Virocomb

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Virocomb (VIROCOMB)

Composition:

Active substances: zidovudine, lamivudine;

One tablet contains zidovudine 300 mg, lamivudine 150 mg;

Excipients: microcrystalline cellulose (PH102), sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: Opadry 03H58900 white (hypromellose, titanium dioxide (E 171), propylene glycol).

Pharmaceutical form. Film-coated tablets.

Pharmacotherapeutic group.
Antiviral agents for systemic use. Antiviral agents for treatment of HIV infection, combinations. ATC code J05AR01.

Clinical characteristics.

Indications.

Treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.

Contraindications.

Hypersensitivity to any component of the drug. 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), renal impairment (with creatinine clearance of 50 ml/min or less), severe hepatic insufficiency.

Method of Administration and Dosage.

Treatment with the medicinal product should be prescribed by a specialist experienced in the management of HIV infection.

The medicinal product is administered orally to adults and children with body weight of 30 kg and above, 1 tablet twice daily, regardless of food intake. The tablet should be swallowed whole with water.

Adverse Reactions

Adverse effects have been reported during therapy in HIV-infected patients receiving lamivudine and zidovudine either individually or in combination. For many of these effects, it remains unclear whether they are related to the use of lamivudine, zidovudine, or the broad range of other drugs used in the treatment of HIV disease, or are a result of the disease itself. Since Virocom contains a combination of lamivudine and zidovudine, the type and severity of adverse effects can be expected to be associated with these two components. No data indicating increased toxicity due to concomitant administration of these two components have been identified.

Cases of lactic acidosis, sometimes fatal, associated with severe hepatomegaly and hepatic steatosis have been reported with nucleoside analogues (see section "Special Warnings and Precautions for Use").

Combination antiretroviral therapy has been associated with redistribution (lipodystrophy) of body fat in HIV-infected patients, including loss of peripheral and subcutaneous fat deposits in the face, increased intra-abdominal and visceral fat accumulation, breast hypertrophy, and fat accumulation in the dorsocervical areas (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic disturbances such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia (see section "Special Warnings and Precautions for Use").

In HIV-infected patients with advanced immunodeficiency, inflammatory reactions to asymptomatic or residual opportunistic infections may occur at the initiation of combination antiretroviral therapy (see section "Special Warnings and Precautions for Use").

Cases of osteonecrosis have been reported, primarily in patients with confirmed risk factors, advanced HIV disease, or long-term antiretroviral therapy. The frequency is unknown (see section "Special Warnings and Precautions for Use").

Lamivudine

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

Metabolism and nutrition disorders: hyperlactatemia, lactic acidosis.

Redistribution/accumulation of body fat (see section "Special Warnings and Precautions for Use"). The frequency of occurrence depends on many factors, including the specific antiretroviral drug combination.

Nervous system disorders: headache, insomnia, paresthesia. Cases of peripheral neuropathy have been reported.

Gastrointestinal disorders: nausea, vomiting, upper abdominal pain, diarrhea; pancreatitis, although the relationship to treatment is not fully established. Increased serum amylase levels.

Hepatobiliary disorders: transient elevations in liver enzymes (AST, ALT).

Skin and subcutaneous tissue disorders: rash, alopecia, angioneurotic edema.

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

Other: increased fatigue, malaise, fever.

Respiratory system disorders: cough, cold symptoms.

Zidovudine

Blood and lymphatic system disorders: anemia (which may require blood transfusions), neutropenia, and leukopenia. These are more commonly observed with high-dose regimens (1200–1500 mg daily) and in patients with advanced stages of HIV (particularly those with reduced bone marrow reserve prior to treatment), especially in patients with CD4+ cell counts below 100/mm³. Due to these adverse effects, dose reduction or discontinuation of therapy may be necessary. The frequency of neutropenia is also increased in patients who had low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels at the start of zidovudine therapy; thrombocytopenia and pancytopenia with bone marrow hypoplasia are uncommon; pure red cell aplasia; aplastic anemia.

Metabolism and nutrition disorders: hyperlactatemia; lactic acidosis, anorexia. Redistribution/accumulation of body fat (see section "Special Warnings and Precautions for Use"). The frequency of occurrence depends on many factors, including the specific antiretroviral drug combination.

Psychiatric disorders: restlessness, depression.

Nervous system disorders: headache; dizziness; insomnia, paresthesia, somnolence, decreased mental activity, seizures.

Cardiac disorders: cardiomyopathy.

Respiratory, thoracic and mediastinal disorders: dyspnea; cough.

Gastrointestinal disorders: nausea; vomiting, abdominal pain, diarrhea; flatulence; pigmentation of oral mucosa, taste alteration, dyspepsia, pancreatitis.

Hepatobiliary disorders: elevated liver enzymes and bilirubin; hepatic disorders (severe hepatomegaly with steatosis).

Skin and subcutaneous tissue disorders: rash, pruritus; skin and nail pigmentation, urticaria, increased sweating.

Musculoskeletal and connective tissue disorders: myalgia; myopathy.

Renal and urinary disorders: frequent micturition.

Reproductive system and breast disorders: gynecomastia.

Other: malaise; fever, generalized pain, asthenia; chills, chest pain, flu-like syndrome.

Overdose

Data on overdose are limited. No specific signs or symptoms of acute overdose with zidovudine and lamivudine, other than those described in the "Adverse Reactions" section, have been identified. No fatal cases have been reported; all patients recovered.

In case of overdose, the patient should be monitored for toxicity (see section "Adverse Reactions"), and standard supportive treatment should be administered as needed. Lamivudine is dialyzable, so continuous hemodialysis may be used in overdose, although this has not been studied. Hemodialysis and peritoneal dialysis have limited effects on the elimination of zidovudine but accelerate the removal of its metabolite. For further information, the physician may refer to the prescribing information for lamivudine and zidovudine.

Use during pregnancy or breastfeeding

Fertility

Animal studies have shown no evidence of effects of either zidovudine or lamivudine on male or female fertility. There are no data on the effects of these two drugs on human fertility. It has been established that zidovudine does not affect sperm count, morphology, or motility in men.

Pregnancy

The safety of lamivudine use during human pregnancy has not been established. Use of zidovudine alone in pregnant women, followed by treatment of the newborn, has shown a reduction in mother-to-child transmission of HIV. However, similar data for lamivudine are lacking, as are data on the combined use of lamivudine and zidovudine. Virocom should not be administered during the first trimester of pregnancy and should be used only if the expected benefit outweighs the potential risk.

Based on animal carcinogenicity and mutagenicity studies, a carcinogenic risk to humans cannot be excluded.

Mild, transient elevations in serum lactate levels, possibly due to mitochondrial dysfunction, have been reported in newborns and infants exposed to nucleoside reverse transcriptase inhibitors during pregnancy or delivery. The clinical significance of these elevated serum lactate levels is unknown. There have also been isolated reports of developmental delay, seizures, and other neurological disorders. However, a causal relationship between these events and exposure to nucleoside reverse transcriptase inhibitors during pregnancy or delivery has not been established. These data do not affect recommendations for the use of antiretroviral drugs to prevent vertical transmission of HIV in pregnant women.

Breastfeeding

WHO experts recommend that HIV-infected women under any circumstances avoid breastfeeding to prevent transmission of HIV infection. Both lamivudine and zidovudine are excreted in human breast milk at concentrations similar to those found in serum. Since lamivudine, zidovudine, and human immunodeficiency virus can pass into breast milk, mothers receiving this medication are advised not to breastfeed.

Children

The drug is administered to children with body weight of 30 kg or more.

For the treatment of children with body weight less than 30 kg, separate formulations of lamivudine and zidovudine should be used according to the prescribing information for these drugs, noting that film-coated tablets must not be divided.

Special precautions for use.

Special warnings apply to each component of the medicinal product. No additional warnings have been identified for the combined medicinal product.

If dose adjustment is required, it is recommended to use separate lamivudine and zidovudine medicinal products. In such cases, information regarding each of these medicinal products should be consulted.

Patients should be informed that current antiretroviral therapy, including this medicinal product, does not prevent transmission of HIV to others via sexual contact or blood exposure. Therefore, appropriate preventive measures should continue to be used.

Opportunistic infections and other complications of HIV infection may still develop in patients despite treatment with this medicinal product or any other antiretroviral therapy. Therefore, such patients should remain under regular clinical supervision by experienced physicians.

Hematological adverse reactions. Anemia, neutropenia, and leukopenia (usually secondary to neutropenia) may occur in patients receiving zidovudine. These are most commonly observed when high doses of zidovudine (1200–1500 mg per day) are used in patients with advanced stages of HIV disease or in individuals who had reduced bone marrow reserve prior to treatment (see section "Adverse reactions"). Therefore, hematological parameters must be closely monitored in patients receiving this medicinal product (see section "Contraindications").

These hematological changes usually do not occur during the first 4–6 weeks of therapy. Patients with advanced stages of HIV disease should have blood tests performed at least once every 2 weeks during the first 3 months of treatment and at least once a month thereafter. Hematological adverse reactions are rare in patients with early stages of HIV disease. Depending on the patient's overall condition, blood tests may be performed less frequently, e.g., once every one to three months.

In cases of severe anemia or myelosuppression during treatment with this medicinal product, or in patients with already compromised bone marrow (i.e., hemoglobin less than 9 g/dL (5.59 mmol/L) or neutrophil count less than 1 × 10⁹/L), dose reduction of zidovudine may be required. Since dose reduction of the fixed-dose combination is not possible, zidovudine and lamivudine should be administered as separate formulations (see section "Contraindications").

Pancreatitis. Isolated cases of pancreatitis have been reported in patients treated with lamivudine and zidovudine. However, it remains unclear whether these cases are related to drug therapy or are a consequence of the disease itself. In patients presenting with abdominal pain, nausea, vomiting, or elevated biochemical markers, pancreatitis should be suspected and administration of the medicinal product should be discontinued until pancreatitis is ruled out.

Lactic acidosis. Cases of lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, have been reported with nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign gastrointestinal symptoms (nausea, vomiting, and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including muscle weakness).

Lactic acidosis has a high fatality rate and may be associated with pancreatitis, hepatic or renal failure.

Lactic acidosis typically occurs after several months or longer of treatment.

If symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels occur, treatment with nucleoside analogues should be discontinued.

Nucleoside analogues should be used with caution in any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and receiving alpha-interferon and ribavirin are at particular risk.

Patients at increased risk require ongoing monitoring.

Mitochondrial dysfunction. Nucleotide and nucleoside analogues have been shown in vitro and in vivo to cause mitochondrial dysfunction of varying degrees. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogues in utero or during the postnatal period. The most commonly reported adverse reactions include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipidemia). These events are often transient. Late-onset neurological disorders (hypertonia, seizures, abnormal behavior) have also been frequently reported. Whether these neurological disorders are transient or permanent is currently unknown. Any child, even those with HIV-negative status, exposed to nucleoside or nucleotide analogues in utero should be under clinical and laboratory monitoring and fully evaluated for mitochondrial dysfunction if relevant signs or symptoms appear. These data do not affect existing recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Redistribution of body fat. Redistribution/accumulation of body fat, including central obesity, increased fat accumulation in the dorsocervical area (buffalo hump), decreased fat in the limbs and face, increased breast size, elevated serum lipid levels, and elevated blood glucose levels, may occur either individually or in combination in some patients receiving combination antiretroviral therapy (see section "Adverse reactions").

As with all drugs in the class of protease inhibitors and nucleoside reverse transcriptase inhibitors, one or more specific adverse symptoms may occur, which generally may belong to lipodystrophy phenomena. Data suggest that the risk of developing these effects varies with different drugs in this class.

Furthermore, the lipodystrophy syndrome is multifactorial in etiology, with factors such as the stage of HIV disease, older age of the patient, and duration of antiretroviral therapy playing an important role and potentially having a synergistic effect.

The long-term consequences of the aforementioned adverse effects are currently unknown.

During clinical examination, attention should be paid to physical signs of fat redistribution, and serum lipid and blood glucose levels should be assessed. Treatment of lipid distribution disorders should be conducted according to appropriate clinical guidelines.

Liver disease. Zidovudine clearance in patients with mild hepatic impairment without cirrhosis (Child-Pugh score 5–6) is similar to that observed in healthy volunteers; therefore, dose adjustment of zidovudine is not required. For patients with moderate to severe hepatic impairment (Child-Pugh score 7–15), specific dosing recommendations cannot be made due to the wide variability in zidovudine exposure observed; therefore, zidovudine is not recommended in this patient group.

Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects. When used concomitantly with other antiviral agents for the treatment of hepatitis B and C, the respective SmPCs of these agents should be consulted.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk of liver function deterioration during combination antiretroviral therapy and should be under medical supervision. In case of signs of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered (see section "Dosage and administration").

Immune reconstitution syndrome. In HIV-infected patients with severe immunodeficiency at the start of antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur, which can lead to severe clinical conditions or symptom exacerbation. Such reactions typically occur within the first weeks or months of antiretroviral therapy. Appropriate examples include cytomegalovirus retinitis, generalized or focal infections caused by mycobacteria, or Pneumocystis jirovecii pneumonia (P. carinii pneumonia). Any inflammatory conditions must be promptly investigated and, if necessary, treated. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported during immune reconstitution, although their onset is more variable and may occur many months after the start of therapy and sometimes present with atypical features.

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, high body mass index), cases of osteonecrosis have been reported primarily in patients with advanced disease and/or long-term use of combination antiretroviral therapy. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or movement disorders.

Patients co-infected with hepatitis B virus: Clinical trial data and clinical experience with lamivudine have shown that in some patients with chronic hepatitis B, clinical or laboratory signs of relapsing hepatitis may occur after discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. After discontinuation of the medicinal product in patients co-infected with hepatitis B virus, periodic monitoring of liver function tests and markers of hepatitis B virus replication is recommended.

Patients co-infected with hepatitis C virus

Exacerbation of anemia associated with ribavirin use has been observed in patients receiving zidovudine as part of combination HIV treatment, although the exact mechanism remains unclear. Therefore, concomitant use of ribavirin and zidovudine is not recommended. The physician should replace zidovudine with another suitable agent within the combination antiretroviral regimen if already prescribed. This is particularly important for patients with a history of known zidovudine-induced anemia.

Ability to affect reaction speed when driving or operating machinery.

Adverse reactions affecting the nervous system may reduce psychomotor reaction speed; therefore, patients should refrain from driving or operating machinery during treatment with this medicinal product.

Interaction with other medicinal products and other forms of interaction.

Since this medicinal product contains lamivudine and zidovudine, any interactions characteristic of each of these components will also apply to this medicinal product. The interactions described below are not exhaustive but include the main classes of medicinal products for which caution is recommended.

Interactions related to lamivudine

The likelihood of metabolic interaction with lamivudine is low due to its limited metabolism, low protein binding, and almost complete renal elimination of unchanged lamivudine.

Lamivudine is primarily eliminated via active organic cationic secretion. There is a potential for interaction when used concomitantly with medicinal products primarily eliminated via active tubular secretion, mainly through the organic cation transport system (e.g., trimethoprim). Other active substances (ranitidine, cimetidine) are only partially eliminated via this route and therefore do not interact with lamivudine.

Active substances primarily eliminated via active organic anion secretion or glomerular filtration are unlikely to have significant interactions with lamivudine.

Trimethoprim

Prophylactic dosing of co-trimoxazole (160 mg/800 mg trimethoprim/sulfamethoxazole) increases lamivudine levels by 40% due to trimethoprim in co-trimoxazole. However, dose adjustment is not required if the patient does not have renal impairment (see section "Dosage and administration"). Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. The effect of concomitant administration of lamivudine with higher doses of co-trimoxazole used for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis has not been studied.

Zalcitabine

Lamivudine may inhibit intracellular phosphorylation of zalcitabine when these medicinal products are used concomitantly. Therefore, this medicinal product is not recommended to be used in combination with zalcitabine.

Interactions related to zidovudine

Zidovudine is primarily eliminated via conjugation in the liver to an inactive glucuronide metabolite. Active substances primarily eliminated via hepatic metabolism, especially through glucuronidation, may inhibit zidovudine metabolism.

Atovaquone

There is no information on the effect of zidovudine on atovaquone pharmacokinetics. However, based on pharmacokinetic data, atovaquone reduces the metabolism of zidovudine to its glucuronide metabolite (AUC of zidovudine increases by 33%, and peak plasma concentration of glucuronide decreases by 19%). When dosed at 500 or 600 mg/day for 3 weeks for treatment of Pneumocystis carinii pneumonia, atovaquone may rarely increase the frequency of adverse effects related to higher plasma levels of zidovudine. Close monitoring of the patient is required during prolonged atovaquone treatment.

Clarithromycin

Clarithromycin tablets reduce the absorption of zidovudine; therefore, a two-hour interval should be maintained between administration of these medicinal products.

Lamivudine

A moderate increase in Cmax (28%) of zidovudine is observed when used concomitantly with lamivudine, but its overall exposure is not significantly altered. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin

In some patients receiving zidovudine, low blood levels of phenytoin have been observed, while in one patient, elevated levels were noted. These observations indicate the need for careful monitoring of phenytoin blood levels in patients receiving both this medicinal product and phenytoin.

Valproic acid, fluconazole, or methadone

It has been shown that concomitant use with zidovudine increases its AUC with a corresponding decrease in zidovudine clearance. Since data are limited, the clinical significance is unknown. The patient should be under close monitoring for signs of zidovudine toxicity.

Probenecid

Limited data indicate that probenecid increases the half-life and plasma levels of zidovudine by inhibiting glucuronidation. Renal excretion of the glucuronide (and possibly zidovudine itself) is reduced in the presence of probenecid.

Ribavirin

Exacerbation of anemia associated with ribavirin use has been observed in patients receiving zidovudine as part of a combination HIV treatment regimen, although the exact mechanism remains unclear. Therefore, concomitant use of ribavirin and zidovudine is not recommended. The physician should replace zidovudine with another suitable agent within the combination antiretroviral regimen if already prescribed. This is particularly important for patients with a history of known zidovudine-induced anemia.

Rifampicin

Limited data indicate that concomitant administration of zidovudine and rifampicin reduces zidovudine levels by 48 ± 34%. However, the clinical significance of this phenomenon is unknown.

Stavudine

Zidovudine may inhibit intracellular phosphorylation of stavudine when both medicinal products are used concomitantly. Therefore, stavudine is not recommended to be used in combination with this medicinal product.

Other medicinal products, including acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, and isoprinosine (the list is not limited to these), may alter zidovudine metabolism by competitively inhibiting glucuronidation or directly inhibiting microsomal metabolism in the liver. Therefore, caution should be exercised when using these medicinal products in combination with this medicinal product, especially for chronic treatment.

Concomitant use, primarily in acute situations, with medicinal products that are potentially nephrotoxic or have myelosuppressive properties (e.g., systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, and doxorubicin) may also increase the risk of zidovudine adverse effects. If concomitant use of this medicinal product and any of these medicinal products is necessary, monitoring of renal function and hematological parameters should be performed, and the dose of one or more components of therapy should be reduced if necessary.

Given that opportunistic infections may develop in patients receiving this medicinal product, prophylactic antibacterial therapy may be required, which may include co-trimoxazole, pentamidine, pyrimethamine, and acyclovir. Limited clinical trial data suggest no significant increase in the risk of zidovudine adverse effects with these medicinal products.

Pharmacological Properties.

Pharmacodynamics.

This is a combination antiviral medication. The active ingredients of the drug – lamivudine and zidovudine – are selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) replication. Lamivudine and zidovudine exert a synergistic inhibitory effect on human immunodeficiency virus replication within the cell. Both active ingredients of the drug are gradually converted intracellularly into their triphosphates. Lamivudine-triphosphate and zidovudine-triphosphate are competitive inhibitors of HIV reverse transcriptase. Clinically, it has been demonstrated that this combination prevents the development of resistance to zidovudine in patients who have not previously received antiretroviral therapy. Multicomponent antiretroviral therapy including lamivudine has been shown to be effective in patients who have not yet received antiretroviral treatment. Clinical evidence confirms that the combination of lamivudine and zidovudine prevents the emergence of zidovudine resistance in such patients.

Pharmacokinetics.

Absorption. After oral administration, both lamivudine and zidovudine are well absorbed from the gastrointestinal tract. The bioavailability of lamivudine in adults is 80–85%, and that of zidovudine is 60–70%.

Mean peak plasma concentrations for lamivudine and zidovudine were 1.6 µg/mL (32%) and 2 µg/mL (40%), respectively. Corresponding values for the area under the concentration-time curve (AUC) were 6.1 µg × h/mL (20%) and 2.4 µg × h/mL (29%). The elimination half-life for lamivudine and zidovudine is 0.75 (0.5–2) hours and 0.5 (0.25–2) hours, respectively.

Distribution. Following oral administration, the mean volume of distribution for lamivudine and zidovudine is 1.3 and 1.6 L/kg, respectively. Lamivudine exhibits linear pharmacokinetics within the therapeutic dose range and limited binding to the main plasma protein, albumin (less than 36%). Protein binding of zidovudine to plasma proteins ranges from 34% to 38%. Both lamivudine and zidovudine penetrate into the central nervous system and cerebrospinal fluid. The mean ratio of lamivudine and zidovudine concentrations in cerebrospinal fluid to serum concentrations 2–4 hours after oral administration is approximately 0.12 and 0.5, respectively.

Metabolism. The primary metabolite of zidovudine in plasma and urine is 5-glucuronide.

In vitro studies have shown that lamivudine is phosphorylated intracellularly to its active metabolite, 5-triphosphate.

Elimination. Lamivudine is primarily eliminated unchanged by the kidneys. The intracellular half-life of lamivudine is 5–7 hours.

The elimination half-life of zidovudine is 1.1 hours, and the mean systemic clearance is 1.6 L/h/kg. Renal clearance of zidovudine is estimated at 0.34 L/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys.

Pharmacokinetics in Special Clinical Situations.

In patients with severe renal impairment, plasma concentrations of zidovudine are elevated.

In hepatic insufficiency, accumulation of zidovudine may occur due to slowed glucuronidation.

Pharmaceutical Characteristics.

Major physicochemical properties: white or almost white, film-coated tablets, capsule-shaped, with an imprint "RX923" on one side and smooth on the other.

Shelf life. 3 years.

Storage Conditions.

Store in a dry place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

60 tablets in a plastic bottle.

Prescription Category. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Address.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.