUFROM_0-t(μg * h / ml)	5065(±1539)	2387(±608)	156 783 (±45 908)
FROM_m_Oh (μg / ml)	1182 (±453)	1773(±635)	1995(±492)
T_m_Oh (h)	1.65 (±1.24)	0.55 (±0.28)	5.02 (±4.76)

The presence of food in the stomach slows the absorption of lamivudine and zidovudine, its value decreases, but there is no significant effect on bioavailability - the area under the concentration-time curve (AUC) and half-life (T1) practically do not change. Eating food, antacids or preparations containing an alkaline buffer (for example, didanosine), the magnitude and extent of absorption of nevirapine is not affected.

The half-life of lamivudine is 5-7 hours, zidovudine from cells is 3.3 hours, from serum in adults - about 1 hour (0.8-1.2 hours), with renal failure (creatinine clearance less than 30 ml / min) - 1.4 - 2.9 hours, with cirrhosis varies depending on the severity of liver failure; on the average - 2,4 hours; theNewborns whose mothers received zidovudine 13 hours T1 lamivudine TF from the cells is 22 hours, zidovudine TF - about 7 hours after a single oral administration of nevirapine T1 is 45 hours, after repeated administration at a dose of 200-400 mg / day - 25-30 hours.

Lamivudine increases the duration of zidovudine by 13%, C_max - by 28%, while the AUC does not change; zidovudine does not affect the pharmacokinetics of lamivudine.

Connection with plasma proteins: lamivudine 35%, zidovudine 34-38%, nevirapine about 60%, indicating a low probability of Zidolam-H interaction with other drugs due to the displacement of plasma from the bond with proteins.

The volume of lamivudine distribution is 1.3 l / kg, zidovudine - 1.6 l / kg, nevirapine - 2.1 l / kg. All three active components of Zidolam-N overcome the blood-brain barrier (BBB). Lamivudine is found in cerebrospinal fluid (CSF) 2-4 hours after oral administration; the concentration of zidovudine in the CSF is 15 - 64% of the concentration in the plasma, the concentration of nevirapine is 45%.

Zidovudine penetrates most tissues and fluids, the body; accumulates in semen, where its concentrations exceed those in blood serum 1,3-20,4 times, but does not affect the release of HIV with seminal fluid and therefore can not prevent sexual transmission of HIV.

All three active components of Zidolam-H actively penetrate the placental barrier and into breast milk. Concentrations of lamivudine and zidovudine in the serum of infants are identical to those in the serum of maternal blood and cord blood. Lamivudine, zidovudine and nevirapine metabolized in the liver.

Lamivudine is metabolized to an insignificant extent (5 - 10%), with the formation of an inactive transulfoxide metabolite.

Zidovudine is conjugated with glucuronic acid to inactive glucuronides. The main metabolite is 5'-glucuronide, to which 50 to 80% of zidovudine administered inside is metabolized. With intravenous administration of zidovudine, his metabolite, 3'-amino-3'-deoxythymidine, was found.

Nevirapine is extensively metabolized with the participation of cytochrome isoenzymes CYP3A, CYP2B6. More than 80% of the ingested dose of nevirapine undergoes hydroxylation and conjugation to glucuronides. Being the inducer of the isoenzymes of the P450 system, nevirapine induces its own metabolism; the maximum drop of T1 is noted in the first 2-4 weeks of admission.

Lamivudine, zidovudine and nevirapine are excreted mainly through the kidneys.The systemic clearance of lamivudine is 0.32 l / h / kg; with a kidney clearance of 70%, excretion of lamivudine occurs with the participation of a cationic transport system.

The systemic clearance of zidovudine is 1.6 l / h / kg; renal clearance - 0.34 l / h / kg, excretion occurs through glomerular filtration and active tubular secretion. 14-18% of zidovudine is excreted by the kidneys in unchanged form, 60-74% - in the form of glucuronides (main - 5'-glucuronide).

Nevirapine is excreted from the body mainly in the form of metabolites; in unchanged form in urine is detected less than 3% of the dose taken internally. About 10% of nevirapine is excreted through the intestine.

Patients of advanced age.

On the features of pharmacokinetics in this group of patients, there is no data.

Patients with impaired hepatic function.

Correction of the dosing regimen is required for severe hepatic insufficiency and / or cirrhosis of the liver, as zidovudine is cumulated due to a decrease in glucuronidation.

Patients with impaired renal fiction.

Correction of the dosing regimen is required when QC is less than 50 ml / min (for lamivudine). The concentration of zidovudine in plasma increases with severe renal failure, nevirapine - in the terminal stage of CRF.

Pregnant. Features of pharmacokinetics of active components of Zidolam-H were not noted.

Sex, age, race.

There were no significant differences in nevirapine plasma concentrations, depending on gender. The pharmacokinetics of nevirapine in HIV-1-infected adult patients does not change with age (range 18-68 years) or race (Negroid, Latin American or Europoid race). There is no data for lamivudine and zidovudine.

Indications:

HIV infection in adults and adolescents over 16 years of age (body weight not less than 50 kg). Zidolam-H, as a fixed combination, can be administered with known adequate, tolerable active components - lamivudine, zidovudine, nevirapine.

Tolerability is assessed after a course of combined antiretroviral therapy, at which a maintenance dose of nevirapine 200 mg twice a day was achieved and applied for at least 6-8 weeks (a maintenance dose is prescribed only after 14 days of intake at an initial dose of 200 mg once daily).

Contraindications:

Hypersensitivity to any of the active and / or auxiliary components of the drug; neutropenia / leukopenia (the number of neutrophils is below 0.75x10⁹/ l or 750 / μl); anemia (hemoglobin below 7.5 g / dl or 4.65 mmol / l); severe liver failure (class C Child-Pugh or transaminase activity (ALT or ACT), more than 5 times the upper limit of normal (ULN)); severe skin reaction history, generalized rash and / or hepatotoxicity in nevirapine history; impaired renal function (CK less than 50 ml / min); children and adolescents under 16; simultaneous administration of medications containing St. John's wort.

Carefully:

Inhibition of bone marrow hematopoiesis, neutropenia / leukopenia (number of neutrophils 0.75x10⁹/ l - 0.10x10⁹/ l or 750 - 1000 / μl); anemia (hemoglobin 7.5 - 9.0 g / dl or 4.65 - 5.59 mmol / l); deficiency of cyanocobalamin or folic acid, hepatic insufficiency of mild and moderate severity, elderly age (over 65 years), obesity, hepatomegaly, hepatitis or any known risk factors for liver disease, pancreatitis, incl. in the anamnesis, peripheral neuropathy.

Pregnancy and lactation:

Use during pregnancy is only possible if the intended benefit to the mother exceeds the potential risk to the fetus.

In the case of the drug during lactation it is necessary to stop breastfeeding.

HIV-infected women should be instructed to exclude breastfeeding because of the extremely high probability of transmission through breast milk.

Dosing and Administration:

Treatment Zidolam-H should be conducted by a doctor who has experience in managing HIV-infected patients.

Adults and adolescents over 16 years of age (body weight not less than 50 kg)

Inside, regardless of food intake, 1 tablet 2 times a day.

A prerequisite for prescribing Zidolam-H is the previous combination therapy with mono-drugs - lamivudine, zidovudine, nevirapine, in which nevirapine was used in a maintenance dose of 200 mg twice a day for at least 6-8 weeks. In a maintenance dose nevirapine appoint only after 14 days of admission in the initial dose of 200 mg once a day.

Elderly patients (over 65)

With preservation of the excretory function of the kidneys and normal hematological parameters, correction of the dosing regimen is not necessary. Recommended use with caution, adequate monitoring of kidney function and periodic monitoring of blood picture.

General recommendations on the dosage regimen in special clinical cases

For conditions requiring dose reduction of Zidolam-H, the patient should be transferred to mono drugs, following recommendations for correcting the dosing regimen for lamivudine, zidovudine, and nevirapine.

Dose reduction is required for renal dysfunction (KK less than 50 ml / min), moderate hepatic insufficiency, hemoglobin level less than 9 g / dL or 5.59 mmol / l, neutropenia below 1 thousand / μL. With hepatic failure to moderate degree of dose reduction is not required. In severe hepatic insufficiency, Zidolam-N, like nevirapine-containing remedy, is contraindicated.

If for any reason Zidolam-N treatment was interrupted for more than 7 days, the therapy should be resumed by appointing lamivudine, zidovudine and nevirapine separately. Nevirapine should be prescribed at 200 mg once a day for 14 days *, then - in the absence of hypersensitivity reactions and severe gastrointestinal reactions - 200 mg twice a day for 6-8 weeks. Then you can resume taking Zidolam-N. It should also be borne in mind that the maximum daily dose of lamivudine for patients with renal insufficiency (KC from 50 to 30 ml / min) is 150 mg.

* If a rash occurs during the 14-day initial period, the dose should be increased after the rash disappears.

Drug withdrawal / interruption in therapy

Indications for withdrawal of the drug / suspension of treatment Zidolam-H are severe skin reactions, violations of liver function, increased activity. "hepatic" enzymes (with the exception of gamma-glutamyltranspeptidase).

Important! Irregular intake of the drug leads to the development of resistance to the virus and reduce the effectiveness of treatment. If you miss a dose, take the pill as soon as possible without waiting for the next time. Do not double!

Side effects:

Side effect of Zidolam-H is identical with the aggregate of adverse reactions of lamivudine, zidovudine, nevirapine. Additivism of undesirable reactions, as well as competitive interaction, between active components of Zidolam-P is not present.

The frequency of adverse reactions is given in accordance with the recommendations of WHO: very often - more than 10%; often - more than I and less than 10%; infrequently - more than 0.1 and less than 1%; rarely - more than 0.01 and less than 0.1%; rarely - less than 0.01%.

When Zidolam-H is taken in more than 10% of cases, rash, headache, nausea, diarrhea, abdominal pain and myalgia are noted.Of serious adverse reactions, anemia, neutropenia, leukopenia, hypersensitivity reactions and hepatotoxic reactions also develop.

Systems of organs	Nevirapine	Lamivudine	Zidovudine
From the nervous system	Often - a headache	Often - headache, insomnia; very rarely - peripheral neuropathy or paresthesia (sensation of tingling, burning, numbness and pain in the hands, hands, feet or feet)	very often - headache; often dizziness; rarely - insomnia, paresthesia, drowsiness, confusion, convulsions, anxiety, depression
From the side of the cardiovascular system	infrequently - increase of arterial pressure		Rarely - cardiomyopathy
On the part of the organs of hematopoiesis	often - granulocytopenia; infrequently - anemia	infrequently - neutropenia and anemia (in some cases - pronounced), thrombocytopenia; very rarely - true erythrocyte aplasia	often - anemia, neutropenia, leukopenia; infrequently - thrombocytopenia, pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely aplastic anemia
From the respiratory system		Often cough, rhinitis	Infrequent - shortness of breath; rarely - cough
From the digestive system	often - nausea, vomiting, abdominal pain, diarrhea, increased activity of "liver" enzymes (AST, ALT, GGT (γ-glutamyl transferase), hepatic insufficiency (including severe, life-threatening, (1.9%)), infrequently - jaundice , rarely fulminant (fulminant) hepatic insufficiency, including fatal outcome	Often - nausea, vomiting, abdominal pain or colic, diarrhea; infrequently - transient increase in the activity of "liver" enzymes (ACT, ALT): rarely - pancreatitis, increased activity of amylase, hepatitis.	very often - nausea; often - vomiting. abdominal pain, diarrhea, increased activity of "liver" enzymes, hyperbilirubinemia; infrequent meteorism: rarely - pigmentation of the oral mucosa, taste disorders, dyspepsia, pancreatitis, severe hepatomegaly with steatosis
From the side of metabolism	Infrequently - hypophosphatemia		Rarely - lactic acidosis in the absence of hypoxemia, anorexia
From the urinary system			Rarely - frequent urination
From the side of the reproductive system			Rarely - gynecomastia
From the skin	very often - a rash, (12.5%)	Often - a rash, hair loss	infrequently - itching, rash; rarely pigmentation of skin and nails, increased sweating
From the musculoskeletal system	Infrequent - arthralgia, myalgia	Often - arthralgia, muscle damage; rarely - rhabdomyolysis	often - myalgia; infrequently - myopathy
Allergic reactions	often - hypersensitivity reactions (including anaphylactic reactions, angioedema, urticaria); infrequently, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome, 0.2% fatal), angioedema, urticaria; rarely - a drug reaction with eosinophilia and systemic manifestations (DRESS-syndrome)	Rarely, angioneurotic edema	Rarely - urticaria
Other	often - fever, fatigue; frequency is not known - immune reactivation syndrome, redistribution of adipose tissue	often fatigue, malaise, fever	often - malaise; infrequently - fever, generalized pain, asthenia; rarely - chills, chest pain, flu-like syndrome

In assessing tolerability Zidolama-H, it should be considered that skin rash, dizziness, weakness, headache, anorexia, diarrhea, myalgia, anemia, thrombocytopenia may be a manifestation of HIV infection itself and secondary diseases connected with it, rather than a toxic effect within the composition of the preparation of active components.

Overdose:

Symptoms

Nausea, vomiting, weakness / fatigue, fever, headache, dizziness, insomnia, rashes, swelling, erythema nodosum, pulmonary infiltrates, increase in transaminases and weight loss.

Treatment

Standard maintenance therapy, continuous hemodialysis. There is no specific antidote to any of the active components of the drug.

Data on cases of overdose with a combination of lamivudine / zidovudine / nevirapine are not available.

Acute overdose of lamivudine or zidovudine specific symptoms is not different, there are only side effects. There is a case of overdose with nevirapine (800 - 6000 mg for 15 days), the symptoms are listed above.,

There were no deaths in any case, the condition, all patients against the background of standard maintenance therapy normalized.

Interaction:

Interactions due to the presence of lamivudine

The likelihood of adverse interaction of lamivudine with other drugs is extremely low due to the insignificant degree of its binding to proteins, limited biotransformation and excretion mainly by the kidneys in unchanged form. Lamivudine is excreted from the body mainly through the cationic transport system, which should be taken into account when prescribing other drugs that have the same pathway.

Emtricitabine - Combine these medications is not recommended.

Because the lamivudine can inhibit intracellular phosphorylation zalcitabine, it is not recommended to combine these medications.

Lamivudine, by inhibiting intracellular phosphorylation cladribine (in vitro), reduces the effectiveness of the latter. A few clinical information confirm the existence of such an interaction. Combine these medications is not recommended.

Simultaneous application co-trimoxazole (trimethoprim / sulfamethoxazole, 160 mg / 800 mg) increases the concentration of lamivudine in plasma by approximately 40%. With the preserved function of the kidneys, there is no need to reduce its dose, in patients with renal insufficiency, use with caution. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. The combined use of lamivudine with higher doses of co-trimoxazole (trimethoprim / sulfamethoxazole) used to treat PCP and toxoplasmosis has not been studied; it is not recommended to combine these medications.

Simultaneous reception pentamidine, sulfonamides and ethanol increases the risk of developing pancreatitis.

Dapsone, isoniazid and stavudine increase the risk of peripheral neuropathy.

Pharmacokinetic interaction in the combination of lamivudine with interferon alfa and immunosuppressive drugs (eg, cyclosporin A) not visible.

Lamivudine increases the duration of action zidovudine 13%, C_max - by 28%, while the AUC does not change; zidovudine does not affect the pharmacokinetics of lamivudine.

Interactions due to the presence of zidovudine

Clinically significant interaction between zidovudine and lamivudine is not observed.

Clinically significant are the interactions of zidovudine and zidovudine-containing combination drugs with other drugs that compete with zidovudine for the glucuronization route and / or are able to affect the activity of microsomal liver enzymes. So, paracetamol, acetylsalicylic acid, codeine, methadone, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, clofibrate, dapsone, inosine pranobex, atovahon modify the intensity of the biotransformation of zidovudine, which in turn increases the likelihood and frequency of adverse events. For example, the combination of paracetamol increases the frequency of neutropenia.

When combined with atavahone AUC zidovudine increases by 33%, the atovahona AUC does not change significantly; But due to the lack of knowledge, combining these drugs is not recommended.

Probenecid inhibits glucuronization of zidovudine, increases its T1, also increases AUC by 106% (100-170%). In the presence of probenecid, as well as other inhibitors of tubular secretion, renal excretion of zidovudine and its glucuronide decreases.

Use with caution is recommended with potentially nephro- and myelotoxic drugs, such as pentamidine, dapsone, co-trimoxazole (trimethoprim / sulfamethoxazole), amphotericin B, flucytosine, ganciclovir, interferon-alpha, vincristine, vinblastine, pyrimethamine.

Radiation therapy enhances the myelosuppressive effect of zidovudine.

When combined with zidovudine with phenytoin it is possible to change the concentration of the latter in the blood.

Clarithromycin reduces the absorption of zidovudine, should be observed between the reception of clarithromycin and Zidolam-H for at least 2 hours.

Combination rifampicin with zidovudine leads to a decrease in AUC zidovudine by 48 ± 34%. Combine these medications is not recommended.

Ribavirin is an antagonist of zidovudine (in vitro), therefore, combining these medications is not recommended. According to clinical data, the combined use of zidovudine with ribavirin is a very high risk factor for anemia and lactic acidosis.

Simultaneous use of zidovudine and doxorubicin It is not recommended, since the interaction in vitro shows a mutual weakening of the activity of both drugs.

Zidovudine is more actively phosphorylated by intracellular thymidine kinase, thereby preventing phosphorylation stavudine; in this connection, simultaneous reception is not recommended.

Valproic acid, fluconazole, methadone increase zidovudine AUC by 80%. 74% and 43% respectively. In addition, there is a decrease in zidovudine clearance. The clinical significance of this modification is not completely clear, as there is little data, nevertheless, it is recommended that combined treatment with these drugs be performed under strict medical supervision. It is necessary to monitor hematological parameters and kidney function.

Phenobarbital is an inducer of isoenzymes of the liver and potentially can contribute to some increase in the concentration of zidovudine in the blood and, as a result, the development or aggravation of undesirable reactions of the latter. Information on the characteristics of the interaction of phenobarbital with zidovudine, as well as lamivudine, for developing recommendations for correcting the dosage regimen is not enough.

Additional antimicrobial therapy for opportunistic infections using co-trimoxazole, pentamidine (in aerosol form), acyclovir on the background of the combination of zidovudine / lamivudine was not accompanied by an increase in the frequency of undesirable side reactions.

There is synergistic effect with other drugs used against HIV (especially lamivudine), with respect to HIV replication in cell culture.

Cimetidine, ranitidine - correction of the subsidy regime with simultaneous use with Zidolam-H is not required, since clinically significant interaction with lamivudine, as well as with zidovudine, is not expected.

Interactions due to the presence of nevirapine

Nevirapine is metabolized by the isoenzymes of the P450-CYP3A, CYP2B system. It is known that nevirapine is an inducer of the same isoenzymes: therefore, it can lead to a decrease in the concentration of co-used agents that are metabolized with the participation of CYP3A and CYP2B isoenzymes and cause a need to correct their dosing regimen.

Potentially possible interactions

Nevirapine can help reduce the concentration of the following drugs:

Antiarrhythmic: amiodarone, disopyramine, lidocaine;

Anticonvulsants: carbamazepine, clonazepam, ethosuximide;

Blocks of "slow" calcium channels: diltiazem, nifedipine, verapamil;

Cytotoxic: cyclophosphamide;

Ergot alkaloids: ergotamine;

Immunosuppressive drugs: ciclosporin, tacrolimus, sirolimus;

Prokinetics: cisapride;

Opioid receptor agonists: fentanyl.

Nevirapine may help increase the concentration of the following medicines:

Antithrombotic: warfarin. It is necessary to monitor the concentration of warfarin in the blood. By results of interaction in vitro it can be concluded that prothrombin time with simultaneous application of nevirapine and warfarin may both increase and decrease, which necessitates frequent monitoring of prothrombin time.

Known interactions

Clarithromycin. In the presence of nevirapine, the total exposure of clarithromycin decreases, despite an increase in the concentration of its active 14-OH metabolite. It should be taken into account that it is possible to reduce the activity of the antibiotic against Mycobacterium avium, in such cases it is necessary to evaluate the acceptability of alternative drugs - azithromycin, etc.It is recommended to monitor liver function.

Nucleoside analogues

Zidovudine, lamivudine, tenofovir - correction of the dosing regimen is not required. There is a risk of developing granulocytopenia during therapy with zidovudine in combination with nevirapine. There is a relatively high risk of developing granulocytopenia in children, in patients with initial myelodepression (low bone marrow reserve), progressive HIV infection, etc. (see section "Special instructions", "Hematologic disorders").

Didanosine, emtricitabine, abacavir, stavudine - correction of the dosing regimen is not required.

Non-nucleoside analogues

Efavirenz - joint use is not recommended, since there is additivity in undesirable reactions.

Etravirine It should not be used simultaneously with Zidolam-H, since nevirapine contributes to a significant decrease in the concentration of etravirin in the blood plasma, which, in turn, significantly reduces the therapeutic effect of etravirine.

Rilpivirin, delavirdine - Combine these medications with nevirapine is not recommended.

Zalcitabine - there is no pharmacokinetic and pharmacodynamic interaction.It should be noted that it is not recommended to combine Zidolam-H with zalcitabine (for lamivudine, see above).

Protease Inhibitors

Saquinavir does not affect the pharmacokinetics of nevirapine. However, the presence of nevirapine leads to a decrease in saquinavir AUC. The clinical significance of this fact is not clear; it is possible that an increase in the dose of saquinavir may be required. Nevirapine Do not change the AUC of saquinavir when combined with ritonavir use. The effect of nevirapine on the pharmacokinetics of saquinavir in the presence of ritonavir is regarded as weak and clinically insignificant.

Ritonavir - correction of the dosing regimen is not required.

Indinavir does not have a significant effect on nevirapine concentrations, with mean values of indinavir AUC decreasing, which may require an increase in the dose of indinavir.

Nelfinavir. Pharmacokinetic interaction between nevirapine and nelfinavir is not observed. However, AUC, C_max, FROM_min the main metabolite of nelfinavir M8, comparable in activity with unaltered nelfinavir, decreases almost 1.5 times.

Lopinavir / ritonavir. Nevirapine leads to a decrease in the average values of AUC, C_max, FROM_min lopinavir. Correction of the dose of nevirapine (solid dosage forms) is not required. However, when using a solution for oral administration in children, especially when suspected of a decreased sensitivity to the lopinavir / ritonavir combination, consideration should be given to increasing the dose of lopinavir / ritonavir. It is recommended to take drugs during meals.

The pharmacokinetic interaction of nevirapine is not clinically significant, correction of the dosing regimen is not required with the following combinations:

fosamprenavir / ritonavir,

darunavir / ritonavir,

tipranavir / ritonavir.

It should be noted that fosamprenavir, not boosted with ritonavir, Do not use with Nevirapine, since AUC, C_max, FROM_min amprenavir, its main metabolite, are reduced, and nevirapine is increased.

Atazanavir / ritonavir. The combination is not recommended for use with nevirapine, since the mean values of AUC, C_max, FROM_minAtazanavir decreased, and nevirapine increased.

HIV penetration blockers

CCR5 receptor antagonist maraviroc, as well as the blocker fusii enfuvirtide, can be used with nevirapine without correction of doses of drugs.

Integrase inhibitors

Raltegravir can be used with nevirapine without correction of the dosing regimen, because the drugs are metabolized in various ways, which excludes competitive interaction.

Combination elvitegravir / cobicystate It is not recommended for joint use with nevirapine. Kobitsystat is a potent inhibitor of enzymes involved in metabolic processes, including the isoenzyme CYP3A. resulting in a significant change in plasma concentrations of nevirapine and cobicystate.

Antiviral drugs used in viral hepatitis B u FROM

Adefovir shows a weak antagonism with nevirapine, which is not clinically significant and does not serve as an indication for changing the dosage regimen.

Boceprevir partially metabolized by isoenzymes CYP3A4 / 5. When combined with NNRTIs that are metabolized by a nevirapine-like route, a decrease in plasma concentrations of bocetrephir was observed. To date, there is insufficient information to accurately assess the clinical significance of this fact: recommended use with caution.

Telaprevir is a substrate of the isoenzyme CYP3A and P-glycoprotein.Based on information on the interaction of telaprevir with NNRTI, as in the case of boceprevir. recommended use with caution.

Entecavir, as well as telbivudine, are not substrates of cytochrome P450, and clinically significant interaction with nevirapine is not detected. Correction of the dosing regimen is not required.

Interferons (pegylated interferons alpha 2a and alpha 2b) have no clinically significant effect on the isoenzymes CYP3A4 and CYP2B6, and can be used with nevirapine without correcting the dosage regimen.

Ribavirin in vitro shows a weak antagonism with nevirapine, and in clinical practice can be used with nevirapine without dose adjustment. However, it is not recommended to apply ribavirin with Zidolam-N (for zidovudine (see above)).

Antifungal drugs

Fluconazole contributes to an increase in exposure to nevirapine by 100%. which increases the risk of developing unwanted reactions of nevirapine; recommended use with caution in hospital settings.

Itraconazole does not affect the pharmacokinetic parameters of nevirapine. However, AUC, C_max and C_min itraconazole significantly reduced, which requires an increase in the dose of itraconazole.

Ketoconazole and nevirapine should not be used together.

Rifampicin contributes to a significant decrease in AUC, C_max and C_min nevirapine, in connection with which rifampicin and nevirapine should not be applied simultaneously.

Rifabutin contributes to an increase in the total clearance of nevirapine: in the presence of nevirapine there is an increase in AUC, C_max and C_min rifabutin. Changes in the pharmacokinetic parameters of rifabutin are distinguished by significant interindividual variability; In rare cases, there was a significant increase in the concentration, and as a consequence, the toxicity of rifabutin. Recommended use with caution.

Depo-medroxyprogesterone acetate (DMPA) in a dose of 150 mg once every three months - can be used on a nevirapine background without correction of the dosing regimen.

Ethinyl estradiol, norethindrone, oral contraceptives - nevirapine helps to reduce the concentrations and effectiveness of these funds. Exact recommendations for correcting the dosage regimen have not been developed. Additional methods of contraception should be used.

Cimetidine with nevirapine have no clinically significant interaction and can be used without correction of the dosing regimen.

Drugs containing St. John's wort. Being inductors of isoenzymes, with which drugs are metabolized, and / or transport proteins, reduce the concentration of nevirapine in the blood: it is contraindicated to combine these medications with nevirapine. At the stage of prescribing nevirapine monopreparation it is necessary to take into account that this inducing effect is retained for at least 2 more weeks after stopping the intake of St. John's wort preparations. Prescribe a combination drug Zidolam-H is necessary in accordance with the section "Method of administration and dose."

Methadone

In the presence of nevirapine, there is a decrease in the concentration of methadone. It may be necessary to adjust the dose of methadone.

Special instructions:

Treatment with Zidolam-H should only be performed by a physician with experience in managing HIV-infected patients.

It is not recommended simultaneous use of Zidolam-H with the following drugs: zalcitabine, cladribine, ribavirin, doxorubicin, stavudine, rifampicin, efavirenz, ketoconazole, delavirdine, etravirine, rilpivirin, bocepivir; a combination of elvitegravir / co-bicystate, a combination of atazanavir / ritonavir, fosamprenavir, not reinforced with a low dose of ritonavir.

If it is necessary to reduce (reduce) the dose, replace the fixed combination, in this case Zidolam-H, with the mono-preparations that make up its combination, combining them in prescribed doses.

It is necessary to inform the patient about the danger of using other medications simultaneously with Zidolam-H, including over-the-counter leave, without consulting the doctor in advance. With the development of opportunistic infections or other complications of HIV infection, treatment should continue in a hospital setting. The patient should be informed that antiretroviral therapy, in particular Zidolam-H therapy, does not prevent or reduce the risk of transmission of the immunodeficiency virus to healthy people through blood and through sexual contact.

It is recommended that all HIV-infected patients be tested for chronic hepatitis B before initiating antiretroviral therapy.

The drug is not designed to prevent the transmission of the immunodeficiency virus, moreover, there are cases of serious adverse events in the use of nevirapine outside the approved indications (off-label).

Before starting therapy with Zidolam-N, all patients need to conduct laboratory tests to assess the likelihood of developing potentially dangerous side effects. Patients who previously received antiretroviral therapy should be tested for genotypic analysis of the virus.

The most dangerous side effects

Liver disorders

Severe life-threatening liver damage, including fulminant liver failure, is a hypersensitivity reaction to nevirapine. Immune-mediated liver reactions may be combined with skin reactions (rash, etc.) or common phenomena such as fever, arthralgia, myalgia, malaise. The most dangerous are the first 6 weeks of therapy with nevirapine, then a minor danger persists until the 18th week.

Risk factors are female sex, initially high number of CD4 cells, increased (> 2.5 upper limit of normal) activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), co-infection with hepatitis C virus, alcohol abuse. Thus, in women with CD4 count> 250 cells / mm³, compared with women who have CD4 <250 cells / mm³, the risk of developing hepatotoxic reactions is 12 times higher. In men with a CD4 count> 400 cells / mm³ the risk of developing hepatotoxic reactions is 5 times higher. Begin treatment with nevirapine for women with CD4 count> 250 cells / mm³ and men with CD4 count> 400 cells / mm³ It does not follow, unless the expected benefit substantially exceeds the possible risk.

Monitoring of liver function

Active monitoring of liver function parameters should be performed in patients who previously had complaints of dyspeptic phenomena, anorexia, nausea, discolored stool, pain in the liver, jaundice, hepatomegaly, and patients who had biochemical markers of liver dysfunction: bilirubinuria, a moderate or significant increase in the activity of "hepatic" enzymes, including the activity of γ-glutamyltransferase.

At the same time, the asymptomatic increase in the activity of "hepatic" enzymes against the background of therapy with nevirapine is not an indication for the withdrawal of the drug.

Monitoring of liver function indicators should be organized at intervals of every two weeks during the first two months of use, then at the end of the third month, then regularly, throughout the entire period of use.In case the therapy was started against a background of increased activity of "liver" enzymes exceeding the upper limit of the norm by more than 2.5 times, control of liver function markers should be performed more often. Activity "liver" enzymes, more than 5 times higher than UGN, is a contraindication to the use of nevirapine, respectively, is critical, and the achievement of such values during the therapy is an indication for immediate withdrawal of the drug.

Any signs of the development of hypersensitivity reactions, as well as hepatotoxic reactions, are an indication to stop taking the drug and immediate medical treatment.

If you have such complaints as anorexia (loss of appetite), nausea, vomiting, pain in the right hypochondrium, icterus of the skin, dark color of urine and discolored stool should immediately consult a doctor!

Special surveillance is required when HIV is co-infected with hepatitis B or C, due to the increased risk of developing hepatic complications of antiretroviral therapy, including dangerous and potentially fatal.

Also at high risk are patients with previous liver dysfunction / activeliver diseases (class B by Child-Pugh). Appropriate monitoring of the condition of these patient groups is recommended. If there is an increase in liver dysfunction or worsening of the general condition of the patient, consideration should be given to interrupting or canceling antiretroviral therapy.

It should be borne in mind that with the reversal of lamivudine (and, accordingly, lamivudine-containing Zidolam-H) may exacerbate hepatitis. Use with caution is recommended for decompensated hepatic cirrhosis due to chronic hepatitis B. Periodic monitoring of liver function and markers of hepatitis B virus replication should be carried out: in patients with hepatitis B, liver function should be monitored also after discontinuation of Zidolam-H for 4 months.

Hypersensitivity reactions

In patients who received nevirapine, serious and life-threatening dermatological reactions were noted, including fatal - malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), hypersensitivity syndrome - a combination of rash, general phenomena and internal organs.The most dangerous for the likelihood of developing the rash are the first 6 weeks of therapy with nevirapine, to a lesser extent - until the 18th week. Even in the case of isolated rash, careful monitoring is required.

In the case of generalized rash or rash, combined with common symptoms such as malaise, fever, mucous membrane damage (swelling, redness, tenderness, blisters), conjunctivitis, facial edema, blistering of the skin, joint and muscle pain - You should stop taking the drug and immediately consult a doctor.

Compliance with the regimen of nevirapine (see the sections "Indications", "Dosage regimen") before the reception of a fixed combination - Zidolam-N allows to minimize the likelihood of developing the rash.

Prednisone and antihistamines are ineffective; according to some data, with the preventive administration of prednisone concomitantly with nevirapine in the first 14 days of therapy, even increases the incidence of rash. Repeated administration after severe hypersensitivity reactions is not allowed.

Rhabdomyolysis

On the background of taking nevirapine, the cases of development of rhabdomyolysis in combination with severe cutaneous hypersensitivity reactions and / or liver damage are described.

Lactic acidosis / Hepatomegaly with steatosis

With long-term use of nucleoside analogues, including lamivudine and zidovudine, the development of lactic acidosis, a marked increase in the liver with steatosis, including fatal outcome. In clinical practice, lactic acidosis was observed after several months of NRTI use, which is why it is considered a relatively late complication of NRTI therapy.

Early clinical manifestations (symptomatic hyperlactatemia) are not specific: moderately expressed gastrointestinal symptoms - nausea, vomiting, abdominal pain, weakness, loss of appetite, weight loss, respiratory symptoms - hyperpnoea and / or tachypnea, neurological symptoms, including motor weakness.

Lactic acidosis may be associated with pancreatitis, hepatic or renal insufficiency, and high mortality.

When clinical or laboratory signs of lactic acidosis (symptomatic hyperlactatemia and metabolic / lactic acidosis, progressive hepatomegaly, rapidly increasing transaminase activity), the drug (NRTI) should be stopped.

Risk factors for the development of lactic acidosis when NRTIs are used are the initial hepatomegaly (infeatures in women with obesity), hepatitis, any other known risk factors for the development of hepatic diseases, fatty liver, alcohol and drug damage to the liver. A special group of risk consists of patients co-infected with hepatitis C and receiving ribavirin and alpha-interferon therapy.

Patients at high and very high risk need careful monitoring.

Pancreatitis

There are rare reports of the development of pancreatitis in patients taking lamivudine / zidovudine. It is not established whether pancreatitis is an adverse drug reaction or a complication of HIV infection. And, nevertheless, when the appearance of clinical or laboratory signs indicating the development of pancreatitis (abdominal pain, nausea and vomiting, increased values of biochemical markers), the drug should be discontinued.

Other side effects

Hematologic disorders

Possible development of anemia, neutropenia and leukopenia (usually secondary to neutropenia) in patients receiving zidovudine-containing combinations. The risk group is patients with progressive HIV infection, with initial myelodepression, vitamin B deficiency₁₂. Serious hematologic reactions are characteristic for high doses of zidovudine (1200-1500 mg / day), and it would be incorrect to approximate these data to a fixed combination.

Since the peak of hematologic abnormalities is usually observed after 4-6 weeks of therapy, it is recommended to conduct blood tests at the following intervals:

in patients with progressive HIV infection: at least 1 time in 2 weeks during the first three months of therapy, then - at least 1 time per month;

at patients at an early stage, at an asymptomatic current: 1 time in 1-3 months, based on the general condition of the patient.

With the development of severe anemia and / or myelosuppression, a decrease in the dose of zidovudine is required, respectively, the patient should be transferred to monopreparations.

Granulocytopenia as a complication of therapy with nevirapine, especially in combination with zidovudine, was detected in the postmarketing period. It is noted that in children this reaction develops much more often.

Mitochondrial toxicity

Examination of children exposed to NRTI in utero and / or postnatal period revealed the following disorders: hematologic (anemia, neutropenia), metabolic (hyperlactatemia, hyperlipazemia); in most cases transient.There are several cases of distant side effects from the nervous system: hypertension, convulsions, abnormal behavior. It is not known whether these violations are transient; nevertheless, children exposed to NRTIs need to be monitored.

The given data on mitochondrial toxicity are not grounds for introducing changes in recommendations for the prevention of vertical transmission of HIV.

Redistribution of adipose tissue

In patients receiving antiretroviral therapy, there was a redistribution / accumulation of adipose tissue, including abdominal obesity, dorsocervical fat deposition ("buffalo buffalo"), lipoatrophy on the limbs and face, breast enlargement and "cushingoid" type of obesity. Risk factors are metabolic disorders, the duration of antiretroviral therapy, and older patients. The mechanism of occurrence and long-term effects are not known. Causal relationship with the use of ARB drugs has not been proven. It is recommended to periodically check the concentration of glucose and lipids in the blood; if necessary, an adequate pharmacological correction.

Syndrome of reactivation of immunity

A syndrome of reactivation of immunity was reported in patients taking combined antiretroviral therapy. The immune reactivation syndrome manifests itself as exacerbation of sluggish and opportunistic infections, activation of opportunistic flora: it is observed at the initial stage of treatment in HIV-infected patients with initial expressed immunosuppression.

Characteristic development of cytomegalovirus retinitis, localized or generalized mycobacterial infection, pneumocystis pneumonia. Cases of autoimmune diseases, for example, Graves' disease (autoimmune thyroiditis) have been reported. At the same time for infections caused by the reactivation of immunity, characterized by the development during the first few weeks of treatment, while autoimmune diseases develop many months after the initiation of therapy.

Effect on bone tissue

It is possible to reduce the initial level of bone density, there are cases of osteonecrosis. Etiology multifactorial: simultaneous reception of corticosteroids, alcohol abuse, severe immunosuppression, high body mass index; The risk is higher in patients with progressive HIV infection, and increases in direct proportion to the duration of therapy.The patient should be warned about the need to consult a doctor if there are complaints of restricted mobility of the joints, arthralgia, in particular pain in the shoulder, knee, hip, discomfort / movement difficulties.

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

During the treatment period, due to possible side effects such as severe weakness, dizziness, sensitivity of the hands and feet, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions. When these undesirable reactions appear, one should refrain from performing these activities.

Form release / dosage:

The film-coated tablets are 300 mg + 150 mg + 200 mg.

Packaging:

For 60 tablets in a can of polymeric, sealed aluminum foil, with a screw cap; having a device that prevents the opening of the can of children or 60 tablets in a polymer can with a screw cap. 1 bank together with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-001762

Date of registration:02.07.2012 / 14.04.2015

Expiration Date:02.07.2017

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

Manufacturer: & nbsp

HETERO DRUGS Limited India

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zidolam-N (Zidolam-N)