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

Excipients: cellulose microcrystalline 269.6 mg, hypromellose-2910 16.3 mg, sodium carboxymethyl starch 22.5 mg, silicon dioxide colloid 2.3 mg, magnesium stearate 5.6 mg;

sheath: film coating 15.3 mg;

The film coating includes: hypromellose-2910 (61.0%), titanium dioxide (E 171) (28.0%), macrogol (10.0%), polysorbate-80 (1.0%).

Description:

Biconvex tablets capsular shaped, covered with a film coat of white or almost white color.

The cross-section of the tablet is white or almost white.

Pharmacotherapeutic group:Means for treating HIV infection in combination

ATX: & nbsp

J.05.A.R.01 Zidovudine + Lamivudine

Pharmacodynamics:

Combined antiviral drug, which includes lamivudine and zidovudine, which are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Lamivudine is a synergist of zidovudine against the suppression of HIV replication in cell culture. Both drugs are sequentially metabolized by intracellular kinases to 5'-triphosphate (TF). Lamivudine-TF and zidovudine-TF are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of the preparations 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 human cells. In vitro shows low cytotoxicity of lamivudine against lymphocytic and monocyte-macrophage colonies and a number of precursor cells of the red bone marrow. In this way, lamivudine has a wide therapeutic index.

Resistance. The resistance of HIV-1 to lamivudine is due to a mutation in the codon M184V near the active center of HIV reverse transcriptase. This strain stands out as in vitro, and in HIV-1-infected patients receiving antiretroviral treatment regimens, including lamivudine. Strains of viruses with M184V mutation show a significant decrease in sensitivity to lamivudine and show less replicative activity in vitro. Studies conducted in vitro, showed that zidovudine-resistant virus isolates may develop sensitivity to zidovudine if they acquire resistance to lamivudine. The clinical significance of this phenomenon is unclear.

Cross-resistance. Cross-sensitivity due to M184V mutation in HIV reverse transcriptase limits the use of all drugs of the class of nucleoside reverse transcriptase inhibitors (NRTIs). Zidovudine and stavudine retain their antiretroviral activity against lamivudine-resistant strains of HIV-1. Abacavir exhibits antiretroviral properties for lamivudine-resistant HIV-1, the resistance of which is due only to the M184V mutation. M184V mutant strains exhibit a 4-fold lower sensitivity to didanosine and zolcitabine; the clinical significance of this phenomenon is still unclear.

Resistance to thymidine analogues (such as zidovudine) is well described and correlates with sequential accumulation of up to 6 specific mutations of HIV reverse transcriptase in codons 41, 67, 70, 210, 215 and 219. The viruses acquire phenotypic resistance to thymidine analogs by combining mutations in codons 41 and 215 or by accumulation, at four of the six mutations. These mutations against the background of thymidine analogs alone do not cause high cross-resistance to other nucleosides, which subsequently allows the use of other approved NRTIs. There are two types of development of mutations leading to multidrug resistance, the first type - mutations of viral reverse transcriptase in codons 62, 75, 77,116 and 151, the second type is the T69S mutation with an insert in the position of 6 pairs of nitrogenous bases in this position, which is accompanied by the appearance of phenotypic resistance to zidovudine and other NRTIs. Any of these types of mutations leading to the development of multidrug resistance severely limits the possibilities of treatment.

In clinical trials, the combination of lamivudine and zidovudine led to a decrease in HIV-1 load and an increase in CD4 + cells. Clinical evidence suggests that the use of a combination of lamivudine and zidovudine or a combination of lamivudine and zidovudine-containing regimens leads to a significant reduction in the risk of disease progression and mortality. Separately, monotherapy with lamivudine or zidovudine led to the appearance of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical evidence suggests that combination therapy with lamivudine and zidovudine inhibits the emergence of zidovudine-resistant strains in patients who have not previously received antiretroviral therapy (APT). The clinical significance of the in vitro viral sensitivity to zidovudine and lamivudine is investigated.Combination therapy with lamivudine and zidovudine is widely used as an APT component in conjunction with other antiretroviral drugs from other classes (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors [NNRTIs]). Combined regimens of antiretroviral therapy, including lamivudine, are effective in the treatment of patients who have not previously received antiretroviral drugs and patients who have strains of HIV with an M184V mutation.

Pharmacokinetics:

Suction: lamivudine and zidovudine well absorbed from the intestine. In adults, after oral administration, the bioavailability of lamivudine is 80-85%, and of zidovudine 60-70%.

A bioequivalence study was conducted to compare a fixed combination of lamivudine / zidovudine with lamivudine (150 mg) and zidovudine (300 mg) taken alone at the same time, while the extent of absorption and the effect of food were examined. The combination of lamivudine / zidovudine is equivalent to taking lamivudine and zidovudine on an empty stomach separately.

After receiving a combination of lamivudine / zidovudine, the maximum concentrations (C_max) of lamivudine and zidovudine were observed through 0.75 (0.5-2) h and 0.5 (0.25-2) h and were 1.5 (1.3-1.8) mg / ml and 1.8 (1.5-2.2) mg / ml, respectively.

The degree of absorption of lamivudine and zidovudine (based on the area under the concentration-time curve AUC) and the half-life (T_1/2) after ingestion with food were similar to those after fasting, although the rate of absorption was somewhat slowed.

Receiving crushed tablets together with a small amount of semi-solid food or liquid does not affect the pharmacological properties of the drug and, therefore, the clinical effect. This conclusion is based on the physico-chemical and pharmacokinetic characteristics of the active substances, provided that the patient immediately takes 100% of the ground tablets.

Distribution: the average apparent volume of distribution (V_d) for lamivudine and zidovudine is 1.3 and 1.6 l / kg, respectively. Lamivudine has linear pharmacokinetics when used in therapeutic doses and is bound to bound to blood plasma albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34-36%. In this way,the interaction of lamivudine and zidovudine with other drugs by replacing protein bonds is unlikely.

Determined that lamivudine and zidovudine penetrate into the central nervous system and cerebrospinal fluid. 2-4 hours after oral administration, the ratio between the concentration of lamivudine and zidovudine in the cerebrospinal fluid and in serum is on average 0.12 and 0.5, respectively.

Metabolism: lamivudine is excreted from the body mainly by the kidneys in an unchanged form. Metabolic interactions of lamivudine are unlikely because of a slight metabolism in the liver (from 5 to 10%) and low binding to plasma proteins.

Zidovudine 5'-glucuronide is the main metabolite in plasma and urine, with approximately 50-80% of the administered dose of zidovudine excreted by renal excretion. 3'-amino-3'deoxythymidine is detected in the urine after intravenous administration.

Excretion: half-life (T_1/2) lamivudine is 5-7 hours. The systemic clearance of lamivudine is approximately 0.32 l / h / kg, with a kidney clearance of more than 70% with the participation of organic cations of the transport system.

With intravenous administration of zidovudine, the mean T_1/2was 1.1 hours, and the average system clearance was 1.6 l / h / kg. The renal clearance of zidovudine is 0.34 l / h / kg by glomerular filtration and active tubular secretion in the kidneys.

Pharmacokinetics in special groups

Elderly age

The pharmacokinetics of lamivudine and zidovudine has not been studied in patients older than 65 years.

Childhood

In children older than 5-6 months, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine Well absorbed from the intestine after administration in all studied doses in adults and children; its bioavailability is 60-74%, an average of 65%. The maximum concentration in the equilibrium state (C_{ss max}) is 4.45 μmol (1.19 μg / ml) after taking zidovudine at a dose of 120 mg / m² body surface area in the form of a solution and 7.7 μmol (2.06 μg / ml) after taking in a dose of 180 mg / m² body surface area. The dose of 180 mg / m² body surface area 4 times / day leads to the same systemic exposure in children (AUC₂₄is 10.7 hours x μg / ml), as well as the dose of 200 mg / m² body surface area 6 times / day in adults (AUC₂₄ is 10.9 h x μg / ml).

In the study, 6 HIV-infected children aged 2 to 13 years were evaluatedpharmacokinetics of zidovudine after administration of 120 mg / m² body surface area 3 times / day and after switching to a dose of 180 mg / m² body surface area 2 times / day system exposure (AUC and C_max) in the plasma was similar in the double and triple dosing regimen (the daily dose is the same).

In general, the pharmacokinetics of lamivudine in children is similar to the pharmacokinetics in adult patients. However, absolute bioavailability (approximately 55-65%) was reduced in children younger than 12 years. Systemic clearance in children is higher than in adults, and is prone to decline as it grows up, reaching indicators as in adults by the age of 12. Taking into account these differences, the recommended dose of lamivudine in children (aged 3 months to 12 years with a body weight of 6 kg to 40 kg) is 8 mg / kg / day. After taking this dose of AUC_0-12reaches 3800-5300 ng x h / ml. Recent data indicate that exposure in children aged 2 to 6 years can be reduced by 30% compared with other age groups.

Impaired renal function

With renal failure, excretion of lamivudine is impaired due to reduced renal clearance. Reduction of the dose of lamivudine is recommended in patients with creatinine clearance less than 50 ml / min.The concentration of zidovudine in plasma also increases in patients with severe renal insufficiency.

Impaired liver function

Decreased glucuronuclease due to cirrhosis of the liver may result in the cumulation of zidovudine. Correction of doses is required in patients with severe hepatic insufficiency.

Pregnancy

Pregnancy does not affect the pharmacokinetics of lamivudine and zidovudine. Lamivudine and zidovudine are found in the serum of the child at birth in the same concentrations as in the mother's serum and cord blood during labor, which confirms the theory of passive penetration through the hematoplacental barrier.

Indications:Treatment of HIV infection in adults and children with a body weight of at least 30 kg.

Contraindications:

Zidovudine and Zilacombe® are contraindicated in patients with severe neutropenia (neutrophil counts less than 0.75x10⁹/ l) or anemia (hemoglobin less than 75 g / l or 4.65 mmol / l);
increased sensitivity to lamivudine, zidovudine or any other component of the drug.

Pregnancy and lactation:

It is not recommended to use Zilacom® in the first 3 months of pregnancy, except when the expected benefit of therapy for the mother exceeds the likely risk to the fetus.

It was shown that zidovudine treatment of pregnant women and the subsequent introduction of this drug to newborns reduces the frequency of HIV transmission from mother to fetus. There is no such data regarding lamivudine. Therefore, Zilacom® can be given to pregnant women only when the expected benefit to the mother exceeds the possible risk to the fetus.

HIV-infected patients are recommended not to breast-feed children in order to avoid the transmission of HIV infection.

In newborns and infants who were exposed to NRTI during pregnancy or during childbirth, there was a slight temporary increase in the concentration of lactate in the blood. There are also rare reports of cases of delayed development and convulsive seizures. In general, for children whose mothers took NRTIs during pregnancy, the benefits of reducing the risk of HIV infection obviously exceed the risk associated with the side effects of these drugs.

Dosing and Administration:

Inside.

Treatment with Zilacom® should be performed by physicians with experience in HIV therapy.

Zilakomb® can be taken regardless of food intake.

To ensure the accuracy of dosing, the tablets must be swallowed whole. For those patients who have difficulty in swallowing, it is recommended to crush the tablets with the addition of a small amount of semi-solid food or liquid. All the amount of the mixture should be taken immediately.

Adults and adolescents with a body weight of at least 30 kg the recommended dose of Zilacom® is 1 tablet 2 times a day.

In children weighing less than 30 kg separate medications for lamivudine and zidovudine should be used.

In cases where it is necessary to reduce the dose of Zilacom®, reduce the dose or cancel one of its components (lamivudine or zidovudine), it is possible to use separate preparations of lamivudine and zidovudine in dosage forms of a tablet / capsule and a solution for oral administration.

Use in special patient groups

Application for violations of liver function

With hepatic insufficiency, cumulation of zidovudine may be noted as a result of a delay in binding it to glucuronic acid. In patients with severe liver function impairment, it is recommended that lamivudine and zidovudine in the form of individual drugs to be able to individually select the dose of zidovudine.

Application for violations of kidney function

In patients with renal insufficiency, concentrations of lamivudine and zidovudine in the blood are increased due to a slowing of their elimination. Since patients with impaired renal function (creatinine clearance less than 50 ml / min) in a number of cases, it is necessary to individually select the dose of lamivudine and zidovudine, it is recommended that they be given separate preparations of lamivudine and zidovudine.

Use in elderly patients

Specific data on the use of Zilacomb® in elderly patients do not exist. However, in the treatment of elderly patients, special care should be taken, taking into account age-related changes, for example, changes in hematological parameters and impaired renal function.

Use in patients with hematologic side effects

With severe anemia (hemoglobin content less than 90 g / L or 5.59 mmol / L) or neutropenia (the number of neutrophils is less than 1.0 × 10⁹/ l), a dose adjustment of zidovudine may be required. When using the drug Zilacom® it is impossible to individually select the doselamivudine and zidovudine, it is recommended to use separate preparations of lamivudine and zidovudine.

Side effects:

Treatment of HIV infection with lamivudine and zidovudine in the form of monotherapy or as a combination of these drugs can cause side effects. For many side effects, it is not known whether they are caused by lamivudine, zidovudine, a wide range of other drugs used to treat HIV infection, or are a consequence of the underlying disease. When carrying out combined antiretroviral therapy, metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia are possible.

The composition of the drug Zilakomb® includes lamivudine and zidovudine, and therefore it can cause side effects, characteristic of each of these ingredients. At present, there is no evidence that the combination of lamivudine and zidovudine has additive toxicity.

Determination of the frequency of side effects: very often (≥1 / 10); often (≥1 / 100 and <1/10); infrequently (≥1 / 1000 and <1/100); rarely (≥ 1/10 000 and <1/1000); very rarely (<1/10 000).

Lamivudine

Violations from the blood and lymphatic system: infrequently - neutropenia, anemia, thrombocytopenia; very rarely - true erythrocytic aplasia.

Disorders from the immune system: rarely - angioedema.

Disorders from the metabolism and nutrition: often - hyperlactatemia; rarely - lactic acidosis; redistribution / accumulation of adipose tissue (the frequency of this side effect depends on many factors, including the specific combination of antiretroviral drugs).

Impaired nervous system: often - headache, insomnia; very rarely paresthesia, there are reports of peripheral neuropathy, but its association with lamivudine therapy is not clear.

Disturbances from the respiratory system, chest and mediastinal organs: often - coughing, nasal symptoms.

Disorders from the gastrointestinal tract: often - nausea, vomiting, epigastric pain, diarrhea; rarely - pancreatitis (association with treatment with lamivudine not established), increased serum amylase activity.

Disorders from the liver and bile ducts: infrequently, a transient increase in the activity of hepatic enzymes alanine aminotransferase (ALT), aspartate aminotransferase (ACT), and rarely hepatitis.

Disturbances from the skin and subcutaneous tissues: often - a rash, alopecia.

Disturbances from the musculoskeletal system and connective tissue: often - arthralgia, muscle disorders; rarely rhabdomyolysis.

General disorders and disorders at the site of administration: often - fatigue, general malaise, fever.

Zidovudine

Violations from the blood and lymphatic system: often anemia (blood transfusion may be required), neutropenia and leukopenia. These side effects are more likely to occur with zidovudine at high doses (1200-1500 mg / day), in patients with advanced HIV infection (especially with a reduced bone marrow reserve before treatment) and in particular in patients with CD4 + cell counts less 100 in μl. In some patients it is necessary to reduce the dose of zidovudine up to cancellation. Neutropenia occurs more often in those patients whose neutrophil count, hemoglobin concentration and vitamin B concentration₁₂in the serum decreased at the time of starting treatment with zidovudine. Infrequent - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely - aplastic anemia.

Disorders from the metabolism and nutrition: often - hyperlactatemia; rarely - lactic acidosis,anorexia; redistribution / accumulation of adipose tissue (the frequency of this side effect depends on many factors, including the specific combination of antiretroviral drugs).

Disorders of the psyche: rarely - anxiety and depression.

Impaired nervous system: very often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased mental activity, convulsions.

Disorders from the side of the organ of vision: frequency unknown - macular edema, amblyopia, photophobia.

Hearing disorders and labyrinthine disturbances: vertigo, hearing loss;

From the cardiovascular system: rarely - cardiomyopathy.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath; rarely - a cough.

Disorders from the gastrointestinal tract: very often - nausea; often - vomiting, abdominal pain and diarrhea, infrequently - flatulence; rarely - pigmentation of the oral mucosa, taste perversion (dysgeusia) and dyspepsia, pancreatitis.

Disorders from the liver and bile ducts: often - increased activity of "hepatic" enzymes and bilirubin concentration; rarely - liver damage, such as severe hepatomegaly with steatosis.

Disturbances from the skin and subcutaneous tissues: infrequent - rash, itching; rarely - pigmentation of nails and skin, hives and sweating.

Disturbances from the musculoskeletal system and connective tissue: often - myalgia; infrequently - myopathy.

Disorders from the kidneys and urinary tract: rarely - frequent urination.

On the part of the reproductive system and mammary glands: rarely - gynecomastia.

General disorders and disorders at the site of administration: often - a general malaise; infrequently - fever, generalized pain syndrome and asthenia; rarely - chills, chest pain and flu-like syndrome.

Overdose:

There are no reports of cases of an overdose of Zilacom®. However, there are limited data on the consequences of an acute overdose of lamivudine and zidovudine. None of these cases ended in a fatal outcome, and the condition of all patients returned to normal. No specific signs or symptoms were described.

Treatment: it is recommended to monitor the patient's condition for the timely detection of symptoms of intoxication and to conduct standard maintenance therapy. Because the lamivudine is derived by dialysis, continuous hemodialysis can be used for overdose, however, there is no relevant clinical experience yet. Apparently, hemodialysis and peritoneal dialysis are ineffective when removing zidovudine from the body, but accelerate the elimination of its metabolite (glucuronide).

Interaction:

Since the preparation Zilacomb® contains lamivudine and zidovudine, it can enter into any interactions that are characteristic of each of its components. The probability of metabolic interaction with lamivudine is low, Only a small part of the injected drug is metabolized and binds to plasma proteins, and the drug is almost completely excreted by the kidneys unchanged. Zidovudine also binds to a small extent with plasma proteins, but is eliminated mainly through hepatic metabolism to inactive glucuronide. Drugs with a predominant hepatic metabolism, especially through glucuronization, can potentially inhibit zidovudine metabolism.

Listed below are some medicines that represent classes of drugs that should be used with caution in the face of Zilacom®.

Interaction with lamivudine

Lamivudine is mainly excreted by means of organic cations of the transport system, therefore, it should be remembered that the drug Zilacombe® can interact with drugs having the same pathway. Trimethoprim. Simultaneous reception of lamivudine and trimethoprim (one of the components of the drug co-trimoxazole) leads to an increase in the concentration of lamivudine in plasma by 40% when taking this drug in therapeutic doses. However, patients with normal renal function are not required to individually select a dose of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Caution should be exercised while using co-trimoxazole and Zilacombe® in patients with renal insufficiency. The combined use of lamivudine and co-trimoxazole in high doses for the treatment of pneumocystis pneumonia and toplasmoplasmosis has not been studied and should be avoided.

Zalcitabine. Lamivudine can inhibit intracellular phosphorylation of zalcitabine with simultaneous administration. Thus, it is not recommended to use the drug Zilacombe¹⁵'in combination with zalcitabine.

Emtricitabine. The use of this combination of drugs for the treatment of HIV infection can not be recommended because of the similarity of lamivudine with emtricitabine.

Ranitidine. Clinically significant interaction is unlikely. Ranitidine only partially excreted by the kidney system of transport of organic cations. Correction of doses of drugs is not required.

Cladribine. In vitro lamivudine inhibits the process of intracellular phosphorylation of cladribine, thus there is a risk of a decrease in the effectiveness of cladribine when used together with lamivudine in clinical practice. Some clinical findings also confirm the possibility of interaction between lamivudine and cladribine. The simultaneous use of lamivudine and cladribine is not recommended.

Didanosine. The interaction has not been studied. Correction of doses of drugs is not required. Fluconazole. The interaction has not been studied.

Phenobarbital. The interaction has not been studied.

Valproic acid. The interaction has not been studied.

Interaction with zidovudine

Atovahon. Zidovudine does not affect the pharmacokinetics of atovahona. However, the pharmacokinetic data indicate that,that atovahon reduces the degree of metabolism of zidovudine to its glucuronide (in the equilibrium state, the zidovudine AUC is increased by 33%, C_maxin the plasma, glucuronide is reduced by 19%). When zidovudine is prescribed in doses of 500-600 mg / day and the concomitant course of treatment of acute pneumocystis pneumonia with atovahona, an increase in the incidence of adverse reactions associated with elevated zidovudine concentrations in plasma is unlikely.

Clarithromycin. Absorption of zidovudine decreases with the simultaneous administration of clarithromycin in the form of tablets. Observe the interval between clarithromycin and zidovudine at least 2 hours.

Lamivudine. Simultaneous reception of zidovudine and lamivudine leads to an increase of 13% of the time of exposure to zidovudine and an increase of 28% in its C_maxin the plasma. However, the overall exposure of zidovudine (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin. In some patients who received zidovudine in combination with phenytoin, a decrease in the concentration of phenytoin in the blood was detected, and in one case an increase in the concentration of phenytoin was noted. These observations indicate the need to monitor the concentration of phenytoin in the blood in patients who simultaneously take Zilacomb® and phenytoin.

Probenecid. According to some data, probenecid increases the mean T_1/2zidovudine and AUC as a result of inhibition of the formation of glucuronide. In the presence of probenecid, renal excretion of glucuronide and, possibly, zidovudine itself decreases. Rifampicin. Limited data show that when zidovudine and rifampicin are combined, the AZUC of zidovudine is reduced by 48 ± 34%. However, the clinical significance of this observation is unknown.

Stavudine. Zidovudine can inhibit the process of intracellular phosphorylation becoming udine during their simultaneous administration. Thus, concomitant use of a combination of stavudine and Zilacom® is not recommended.

Ribavirin. Nucleoside analogues that disrupt DNA replication, such as ribavirin, can in vitro reduce the antiviral activity of zidovudine. Simultaneous use of such drugs with zidovudine is not recommended. There was an increase in anemia caused by ribavirin when zidovudine was included in the complex therapy of HIV infection. It is not recommended to use zidovudine in combination with ribavirin due to an increased risk of anemia.

Doxorubicin. Simultaneous use of zidovudine and doxorubicin is not recommended due to mutual weakening of activity of each of the drugs in vitro.

Emtricitabine. Clinically significant interaction is absent.

Didanosine. The interaction has not been studied. Correction of doses of drugs is not required.

Fluconazole. When used concomitantly with fluconazole, an increase in AUC of zidovudine by 74% is observed due to inhibition of UDP-glucuronosyltransferase (UDF HT). Given the limited data, clinical significance is unknown. It is necessary to monitor the toxic effects of zidovudine.

Phenobarbital. The interaction has not been studied. Perhaps a slight decrease in plasma concentrations of zidovudine due to induction of UDF GT. There is insufficient data for recommendations on dose adjustment.

Valproic acid. When used concomitantly with valproic acid, an increase in zidovudine AUC is observed by 80% due to inhibition of UDP-HT. Given the limited data, clinical significance is unknown. It is necessary to monitor the toxic effects of zidovudine.

Ranitidine. The interaction has not been studied.

Acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex can alter the metabolism of zidovudine as a result of competitive inhibition of the glucuronization process or direct suppression of zidovudine metabolism by microsomal liver enzymes. Before prescribing these drugs in combination with Zilacomb®, especially for long-term treatment, it is necessary to evaluate possible drug interactions.

Simultaneous use, especially for the treatment of acute conditions, zidovudine and potentially nephrotoxic or myelosuppressive drugs (eg, systemic administration of pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk side effects of zidovudine. With the simultaneous administration of Zilacomb® and any of these drugs, kidney function and hematologic parameters should be closely monitored and, if necessary, reduced the dose of one or more drugs.

BecauseIn some patients, despite the use of Zilacom®, opportunistic infections may develop, additional therapy may be required to prevent infections. For such prophylaxis, co-trimoxazole, pentamidine in the form of an aerosol, pyrimethamine and acyclovir. Limited data from clinical trials indicate that there is no significant increase in the incidence of side effects of zidovudine when used concomitantly with these drugs.

Special instructions:

If it is necessary to individually select the dose, it is recommended to use separate preparations of lamivudine and zidovudine. Doctors should be guided by information on the use of these drugs.

Despite the use of Zilacomb® or any other antiretroviral drug, opportunistic infections and other complications of HIV infection can develop in patients. Therefore, patients should be under constant supervision of physicians with experience in the treatment of HIV infection.

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

It is necessary to warn patients about the possible interaction of the drug Zilacomb® with other drugs at their concomitant reception.

Hematologic disorders

Against the background of therapy with Zilakomb®, it is possible to develop hematological disorders: anemia, neutropenia and leukopenia (the latter is usually secondary to neutropenia). These phenomena are more often observed when zidovudine is prescribed in high doses (1200-1500 mg / day) in patients with advanced stages of HIV infection with a reduced bone marrow reserve before the start of treatment. Therefore, during the treatment with Zilacom® it is necessary to carefully monitor hematological parameters. These hematologic changes usually appear no earlier than 4-6 weeks after the start of therapy. In patients with late stage of clinically expressed HIV infection, blood tests should be performed at least once every 2 weeks during the first 3 months of therapy, and then at least once a month.

In patients with early stage of HIV infection, side effects from the blood system are rare. Blood tests can be done less often, focusing on the general condition of patients, for example, 1 time in 1-3 months. A special dose of zidovudine may be required if severe anemia or myelosuppression develops during treatment with Zilacomb®, as well as in patients with previous bone marrow suppression, for example at a hemoglobin concentration of 90 g / L (5.59 mmol / L) or neutrophil count less than 1,0х10⁹/ l. Since it is not possible to select the dose of Zilacom® completely, it is recommended to use separate preparations of lamivudine and zidovudine.

Pancreatitis

In patients who took lamivudine and zidovudine, rare cases of development of pancreatitis are described. However, it is not established whether this complication is caused by medications or the underlying disease - HIV infection. Treatment with Zilacomb® should be stopped immediately if clinical symptoms or laboratory evidence of pancreatitis develops (abdominal pain, nausea, vomiting, or increased activity of biochemical markers).

Lactic acidosis / severe hepatomegaly with steatosis

In patients who took analogues of nucleosides in the form of monotherapy or in combination, including, lamivudine and zidovudine, rare cases of lactic acidosis and severe hepatomegaly with fatty liver dystrophy are described, but with a possible fatal outcome. Similar phenomena were observed, mainly, in women. Clinical symptoms of lactic acidosis include general weakness, loss of appetite, sudden, unexplained weight loss, symptoms of gastrointestinal tract damage (nausea, vomiting, abdominal pain), respiratory disorders (shortness of breath and increased breathing), neurologic symptoms (muscle weakness).

Nucleoside analogues should be used with caution in all patients (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including certain drugs and alcohol). At increased risk patients with co-infection with hepatitis C who receive therapy with interferon alfa and ribavirin are exposed. Reception of nucleoside analogs should be discontinued when clinical or laboratory signs of lactic acidosis or hepatotoxicity appear (including hepatomegaly and steatosis,even in the absence of a significant increase in aminotransferase activity).

Redistribution / accumulation of subcutaneous fat

In some patients receiving combined antiretroviral therapy, there is a redistribution / accumulation of adipose tissue, including central obesity, dorsovissorial fat deposition ("buffalo buffalo"), weight loss of limbs and face, breast enlargement, increased serum lipid and blood glucose levels. The listed symptoms in patients can be observed together or separately.

Although one or more of the above side effects associated with a common syndrome, often attributed to lipodystrophy, can cause all drugs related to protease inhibitors and NRTIs, the data suggest that there are differences between individual representatives of these classes of drugs with respect to the ability to cause these side effects effects.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, the elderly age and the duration of antiretroviral therapy play an important, perhaps synergistic role.

The long-term effects of these side effects are currently unknown. Clinical examination of patients should include an assessment of the physical signs of redistribution of adipose tissue. The concentration of serum lipids and blood glucose should be determined. Disorders of lipid metabolism should be treated, guided by their clinical manifestations.

Opportunistic infections.

When taking Zilacomb® and other antiretroviral therapy, the possibility of developing opportunistic infections persists. Therefore, patients should be supervised by a specialist in HIV treatment.

Immunodeficiency Syndrome

At the beginning of antiretroviral treatment of HIV-infected patients with severe immunodeficiency, inflammatory reactions and residual opportunistic infections can develop, which sometimes leads to serious clinical consequences or increased symptoms. Typically, such reactions are observed during the first weeks or months after the onset of antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized or focal infection caused by Pneumocystis jiroveci (R. Carinii).The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Against the background of the immune recovery syndrome, it is also possible to form autoimmune diseases (Graves' disease, polymyositis, Guillain-Barre syndrome). The time of primary manifestations varied, and the disease could occur many months after initiation of therapy and have an atypical course. In the case of muscle weakness, tremors, tremors, hyperactivity, patients are advised to immediately notify the attending physician.

Patients who are simultaneously infected with HIV and hepatitis B virus

Zilacombe® should be used with caution in patients with decompensated hepatic cirrhosis due to chronic hepatitis B, as in rare cases it may be an exacerbation of hepatitis when lamivudine is withdrawn. It is necessary to monitor liver function and markers of hepatitis B virus replication within 4 months after discontinuation of the drug.

Patients with mild or moderate hepatic impairment or cirrhosis may need a reduction in the daily dose of zidovudine.Zilakomb®, as a fixed-dose combination drug, is not recommended for use in patients with hepatic insufficiency.

Patients who are simultaneously infected with HIV and hepatitis C virus

The aggravation of anemia was observed with the combined administration of ribavirin and zidovudine, although the mechanism of development of this phenomenon remains unclear. Thus, concomitant use of ribavirin and Zilacomb® is not recommended, especially in patients with a history of zidovudine-induced anemia. In this case, it is recommended to consider the possibility of changing the regimen of antiretroviral therapy with a view to the abolition of zidovudine.

Osteonecrosis

The development of osteonecrosis is caused by a variety of factors (including the intake of glucocorticosteroids, alcohol abuse, severe immunosuppression, high body mass index), in particular, cases of osteonecrosis have been reported in patients with advanced HIV and / or long-term combined antiretroviral therapy. This category of patients should be recommended to consult a specialist in case of articular pain, stiffness and stiffness in the joints.

Mitochondrial dysfunction

Analogues of nucleotides and nucleosides show the ability to cause mitochondrial damage in vitro and in vivo. There are data on the development of mitochondrial dysfunctions in HIV-negative infants exposed to nucleoside analogues during fetal and / or postnatal development. The following undesirable phenomena were registered: hematologic disorders - anemia, neutropenia; metabolic disorders - increased concentrations of lactate and lipase. These phenomena were mostly transient. There were distant neurological manifestations (hypertonia, convulsive syndrome, behavioral disorders). At the moment it is not known whether neurological disorders are persistent or transient. Children exposed to nucleotide and nucleoside analogues during fetal development, in cases of manifestation of the relevant symptoms, need clinical observation and examination for the diagnosis of mitochondrial dysfunction.

Diseases of the liver

The risk of serious, even lethal, complications from the liver is increased in patients with hepatitis B or C.Patients with previous hepatic diseases, including chronic active hepatitis, have an increased risk of liver dysfunction associated with combined antiretroviral therapy and need to be monitored in accordance with accepted standards. With an obvious worsening of the course of liver disease in this group of patients, it is necessary to decide whether to interrupt or stop therapy.

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

There was no special study of the effects of lamivudine and zidovudine on the ability to drive and work with machinery. Pharmacological properties of these drugs indicate a low probability of such an effect. The patient's clinical condition, as well as the side effects of lamivudine and zidovudine, should be taken into account.

Form release / dosage:

Tablets coated with a film coat 300.0 mg + 150.0 mg.

Packaging:

For 10 tablets in a contour mesh box made of PVC film and aluminum foil. 6 contour packs with instructions for use in a pack of cardboard.

Storage conditions:

Keep in dry the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002581

Date of registration:14.08.2014 / 11.02.2016

Expiration Date:14.08.2019

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

PHARMSTANDART-TOMSKHIMFARM, OJSC Russia

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zilacombe® (Zilacomb®)