Virocomb (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

Manufactured By

Sun Pharmaceutical Industries, Ltd. (India)

Packaging and Quality Control Release

SUN PHARMACEUTICAL INDUSTRIES, Ltd. (India)

Or

BIOSINTEZ, PJSC (Russia)

ATC Code

J05AR01 (Zidovudine and Lamivudine)

Active Substances

Zidovudine (Rec.INN registered by WHO)

Lamivudine (Rec.INN registered by WHO)

Dosage Form

Virocomb

Film-coated tablets, 300 mg+150 mg: 60 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blisters (6) – cardboard packs.
60 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Lamivudine and Zidovudine are highly effective selective inhibitors of HIV-1 and HIV-2. Lamivudine is a synergist of zidovudine in inhibiting HIV replication in cell culture. Both drugs are sequentially metabolized by intracellular kinases to 5′-triphosphate (TP). Lamivudine-TP and zidovudine-TP are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of the drugs is mainly due to the incorporation of their monophosphate form into the viral DNA chain, resulting in chain termination. The triphosphates of lamivudine and zidovudine have significantly less affinity for human cell DNA polymerases. In vitro, Lamivudine demonstrates low cytotoxicity towards lymphocytic and monocyte-macrophage colonies and a number of bone marrow progenitor cells. Thus, Lamivudine has a wide therapeutic index.

In clinical studies, the use of a combination of lamivudine and zidovudine led to a decrease in HIV-1 load and an increase in CD4⁺ cell count. Clinical data indicate that the use of a combination of lamivudine and zidovudine or a combination of lamivudine and Zidovudine-containing therapy regimens leads to a significant reduction in the risk of disease progression and mortality.

Separately, monotherapy with lamivudine or zidovudine led to the emergence of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical data indicate that combination therapy with lamivudine and zidovudine delays the emergence of Zidovudine-resistant strains in patients who have not previously received antiretroviral therapy (ART). Combination therapy with lamivudine and zidovudine is widely used as a component of ART in combination with other antiretroviral drugs of the same class (NRTIs) or other classes (HIV protease inhibitors [PIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs]).

Post-exposure prophylaxis

International guidelines recommend the use of a combination of lamivudine and zidovudine within 1-2 hours after exposure to HIV-infected blood (e.g., after a needle stick injury). In case of high risk of infection, HIV protease inhibitors should also be included in the prophylaxis regimen. The course of antiretroviral prophylaxis should be 4 weeks. Despite immediate treatment, seroconversion may still occur.

Combination therapy with lamivudine and zidovudine delays the development of resistance to zidovudine in patients who have not previously received antiretroviral therapy.

Pharmacokinetics

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 oral administration, C_max of lamivudine and zidovudine was noted at 1.02 h and 0.58 h and amounted to 2 µg/ml and 2.3 µg/ml, respectively. For lamivudine, the values of AUC_0-t were 7.6 µg × h/ml, AUC_0-∞ 7.8 µg × h/ml. For zidovudine, the values of AUC_0-t were 2.6 µg × h/ml, AUC_0-∞ 2.6 µg × h/ml.

V_d of lamivudine and zidovudine is 1.3 and 1.6 l/kg, respectively. The binding of lamivudine to plasma proteins is 35%, and that of zidovudine is 34-36%. Thus, interaction of lamivudine and zidovudine with other drugs through protein displacement is unlikely. Lamivudine and Zidovudine have been shown to penetrate the CNS and cerebrospinal fluid.

2-4 hours after oral administration, the ratios between the concentration of lamivudine and zidovudine in the CSF and in the blood serum are on average 0.12 and 0.5, respectively.

Lamivudine is excreted from the body mainly by the kidneys unchanged. Metabolic interactions of lamivudine are unlikely due to minimal metabolism in the liver (from 5 to 10%) with the formation of an inactive trans-sulfoxide metabolite and low binding to plasma proteins. It is metabolized in cells to form 5-triphosphate.

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

T_1/2 of lamivudine is 5-7 h. The systemic clearance of lamivudine is 0.32 l/h/kg. 70% of lamivudine is excreted by the kidneys with the participation of the cationic transport system, 10% by the liver.

T_1/2 of zidovudine is 1.1 h. The systemic clearance of zidovudine is 1.6 l/h/kg. The renal clearance of zidovudine is 0.34 l/h/kg through glomerular filtration and active tubular secretion in the kidneys.

Pharmacokinetic parameters in special patient groups.

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

Children. In children older than 5-6 months, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine is well absorbed from the intestine after administration at all studied doses in adults and children; its bioavailability is 60-74%, on average 65%. C_max at steady state is 4.45 µmol (1.19 µg/ml) after administration of 120 mg/m² of zidovudine in solution form and 7.7 µmol (2.06 µg/ml) after a dose of 180 mg/m². A dose of 180 mg/m² 4 times/day leads to the same systemic exposure in children (AUC₂₄ 10.7 µg × h/ml) as a dose of 200 mg/m² 6 times/day in adults (AUC₂₄ 10.9 µg × h/ml). A study in six HIV-infected children aged 2 to 13 years evaluated the pharmacokinetics of zidovudine after administration of 120 mg/m² 3 times/day and after switching to a dose of 180 mg/m² 2 times/day. Systemic exposure (AUC and C_max) in plasma was similar with the twice-daily and three-times-daily dosing regimens (daily dose the same). In general, the pharmacokinetics of lamivudine in children is similar to that 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 with age, reaching levels similar to adults by the age of 12. Taking these differences into account, 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 administration of this dose, AUC_0-12 reaches 3800-5300 mg × h/ml. Recent data indicate that exposure in children aged 2 to 6 years may be reduced by 30% compared to other age groups.

Patients with impaired renal function. In renal failure, due to reduced renal clearance, the excretion of lamivudine is impaired. Dose reduction of lamivudine is recommended in patients with creatinine clearance less than 50 ml/min. The plasma concentration of zidovudine is also increased in patients with severe renal impairment.

Patients with impaired hepatic function. Reduced glucuronidation due to liver cirrhosis may lead to accumulation of zidovudine. In patients with severe hepatic impairment, dose adjustment is required.

Pregnancy. During pregnancy, the pharmacokinetics of lamivudine and zidovudine do not change. Lamivudine and Zidovudine are detected in the child’s serum at birth in the same concentrations as in the maternal serum and umbilical cord blood at delivery, confirming the theory of passive penetration through the hematoplacental barrier.

Indications

• Treatment of HIV infection in adults and children over 12 years of age with progressive immunodeficiency (CD4⁺ cell count less than 500 per 1 mm³). Used as part of combination antiviral therapy.

ICD codes

Dosage Regimen

The drug Virocomb is taken orally regardless of meals. To ensure accurate dosing, the tablets must be swallowed whole. For patients who have difficulty swallowing, it is recommended to crush the tablets and add a small amount of semi-solid food or liquid. The entire amount of the resulting mixture must be taken immediately.

Adults and children over 12 years of age weighing at least 30 kg: 1 tablet 2 times/day.

In cases where it is necessary to reduce the dose of Virocomb or discontinue one of its components (Lamivudine or Zidovudine), separate preparations of lamivudine and zidovudine can be used.

Use in children: Virocomb is not indicated for children under 12 years of age weighing less than 30 kg. Physicians should refer to the prescribing information for lamivudine and zidovudine.

Use in elderly patients: there are no specific data on the use of Virocomb in elderly individuals. However, when treating elderly patients, special caution is recommended, taking into account age-related changes, changes in blood counts, and impaired renal function.

Use in renal impairment: in patients with renal impairment, the blood concentrations of lamivudine and zidovudine are increased due to slowed elimination. Patients with impaired renal function (creatinine clearance less than 50 ml/min) in some cases require individual dose selection of lamivudine and zidovudine, therefore it is recommended to prescribe Lamivudine and Zidovudine separately.

Use in hepatic impairment: in hepatic insufficiency, accumulation of zidovudine may occur due to slowed binding with glucuronic acid. In patients with severe hepatic impairment, it is recommended to use Lamivudine and Zidovudine separately in order to be able to individually select the dose of zidovudine.

Use in patients with hematological adverse effects: in case of severe anemia (hemoglobin level less than 9 g/dl or 5.59 mmol/l) or neutropenia (neutrophil count less than 1 × 10⁹/l), dose adjustment of zidovudine may be required. The likelihood of these adverse effects is higher in patients with reduced bone marrow reserve prior to initiation of therapy, especially in patients with late-stage HIV infection. Since it is impossible to individually select the doses of lamivudine and zidovudine when prescribing Virocomb, it is recommended to use separate preparations of lamivudine and zidovudine.

Adverse Reactions

Treatment of HIV infection with lamivudine and zidovudine as monotherapy or in combination of these drugs can cause side effects. For many side effects, it is unknown whether they are caused by lamivudine, zidovudine, the wide range of other drugs used to treat HIV infection, or are a consequence of the disease itself. Virocomb can cause side effects characteristic of zidovudine and lamivudine. However, there is currently no data that the combination of lamivudine and zidovudine has additive toxicity. By frequency, adverse effects were divided into the following categories: very common > 1:10; common > 1:100 and < 1:10; uncommon > 1:1000 and < 1:100; rare > 1:10,000 and < 1:1000; very rare < 1:10000.

Lamivudine

Blood and lymphatic system disorders: uncommon – neutropenia, anemia, thrombocytopenia; very rare – pure red cell aplasia.

Endocrine and metabolic disorders: common – hyperlactatemia; rare – lactic acidosis, redistribution/accumulation of adipose tissue. The frequency of this adverse effect depends on many factors, including the specific combination of antiretroviral drugs.

Nervous system disorders: common – headache; very rare – paresthesia; there are reports of peripheral neuropathy, however, its connection with lamivudine intake is unclear.

Gastrointestinal disorders common – nausea, vomiting, epigastric pain, diarrhea; rare – pancreatitis, the connection of which with lamivudine treatment has not been established. Increased levels of serum amylase.

Hepatobiliary disorders: uncommon – transient increase in the activity of liver enzymes (AST and ALT).

Skin and subcutaneous tissue disorders: common – rash, alopecia.

Musculoskeletal and connective tissue disorders: common – arthralgia, muscle disorders; rare – rhabdomyolysis.

General disorders and administration site conditions: common – fatigue, malaise, fever.

Zidovudine

Blood and lymphatic system disorders: common – anemia (may require blood transfusion), neutropenia and leukopenia. These adverse effects occur more often when using high doses of zidovudine (1200-1500 mg per day), in patients with late stages of HIV infection (especially with reduced bone marrow reserve before starting treatment) and with a CD4⁺ cell count of less than 100 per 1 mm³. In such cases, it is sometimes necessary to reduce the dose of zidovudine or discontinue it. Neutropenia occurs more often in those patients who have a reduced neutrophil count, hemoglobin level, and serum vitamin B₁₂ level before starting treatment with zidovudine. Uncommon – thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rare – pure red cell aplasia; very rare – aplastic anemia.

Endocrine and metabolic disorders: common – hyperlactatemia; rare – lactic acidosis, anorexia. Redistribution/accumulation of adipose tissue. The frequency of this adverse effect depends on many factors, including the specific combination of antiretroviral drugs.

Nervous system disorders: very common – headache; common – dizziness; rare – insomnia, paresthesia, drowsiness, decreased mental acuity, convulsions.

Psychiatric disorders: rare – anxiety, depression.

Cardiac disorders: rare – cardiomyopathy.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea; rare – cough.

Gastrointestinal disorders very common – nausea; common – vomiting, abdominal pain and diarrhea; uncommon – flatulence; rare – pigmentation of the oral mucosa, taste perversion (dysgeusia), dyspepsia, pancreatitis.

Hepatobiliary disorders: common – increased activity of liver transaminases and bilirubin concentration; rare – liver damage such as severe hepatomegaly with steatosis.

Skin and subcutaneous tissue disorders: uncommon – rash and pruritus; rare – pigmentation of nails and skin, urticaria and sweating.

Musculoskeletal and connective tissue disorders: common – myalgia; uncommon – myopathy.

Renal and urinary disorders: rare – frequent urination.

Reproductive system and breast disorders: rare – gynecomastia.

General disorders and administration site conditions common – malaise; uncommon – fever, generalized pain syndrome, asthenia, bronchial asthma; rare – chills, chest pain and flu-like syndrome.

Contraindications

• Severe neutropenia (neutrophil count less than 0.75 × 10⁹/l) or anemia (hemoglobin level less than 7.5 g/dl or 4.65 mmol/l);
• Children under 12 years of age weighing less than 30 kg (due to the impossibility of dosing this dosage form);
• Hypersensitivity to lamivudine, zidovudine or any other component of the drug.

Use in Pregnancy and Lactation

It is not recommended to use the drug Virocomb in the first trimester of pregnancy, unless the expected benefit to the mother outweighs the potential risk to the fetus. Treatment of pregnant women with zidovudine and subsequent administration of this drug to newborns has been shown to reduce the frequency of HIV transmission from mother to child. There are no such data regarding lamivudine. Therefore, the drug Virocomb can be prescribed to pregnant women only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Women taking Virocomb are not recommended to breastfeed their child. In newborns and infants who were exposed to nucleoside reverse transcriptase inhibitors in utero or during birth, a small transient increase in blood lactate has been observed. There are also rare reports of cases of developmental delay, seizures and other neurotic pathology. A causal relationship between the occurrence of these pathological conditions and the intake of nucleoside reverse transcriptase inhibitors during pregnancy has not been established. In general, in children whose mothers took nucleoside reverse transcriptase inhibitors during pregnancy, the benefit from reducing the risk of vertical HIV transmission clearly outweighs the danger associated with the side effects of these drugs.

Use in Hepatic Impairment

Use in hepatic impairment: in hepatic insufficiency, accumulation of zidovudine may occur due to slowed binding with glucuronic acid. In patients with severe hepatic impairment, it is recommended to use Lamivudine and Zidovudine separately in order to be able to individually select the dose of zidovudine.

Use in Renal Impairment

Use in renal impairment: in patients with renal impairment, the blood concentrations of lamivudine and zidovudine are increased due to slowed elimination. Patients with impaired renal function (creatinine clearance less than 50 ml/min) in some cases require individual dose selection of lamivudine and zidovudine, therefore it is recommended to prescribe Lamivudine and Zidovudine separately.

Pediatric Use

Use in children: Virocomb is not indicated for children under 12 years of age with a body weight of less than 30 kg. Physicians should be guided by the prescribing information for lamivudine and zidovudine.

Geriatric Use

Use in elderly patients: There are no specific data on the use of Virocomb in elderly individuals. However, when treating elderly patients, special caution is recommended, taking into account age-related changes, changes in blood counts, and impaired renal function.

Special Precautions

If individual dose adjustment is necessary, it is recommended to use lamivudine and zidovudine preparations separately. Physicians should be guided by the prescribing information for these drugs.

Lamivudine in combination with zidovudine reduces viral load and increases the number of CD4⁺ cells. Lamivudine in combination with zidovudine significantly reduces the risk of disease progression and death.

Despite taking Virocomb or any other antiretroviral drug, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under the constant supervision of physicians experienced in the treatment of HIV infection.

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

In patients with advanced HIV infection receiving Zidovudine, there is a high probability of developing anemia, neutropenia, and leukopenia (the latter is usually secondary to neutropenia). Therefore, careful monitoring of blood counts is necessary during therapy with Virocomb. Changes in blood counts usually do not appear earlier than 4-6 weeks after the start of therapy. In patients with late-stage HIV infection, blood tests are recommended to be monitored at least once every 2 weeks for the first three months of therapy, and then at least once a month.

In patients with early-stage HIV infection, hematological side effects are rare, so blood tests can be ordered less frequently, guided by the general condition of the patients, for example, once every 1-3 months. If hemoglobin decreases by more than 25% or the neutrophil count decreases by more than 50% compared to the baseline level, blood tests should be performed more frequently.

Special dose adjustment of zidovudine may be required in case of severe anemia or myelosuppression during treatment with Virocomb, as well as in patients with pre-existing bone marrow suppression, for example, with a hemoglobin level of less than 9 g/dL (5.59 mmol/L) or a neutrophil count of less than 1× 10⁹. Since it is impossible to individually adjust the dose of Virocomb, it is recommended to use lamivudine and zidovudine preparations separately.

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 the drugs or by the HIV infection itself. Treatment with Virocomb should be discontinued immediately if clinical or laboratory signs of pancreatitis appear.

Lactic Acidosis

Rare but severe cases of lactic acidosis without hypoxia with possible fatal outcome and pronounced hepatomegaly with hepatic steatosis have been described in patients taking Zidovudine. It is unknown whether these complications are related to zidovudine treatment, as they have been observed in HIV-infected patients without clinical manifestations of HIV infection. If there is a rapid increase in aminotransferase activity, progression of hepatomegaly, or metabolic/lactic acidosis of unknown etiology, treatment with Virocomb should be discontinued.

Caution should be exercised when treating patients with hepatomegaly, hepatitis, or risk factors predisposing to liver damage with Virocomb, especially when prescribing the drug to obese women. These patients should be carefully monitored during treatment with Virocomb.

Redistribution/Accumulation of Adipose Tissue

Some patients receiving combined antiretroviral therapy develop redistribution/accumulation of adipose tissue with fat deposition in the area of the spinous processes of the 6th-7th cervical vertebrae, thinning of the limbs and face, breast enlargement, and increased concentrations of serum lipids and blood glucose. All drugs belonging to HIV protease inhibitors and nucleoside reverse transcriptase inhibitors can cause the listed symptoms of lipodystrophy.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology. The stage of HIV infection, older age, and the duration of antiretroviral therapy play an important role in its development, possibly as synergists. The long-term consequences of lipodystrophy are unknown. During clinical examination of patients, attention should be paid to the presence of symptoms of adipose tissue redistribution. Serum lipid and blood glucose concentrations should be measured.

Concomitant Hepatitis B

Virocomb should be used with caution in patients with decompensated liver cirrhosis due to concomitant hepatitis B, since in rare cases, exacerbation of hepatitis may occur upon discontinuation of lamivudine. Periodic monitoring of liver function and markers of hepatitis B virus replication should be performed.

Concomitant Hepatitis C

In vitro studies have shown that ribavirin may reduce the phosphorylation of pyrimidine nucleoside analogs lamivudine and zidovudine. Although there are no data on the pharmacokinetic and pharmacodynamic interaction of ribavirin with lamivudine and zidovudine, cases of hepatic decompensation (sometimes fatal) have been noted in patients infected with HIV-1 with concomitant hepatitis C, receiving antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving Virocomb, interferon alfa with or without ribavirin, should be carefully monitored for drug interaction toxicity, especially hepatic decompensation, neutropenia, and anemia. If clinical manifestations of toxicity, especially hepatic decompensation, worsen, the doses of interferon alfa, ribavirin, or both drugs should be reduced or discontinued.

Immune Reconstitution Syndrome

At the start of antiretroviral treatment of HIV-infected patients with severe immunodeficiency, inflammatory reactions, as well as residual opportunistic infections, may develop, sometimes leading to serious clinical consequences or worsening of symptoms.

Such reactions are usually observed within the first weeks or months after the start of antiretroviral therapy.

Effect on Ability to Drive and Use Machines

Not studied.

Overdose

No cases of zidovudine or lamivudine overdose have been fatal, and all patients recovered. No specific signs or symptoms have been recorded.

In case of overdose, it is recommended to monitor the patient’s condition for timely detection of signs of intoxication and to carry out standard supportive therapy. Lamivudine is removed by dialysis, so continuous hemodialysis can be used in case of overdose. Hemodialysis and peritoneal dialysis are not very effective in removing zidovudine from the body but accelerate the elimination of its metabolite (glucuronide).

Drug Interactions

Since Virocomb contains Lamivudine and Zidovudine, it can participate in any interactions characteristic of each of its components. The likelihood of metabolic interactions with lamivudine is low, as it is almost completely eliminated by the kidneys and only in small amounts undergoes hepatic metabolism and binds to plasma proteins. The binding of zidovudine to plasma proteins is also low, but it undergoes predominant metabolism in the liver to form an inactive glucuronide.

Drugs with predominant hepatic metabolism, especially via glucuronidation, may potentially inhibit the metabolism of zidovudine. The drugs listed below should be used with caution during therapy with Virocomb.

Interactions Involving Lamivudine

Lamivudine is primarily eliminated via the cationic transport system; therefore, the possibility of interaction of Virocomb with drugs that have the same elimination pathway should be kept in mind.

Interaction with Trimethoprim

Concomitant administration of lamivudine and trimethoprim (one of the components of co-trimoxazole) leads to a 40% increase in lamivudine plasma concentration. Patients with normal renal function do not require individual dose adjustment of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. Caution should be exercised when co-administering co-trimoxazole and Virocomb in patients with renal failure.

Interaction with Zalcitabine

Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when taken concomitantly. Thus, it is not recommended to use Virocomb in combination with zalcitabine.

Interactions Involving Zidovudine

Concomitant administration of zidovudine and lamivudine leads to a 13% increase in the duration of action of zidovudine and a 28% increase in its maximum plasma concentration. It is believed that such an increase is not dangerous for patients. Zidovudine does not affect the pharmacokinetics of lamivudine.

Interaction with Atovaquone

Zidovudine does not affect 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 of zidovudine increases by 33%, and the maximum plasma concentration of the glucuronide decreases by 19%). When prescribing zidovudine at doses of 500-600 mg/day and a concomitant 3-week course of treatment for acute Pneumocystis pneumonia with atovaquone, an increase in the frequency of side effects associated with increased plasma concentration of zidovudine is unlikely.

Interaction with Clarithromycin

When clarithromycin tablets are taken concomitantly, the absorption of zidovudine is reduced. An interval of at least 2 hours between taking clarithromycin and zidovudine should be observed.

Interaction with Phenytoin

In some patients receiving Zidovudine in combination with phenytoin, a decrease in phenytoin blood concentration was detected, and in one case, an increase in phenytoin concentration was noted. Phenytoin blood concentration should be monitored in patients in case of concomitant use of Virocomb and phenytoin.

Interaction with Paracetamol

The combination of paracetamol and zidovudine was accompanied by an increased frequency of neutropenia, especially during long-term therapy. However, paracetamol at therapeutic doses does not cause an increase in the plasma concentration of zidovudine and its glucuronide.

Interaction with Probenecid

Some data indicate that probenecid increases the mean half-life of zidovudine and the area under the pharmacokinetic curve (AUC) as a result of inhibition of glucuronide formation. In the presence of probenecid, the renal excretion of the glucuronide and possibly of zidovudine itself is reduced.

Interaction with Rifampicin

Limited data show that concomitant administration of zidovudine and rifampicin reduces the area under the pharmacokinetic curve (AUC) of zidovudine from 48% to 34%. However, the clinical significance of this observation is unknown.

Interaction with Stavudine

Zidovudine may inhibit the intracellular phosphorylation process of stavudine when taken concomitantly. Thus, concomitant use of the combination of stavudine and Virocomb is not recommended.

Acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex and some other drugs may alter the metabolism of zidovudine as a result of competitive inhibition of the synthesis of its metabolite (glucuronide) or direct suppression of zidovudine metabolism by hepatic microsomal enzymes. Before prescribing these drugs in combination with Virocomb, especially when planning long-term treatment, possible drug interactions should be assessed.

When used concomitantly, especially for acute therapy, zidovudine and potentially nephrotoxic or myelosuppressive drugs (for example, systemic administration of pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon alfa, vincristine, vinblastine, and doxorubicin) the likelihood of side effects increases, so renal function and blood counts should be carefully monitored and, if necessary, the dose of the drugs should be reduced.

While taking Virocomb, some patients may develop infections caused by opportunistic microorganisms. Co-trimoxazole, aerosolized pentamidine, pyrimethamine, and acyclovir are used to prevent these infections. Limited clinical trial data indicate no significant increase in the frequency of zidovudine side effects when used concomitantly with these drugs.

Storage Conditions

In a dry place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Do not use the drug after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.