Zidolam, 300 mg+150 mg 60 pcs

Zidovudine, Lamivudine

Indications

treatment of HIV infection in adults and children weighing at least 14 kg with progressive immunodeficiency (CD4+ cell content less than 500 per 1 mm3).

Pharmacological effect

Pharmacotherapeutic group: Antiviral [HIV] agent

Pharmacological action

Mechanism of action

Lamivudine and zidovudine are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Lamivudine is a synergist with zidovudine in inhibiting HIV replication in cell culture. Both drugs are sequentially metabolized by intracellular kinases to 5′-triphosphate (TP). Lamivudine-TF and zidovudine-TF are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of drugs is primarily due to the inclusion of their monophosphate form in the viral DNA chain, resulting in chain breakage. Triphosphates of lamivudine and zidovudine have significantly lower affinity for DNA polymerases of human cells.

In vitro, lamivudine demonstrates low cytotoxicity towards lymphocytic and monocyte-macrophage colonies and a number of red bone marrow progenitor cells. Thus, lamivudine has a broad therapeutic index.

HIV-1 resistance to lamivudine is caused by a mutation at codon 184 (M184V) near the active site of HIV reverse transcriptase. These viral variants arise both in vitro and in HIV-1-infected patients receiving antiretroviral regimens that include lamivudine. Virus strains with the M184V mutation demonstrate a significant decrease in sensitivity to lamivudine and show less replicative activity in vitro.

In vitro studies have shown that zidovudine-resistant viral isolates may develop sensitivity to zidovudine if they acquire resistance to lamivudine. The clinical significance of this phenomenon is unclear.

Mutations at the M184V site lead to cross-resistance of HIV only to drugs from the group of nucleoside reverse transcriptase inhibitors of HIV (NRTI). Zidovudine and stavudine remain active against lamivudine-resistant strains of HIV-1. Abacavir retains antiretroviral activity against lamivudine-resistant HIV-1 strains that have only the M184V mutation. In HIV strains with M184V mutations, no more than a 4-fold decrease in sensitivity to didanosine and zalcitabine is determined; the clinical significance of this phenomenon has not been established.

Resistance to thymidine analogues (such as zidovudine) is well studied and occurs as a result of the gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. Viruses acquire phenotypic resistance to thymidine analogues as a result of combined mutations at codons 41 and 215 or by the accumulation of at least four or six mutations. These thymidine analogue resistance mutations do not in themselves cause high cross-resistance to other nucleoside analogues, allowing subsequent use of other approved reverse transcriptase inhibitors. Two types of mutation lead to the development of multiple drug resistance. In one case, mutations occur in positions 62, 75, 77, 116 and 151 of HIV reverse transcriptase, and in the second case – T69S mutations with the insertion of 6 nitrogen base pairs at this position, which is accompanied by the appearance of phenotypic resistance to zidovudine, as well as to other nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit therapeutic options for HIV infection.

In clinical studies, the use of a combination of lamivudine and zidovudine led to a decrease in HIV-1 load and an increase in the content of CD4+ cells. Clinical data suggest 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.

Individually, monotherapy with lamivudine or zidovudine resulted in the emergence of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical evidence suggests that combination therapy with lamivudine and zidovudine delays the emergence of zidovudine-resistant strains in antiretroviral therapy (APT)-naïve patients.

In vitro HIV drug susceptibility testing has not been standardized and results may be influenced by various methodological factors. Currently, the relationship between sensitivity to lamivudine and/or zidovudine in vitro and the clinical effect of therapy has not been studied.

Lamivudine and zidovudine are widely used as components of combination therapy with other antiretroviral drugs of the same class (NRTI) or other classes (HIV protease inhibitors [PIs], nonnucleoside reverse transcriptase inhibitors [NNRTIs], integrase inhibitors, and fusion inhibitors). Combination antiretroviral regimens that include lamivudine are effective in treating patients who have not previously received antiretroviral drugs and patients from whom HIV strains with the M184V mutation have been isolated.

Prevention of infection: International guidelines recommend the use of a combination of lamivudine and zidovudine within 1-2 hours after exposure to HIV-infected blood (for example, after a needle stick). In case of a high risk of infection, a drug from the group of protease inhibitors should be included in the antiretroviral therapy regimen. Prophylactic treatment should be carried out for 4 weeks. There is insufficient data on the effectiveness of preventive treatment after accidental HIV infection; no controlled studies have been conducted. Despite the rapid initiation of treatment with antiretroviral drugs, the possibility of seroconversion cannot be excluded.

Pharmacokinetics

Suction

Lamivudine and zidovudine are well absorbed from the intestine. In adults, after oral administration, the bioavailability of lamivudine is 80-85%, and that of zidovudine is 60-70%. After taking the drug Zidolam orally, the Cmax of lamivudine and zidovudine was observed after 0.75 (0.50-2.00) hours and 0.50 (0.25-2.00) hours and amounted to 1.5 (1.3-1.8) μg/ml and 1.8 (1.5-2.2) μg/ml, respectively.

The extent of absorption of lamivudine and zidovudine (based on AUC value, area under the concentration-time pharmacokinetic curve) and T1/2 after administration with food were similar to those after administration on an empty stomach, although the rate of absorption was slightly slower.

Distribution

Lamivudine has linear pharmacokinetics when used in therapeutic doses and has limited binding to plasma albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34-38%. Thus, the interaction of lamivudine and zidovudine with other drugs through their substitution at protein binding sites is unlikely. It has been established that lamivudine and zidovudine penetrate the central nervous system and cerebrospinal fluid. 2-4 hours after oral administration, the ratios between the concentrations of lamivudine and zidovudine in the cerebrospinal fluid and in the blood serum average 0.12 and 0.5, respectively.

Metabolism

Lamivudine is excreted from the body primarily unchanged by the kidneys. Metabolic interactions of lamivudine are unlikely due to insignificant metabolism in the liver (5 to 10%) and low binding to plasma proteins.

Zidovudine 5′-glucuronide is the major metabolite in plasma and urine, with approximately 50-80% of the administered dose of zidovudine eliminated by renal excretion.

Removal

T1/2 of lamivudine is 5-7 hours. Systemic clearance of lamivudine is approximately 0.32 l/h/kg, with renal clearance of more than 70% involving the cationic transport system. The renal clearance of zidovudine is 0.34 l/h/kg via glomerular filtration and active tubular secretion in the kidneys.

Special patient groups

Elderly patients. The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.

Pediatric patients. In general, the pharmacokinetics of lamivudine in children are similar to those in adult patients. However, absolute bioavailability (approximately 55-65%) was reduced in children under 12 years of age. Systemic clearance in children is higher than in adults and tends to decrease as they grow older, reaching levels similar to adults by 12 years. Recent evidence suggests that exposure in children aged 2 to 6 years may be reduced by 30% compared with other age groups.

Renal dysfunction. Due to reduced renal clearance, the elimination of lamivudine is impaired in renal failure. A dose reduction of lamivudine is recommended in patients with creatinine clearance less than 50 ml/min. Plasma zidovudine concentrations are also increased in patients with severe renal impairment.

Liver dysfunction. Decreased glucuronidation in patients with impaired liver function due to cirrhosis may result in accumulation of zidovudine. Dose adjustments are required in patients with severe hepatic impairment.

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 serum of the mother and umbilical cord blood at birth, which confirms the theory of passive penetration of the blood-placental barrier.

Special instructions

If individual dose selection is necessary, it is recommended to use separate preparations of lamivudine and zidovudine. Physicians should refer to information on the use of these drugs. Patients should be warned about the possible consequences associated with the concomitant use of other drugs without a doctor’s prescription.

Patients should be informed that treatment with antiretroviral drugs such as Zidolam does not prevent the risk of transmitting HIV to others through sexual contact or blood contamination, and patients should take appropriate precautions.

Despite taking Zidolam or any other antiretroviral drug, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should be under constant supervision of doctors experienced in treating patients with HIV-associated diseases.

Hematological disorders

Anemia, neutropenia and leukopenia (usually secondary to neutropenia) may develop in patients receiving zidovudine. These phenomena are more often observed when high doses of zidovudine (1200-1500 mg/day) are prescribed in patients in the later stages of HIV infection with reduced bone marrow reserve before treatment. Therefore, in patients receiving the drug Zidolam, it is necessary to carefully monitor hematological parameters. These hematological changes usually appear no earlier than 4-6 weeks from the start of therapy. In patients with an advanced clinical picture of HIV infection, it is recommended to monitor blood counts at least once every 2 weeks during the first three months of therapy, and then at least once a month. In patients at an early stage of HIV infection, side effects from the blood system are rare. In this situation, a general blood test can be done less frequently, focusing on the general condition of the patients, for example, once every 1 – 3 months.

Special titration of the dose of zidovudine may be required if severe anemia or myelosuppression develops during treatment with Zidolam, as well as in patients with pre-existing bone marrow suppression, for example, a hemoglobin level of less than 9 g/dL (5.59 mmol/L) or a neutrophil count of less than 1.0 x 109/L. Since it is impossible to individually select the dose of Zidolam, it is recommended to use separate preparations of lamivudine and zidovudine.

Pancreatitis

Rare cases of pancreatitis have been described in patients taking lamivudine and zidovudine. However, it has not been established whether this complication is caused by medications or the underlying disease – HIV infection. Treatment with Zidolam should be stopped immediately if clinical symptoms or laboratory data indicating the development of pancreatitis (abdominal pain, nausea, vomiting or increased levels of biochemical markers) appear. You should stop taking Zidolam until the diagnosis of pancreatitis is excluded.

Lactic acidosis and severe hepatomegaly with steatosis

In patients taking antiretroviral drugs – nucleoside analogues, in the form of monotherapy or in combination, including lamivudine and zidovudine, rare, but possibly fatal, cases of lactic acidosis in the absence of hypoxia and severe hepatomegaly with fatty liver degeneration have been described. Most cases were reported in women. Clinical symptoms of lactic acidosis include general weakness, loss of appetite and rapid unexplained weight loss, gastrointestinal and respiratory problems (shortness of breath and rapid breathing). The drug Zidolam should be used with caution in patients with risk factors for liver damage. The drug should be suspended in patients with clinical and laboratory symptoms of lactic acidosis or hepatotoxicity (including hepatomegaly and steatosis, even in the absence of increased transaminase activity).

Mitochondrial dysfunction

Nucleoside and nucleotide analogues of HIV reverse transcriptase have demonstrated varying degrees of mitochondrial damage in vitro and in vivo. The main adverse events are hematological disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These conditions are temporary. With later onset, neurological disorders (hypertension, seizures, behavioral disturbances) have been reported; whether these neurological disorders are temporary or permanent is currently unknown.

Redistribution of subcutaneous fat

Some patients receiving combination antiretroviral therapy experience redistribution and/or accumulation of adipose tissue, including central obesity, dorsocervical fat deposition (“buffalo hump”), decreased subcutaneous fat on the face and extremities, breast enlargement, and increased serum lipids and blood glucose. Patients may experience these symptoms together or separately. Although all drugs in the HIV protease inhibitor (PI) and HIV nucleoside reverse transcriptase inhibitor (NRTI) classes may cause one or more of the above side effects associated with the common syndrome often referred to as lipodystrophy, evidence suggests that there are differences among individual members of these drug classes in the ability to cause these side effects. Lipodystrophy syndrome has a multifactorial etiology: for example, stage of HIV infection, advanced age, and duration of antiretroviral therapy play an important, possibly synergistic role.

The long-term consequences of these side effects are currently unknown. Clinical examination of patients should include assessment of physical signs of redistribution of adipose tissue. Serum lipid and blood glucose levels should be determined. Lipid metabolism disorders must be treated based on their clinical manifestations.

Immune reconstitution syndrome

At the beginning of treatment with antiretroviral drugs in HIV-infected patients with severe immunodeficiency, an exacerbation of the inflammatory process against the background of an asymptomatic opportunistic infection or its residual effects is possible, which can cause a serious deterioration of the condition or aggravation of symptoms. Typically, such reactions are observed during the first weeks or months after starting antiretroviral therapy. For example: cytomegalovirus retinitis, generalized and/or focal mycobacterial infection and Pneumocystis pneumonia (P.Carinii). Any symptoms of inflammation must be immediately identified and treatment initiated if necessary.

Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have been observed in the setting of immune reconstitution, but the timing of initial manifestations has varied and the disease may occur many months after the start of therapy and have an atypical course.

Liver diseases

The safety and effectiveness of zidovudine have not been established in patients with advanced liver disease.

Co-infection of HIV and viral hepatitis B

The results of clinical studies and post-registration data indicate that in some patients with chronic hepatitis B, when Zidolam is discontinued, clinical and laboratory signs of exacerbation of hepatitis occur, which can have serious consequences for patients with decompensated liver function. If Zidolam is discontinued in patients with hepatitis B viral co-infection, it is necessary to periodically monitor both liver function and hepatitis B virus replication markers (for 4 months).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, are at increased risk of developing liver dysfunction during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Co-infection with HIV and viral hepatitis C

Worsening of anemia was observed with the combination of ribavirin and zidovudine, although the mechanism of development of this phenomenon remains unclear. Therefore, concomitant use of ribavirin and zidovudine is not recommended, especially in patients with a history of zidovudine-induced anemia. In these cases, it is recommended to consider changing the antiretroviral therapy regimen to discontinue zidovudine.

Osteonecrosis

The etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunodeficiency, high body mass index), and cases of osteonecrosis have been reported in patients with advanced HIV infection and/or long-term use of combination antiretroviral therapy (APBT). Patients should be advised to consult a physician if they experience joint pain, joint stiffness, or difficulty moving.

Zidolam should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.

Impact on the ability to drive vehicles and machinery

There have been no specific studies of the effect of lamivudine and zidovudine on the ability to drive and operate machinery. The pharmacological properties of these drugs indicate a low probability of such an effect. The clinical condition of the patient should be taken into account, as well as the nature of the side effects of lamivudine and zidovudine.

Active ingredient

Zidovudine, Lamivudine

Composition

Active substances
zidovudine
lamivudine
Excipients: microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, sodium carboxymethyl starch.

Pregnancy

Fertility

There are no data on the effect of lamivudine and zidovudine on fertility in women. Zidovudine does not affect the number, morphology and motility of sperm in men.

Pregnancy

It is not recommended to use Zidolam in the first 3 months of pregnancy, unless the expected benefit to the mother outweighs the likely risk to the fetus. Treatment of pregnant women with zidovudine and subsequent administration of this drug to newborns has been shown to reduce the incidence of mother-to-fetus transmission of HIV. There are no such data for lamivudine. Therefore, Zidolam can be prescribed to pregnant women only in cases where the expected benefit to the mother outweighs the possible risk to the fetus.

In newborns and infants who were exposed to nucleoside reverse transcriptase inhibitors during pregnancy or childbirth. a slight transient increase in serum lactate was noted. There are also rare reports of developmental delays, seizures and other neurological pathologies.

The cause-and-effect relationship between the occurrence of these pathological conditions and the use of nucleoside reverse transcriptase inhibitors during pregnancy has not been established.

Overall, for children whose mothers took nucleoside reverse transcriptase inhibitors during pregnancy, the benefits of reducing the risk of HIV infection appear to outweigh the risks associated with the side effects of these drugs.

Lactation

Breastfeeding is not recommended for HIV-infected mothers to prevent vertical transmission of HIV. Since lamivudine, zidovudine and HIV pass into breast milk, breastfeeding is prohibited.

Contraindications

hypersensitivity to lamivudine, zidovudine or any other component of this drug;
neutropenia (less than 0.75 × 109/l), anemia (hemoglobin less than 7.5 g/dl or 4.65 mmol/l);
children weighing less than 14 kg;
lactation;
impaired renal function with creatinine clearance less than 50 ml/min (for this dosage form);
severe degree of liver dysfunction (for this dosage form).
With caution:

Hepatomegaly, hepatitis, cirrhosis, risk factors predisposing to liver damage, mild to moderate liver dysfunction, obesity, pancreatitis (including history), peripheral neuropathy (including history), old age, suppression of bone marrow hematopoiesis, cyanocobalamin or folic acid deficiency, neutropenia/leukopenia (neutrophil count 0.75×109/l or 750-1000/µl), anemia (hemoglobin 7.5 g/dl).

Side Effects

Treatment of HIV infection with lamivudine and zidovudine, either as monotherapy or as a combination of these drugs, may cause side effects. For many side effects, it is not known whether they are caused by lamivudine, zidovudine, or the wide range of other drugs used to treat HIV infection, or whether they are a consequence of the underlying disease. Zidolam contains lamivudine and zidovudine and may cause side effects specific to each ingredient.

There is currently no evidence that the combination of lamivudine and zidovudine has additive toxicity.

Combination antiretroviral therapy has been associated with the development of metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia.

The frequency of occurrence is determined as follows: very often (≥1/10); often (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 and <1/1000); very rare (< 1/10000, including isolated cases).LamivudineFrom the hematopoietic and lymphatic system:Uncommon: neutropenia, anemia, thrombocytopenia.Very rare: true erythrocyte aplasia.Metabolism and nutrition:Common: hyperlactatemia.Rarely: lactic acidosis.Fat redistribution/accumulation: The incidence of this side effect depends on many factors, including the specific antiretroviral drug combination.From the nervous system:Common: headache, insomnia.Very rare: paresthesia, peripheral neuropathy has been reported, but its relationship with lamivudine therapy is unknown.From the respiratory system, chest and mediastinal organs:Common: cough, nasal symptoms.From the gastrointestinal tract:Common: nausea, vomiting, epigastric pain, diarrhea.Rare: pancreatitis, the connection of which with lamivudine treatment has not been established. Increased serum amylase activity.From the liver and biliary tract:Uncommon: transient increase in liver enzyme activity (AST, ALT).Rare: hepatitis.From the skin and pancreas:Common: rash, alopecia.Rare: Quincke’s edema.From the musculoskeletal system and connective tissue:Common: arthralgia, muscle disorders.Rare: rhabdomyolysis.General and local reactions:Common: fatigue, general malaise, fever.ZidovudineFrom the hematopoietic and lymphatic system:Common: anemia (blood transfusion may be required), neutropenia and leukopenia. These side effects occur more often when using high doses of zidovudine (1200-1500 mg per day), in patients in the later stages of HIV infection (especially with reduced bone marrow reserve before treatment) and, in particular, in patients with a CD4+ cell count of less than 100 per mm3. In some patients, it is necessary to reduce the dose of zidovudine until discontinuation. Neutropenia occurs more often in those patients whose neutrophil count, hemoglobin content and serum vitamin B12 content are reduced at the time of initiation of treatment with zidovudine.Uncommon: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).Rare: true erythrocyte aplasia.Very rare: aplastic anemia.Metabolism and nutrition:Common: hyperlactatemia.Rarely: lactic acidosis in the absence of hypoxemia, anorexia.Fat redistribution/accumulation: The incidence of this side effect depends on many factors, including the specific antiretroviral drug combination.From the mental side:Rare: anxiety and depression.From the nervous system:Very common: headache.Common: dizziness.Rarely: insomnia, paresthesia, drowsiness, decreased mental activity, convulsions, confusion.From the cardiovascular system:Rare: cardiomyopathy.From the respiratory system, chest and mediastinal organs:Uncommon: shortness of breath.Rarely: cough, rhinitis, sinusitis, influenza-like syndrome.From the gastrointestinal tract:Very common: nausea.Common: vomiting, abdominal pain and diarrhea.Uncommon: flatulence.Rarely: pigmentation of the oral mucosa, taste perversion, anorexia, dyspepsia, pancreatitis.From the liver and biliary tract:Often: increased activity of liver enzymes and bilirubin levels.Rare: liver damage such as severe hepatomegaly with steatosis.From the skin and pancreas:Uncommon: rash and itching.Rarely: pigmentation of nails and skin, urticaria and sweating.From the musculoskeletal system and connective tissue:Often: myalgia.Uncommon: myopathy.From the kidneys and urinary tract:Rare: frequent urination.From the reproductive system and mammary glands:Rare: gynecomastia.General and local reactions:Often: general malaise.Uncommon: fever, generalized pain and asthenia, angioedema, anaphylactic reactions.Rare: chills, chest pain and flu-like syndrome.

Interaction

Since Zidolam contains lamivudine and zidovudine, it can enter into any interactions characteristic of each of its components. The likelihood of metabolic interactions with lamivudine is low, since only a small part of the administered drug is metabolized and binds to plasma proteins, and the drug is almost completely excreted unchanged by the kidneys.

Zidovudine is also slightly bound to plasma proteins, but is eliminated primarily through hepatic metabolism to an inactive glucuronide. Drugs with predominant hepatic metabolism, particularly via glucuronidation, may potentially inhibit the metabolism of zidovudine.

Listed below are some drugs representing classes of drugs that should be used with caution during therapy with Zidolam.

Interactions involving lamivudine:

Lamivudine is predominantly eliminated via the cationic transport system; therefore, one should be aware of the possibility of interaction of the drug Zidolam with those drugs that have the same route of elimination.

Trimethoprim: Concomitant use of lamivudine and a combination of trimethoprim and sulfamethoxazole (160 mg + 800 mg, co-trimoxazole) leads to an increase in plasma lamivudine concentrations by 40% when taking this drug in therapeutic doses. However, patients with normal renal function do not require individual dosage adjustment of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Caution must be exercised when co-trimoxazole and Zidolam are used simultaneously in patients with renal failure. The effect of co-administration of lamivudine and high doses of co-trimoxazole for the treatment of Pneumocystis pneumonia and toxoplasmosis has not been studied.

Zalcitabine: Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when administered concomitantly. Therefore, it is not recommended to use Zidolam in combination with zalcitabine.

Interactions involving zidovudine:

Atovaquone: Zidovudine has no effect on the pharmacokinetics of atovaquone. However, pharmacokinetic data indicate that atovaquone reduces the extent of metabolism of zidovudine to its glucuronide (at steady state, the area under the pharmacokinetic curve (AUC) of zidovudine increases by 33%, the maximum plasma concentration of glucuronide decreases by 19%). When prescribing zidovudine in doses of 500-600 mg/day. and a concomitant 3-week course of treatment of acute Pneumocystis pneumonia with atovaquone, an increase in the incidence of adverse reactions associated with increased plasma zidovudine concentrations is unlikely. If longer-term combined use of these drugs is necessary, careful monitoring of the patient’s clinical condition is recommended.

Clarithromycin: Absorption of zidovudine is reduced when clarithromycin tablets are taken concomitantly. It is necessary to maintain an interval of at least 2 hours between doses of clarithromycin and zidovudine.

Lamivudine: Concomitant use of zidovudine and lamivudine results in a 13% increase in zidovudine exposure time and a 28% increase in its maximum plasma concentrations. However, the total zidovudine exposure (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin: Some patients receiving zidovudine in combination with phenytoin experienced a decrease in phenytoin blood concentrations, and in one case an increase in phenytoin concentrations. These observations suggest the need to monitor phenytoin blood concentrations in patients taking Zidolam and phenytoin concomitantly.

Probenecid: According to some data, probenecid increases the T1/2 of zidovudine and the area under the pharmacokinetic curve as a result of inhibition of glucuronide formation. In the presence of probenecid, renal excretion of glucuronide and, possibly, zidovudine itself is reduced.

Rifampicin: Limited data show that the combination of zidovudine and rifampicin reduced the AUC of zidovudine by 48% ± 34%. However, the clinical significance of this observation is unknown.

Stavudine: Zidovudine may inhibit the intracellular phosphorylation of stavudine when administered concomitantly. Thus, the combined use of a combination of stavudine and the drug Zidolam is not recommended.

Other drugs: acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone and inosine pranobex may alter the metabolism of zidovudine as a result of competitive inhibition of glucuronidation or direct inhibition of zidovudine metabolism by liver microsomal enzymes. Before prescribing these drugs in combination with Zidolam, especially for long-term treatment, it is necessary to evaluate possible drug interactions.

Concomitant use, especially for the treatment of acute conditions, of zidovudine and potentially nephrotoxic or myelosuppressive drugs (for example, systemic administration of pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon α2β, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse effects. zidovudine. When Zidolam is co-administered with any of these drugs, renal function and hematological parameters should be carefully monitored and the dose of one or more drugs reduced if necessary.

Since some patients may develop opportunistic infections despite taking Zidolam, additional antimicrobial therapy may be required to prevent them. For such prevention, co-trimoxazole, pentamidine in aerosol form, pyrimethamine and acyclovir are used. Limited clinical trial data indicate that there is no significant increase in the incidence of side effects of zidovudine when used concomitantly with these drugs.

When using Zidolam simultaneously with fluconazole, phenobarbital and valproic acid, it is recommended to monitor the toxic effect of zidovudine. Clinically significant interactions between Zidolam and ranitidine/cimetidine are unlikely. These drugs are eliminated by the renal organic cation transport system. No dose adjustment is required.

The simultaneous use of cladribine and lamivudine is not recommended due to the possible inhibition of intracellular phosphorylation of cladribine by lamivudine.

Nucleoside analogues that interfere with DNA replication, such as ribavirin, may reduce the antiviral activity of zidovudine in vitro. The simultaneous use of such drugs with zidovudine is not recommended. The simultaneous use of zidovudine and doxorubicin is not recommended due to the mutual weakening of the activity of each drug in vitro.

When lamivudine and interferon alfa were used concomitantly with or without ribavirin in patients co-infected with HIV-1 and hepatitis C, there was no evidence of pharmacokinetic or pharmacodynamic interactions (for example, loss of anti-HIV-1/hepatitis C virological activity), but the development of liver failure (some cases fatal) was observed in these patients.

Overdose

Symptoms:

There is no information about cases of overdose of the drug Zidolam. No specific symptoms have been identified in acute overdose of lamivudine and zidovudine, except those listed in the “Side Effects” section.

Treatment:

In case of overdose, it is recommended to monitor the patient’s condition for timely detection of signs of intoxication and carry out standard supportive therapy. Since lamivudine is eliminated by dialysis, continuous hemodialysis can be used in case of overdose, but there is no relevant clinical experience yet. Apparently, hemodialysis and peritoneal dialysis are ineffective in removing zidovudine from the body, but these methods accelerate the elimination of its metabolite (glucuronide). More detailed information is contained in the instructions for use of lamivudine and zidovudine.

Manufacturer

Makis-Pharma, Russia