Abacavir + Zidovudine + Lamivudine (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

J05AR04 (Zidovudine, Lamivudine and abacavir)

Active Substances

Zidovudine (Rec.INN registered by WHO)

Lamivudine (Rec.INN registered by WHO)

Abacavir (Rec.INN registered by WHO)

Dosage Form

Abacavir + Zidovudine + Lamivudine

Film-coated tablets, 300 mg+300 mg+150 mg: 3, 6, 9, 10, 12, 15, 18, 20, 24, 30, 36, 40, 50, 60, or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oval, biconvex, with a score; on the cross-section of the tablets, 2 layers are visible: a core of white or white with a yellowish or brownish tint and a coating.

Excipients: microcrystalline cellulose (MCC-101) – 303.4 mg, crospovidone – 48.8 mg, povidone K25 – 36 mg, magnesium stearate – 24.4 mg, colloidal silicon dioxide – 6.1 mg.

Coating composition Opadry II 85F48105 white – 30 mg, incl.: polyvinyl alcohol – 14.07 mg, macrogol – 7.08 mg, talc – 5.22 mg, titanium dioxide – 3.63 mg.

3 pcs. – contour cell packs (1) – cardboard packs.
3 pcs. – contour cell packs (2) – cardboard packs.
3 pcs. – contour cell packs (3) – cardboard packs.
3 pcs. – contour cell packs (4) – cardboard packs.
3 pcs. – contour cell packs (5) – cardboard packs.
3 pcs. – contour cell packs (6) – cardboard packs.
3 pcs. – contour cell packs (10) – cardboard packs.
6 pcs. – contour cell packs (1) – cardboard packs.
6 pcs. – contour cell packs (2) – cardboard packs.
6 pcs. – contour cell packs (3) – cardboard packs.
6 pcs. – contour cell packs (4) – cardboard packs.
6 pcs. – contour cell packs (5) – cardboard packs.
6 pcs. – contour cell packs (6) – cardboard packs.
6 pcs. – contour cell packs (10) – cardboard packs.
10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (10) – cardboard packs.
10 pcs. – jars (1) – cardboard packs.
20 pcs. – jars (1) – cardboard packs.
30 pcs. – jars (1) – cardboard packs.
40 pcs. – jars (1) – cardboard packs.
50 pcs. – jars (1) – cardboard packs.
60 pcs. – jars (1) – cardboard packs.
100 pcs. – jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Combined antiviral agent. Abacavir, Lamivudine and Zidovudine are nucleoside reverse transcriptase inhibitors of HIV, selectively suppressing the replication of HIV-1 and HIV-2. Abacavir, Lamivudine and Zidovudine undergo sequential stages of metabolism with the participation of intracellular kinases and are converted into the corresponding 5′-triphosphates (TP). Abacavir-TP, Lamivudine-TP and Zidovudine-TP are substrates and competitive inhibitors of HIV reverse transcriptase.

The main antiviral action of the active substances is their ability to be incorporated as a monophosphate into the synthesizing HIV DNA, leading to the termination of replication. The affinity of lamivudine, abacavir and zidovudine for host cell DNA polymerases is much lower.

In HIV strains resistant to abacavir obtained in vitro, mutations were found in several codons of the reverse transcriptase (RT) gene – M184V, K65R, L74V and Y115F. HIV resistance to abacavir in vitro and in vivo develops slowly. Multiple mutations of the viral genome are required for a clinically significant increase in the inhibitory concentration for 50% of strains IC50 (8 times relative to the “wild-type” virus). Isolates resistant to abacavir may have reduced sensitivity to the action of lamivudine, zalcitabine and/or didanosine, but completely retain sensitivity to zidovudine and stavudine. The ineffectiveness of the combination of abacavir, lamivudine and zidovudine at the very beginning of treatment is usually due to only one mutation – M184V, so the use of this combination preserves the possibility of a wide choice of second-line therapy regimens.

Pharmacokinetics

When taken orally, Lamivudine, abacavir and Zidovudine are rapidly and well absorbed from the gastrointestinal tract. The absolute bioavailability of lamivudine, abacavir and zidovudine after oral administration in adults is 80-85%, 83% and 60-70%, respectively.

The V_d of lamivudine, abacavir and zidovudine after intravenous administration averages 1.3, 0.8 and 1.6 l/kg, respectively. The binding of lamivudine to the main plasma protein, albumin, is insignificant (in vitro less than 36% of serum albumin), the pharmacokinetics of lamivudine is linear. Zidovudine binds to plasma proteins by 34-38%. According to in vitro studies, abacavir at therapeutic doses binds to serum proteins by approximately 49%.

Lamivudine, abacavir and Zidovudine penetrate the blood-brain barrier and are detected in the cerebrospinal fluid (CSF). The ratio of the concentration of lamivudine and zidovudine in serum to the corresponding concentrations of the drugs in the CSF 2-4 hours after oral administration averages about 0.12 for lamivudine and 0.5 for zidovudine. According to studies in HIV-infected patients, abacavir penetrates well into the CSF, with the AUC of abacavir in the CSF being 30-44% of the AUC of abacavir in plasma. In a phase 1 clinical study of the pharmacokinetics of abacavir, it was shown that 1.5 hours after administration of abacavir at a dose of 300 mcg twice a day, its concentration in the CSF is 0.14 mcg/ml. When using abacavir at a dose of 600 mg twice a day, its concentration in the CSF increases from 0.13 mcg/ml 0.5-1 hour after its administration to 0.74 mcg/ml after 3-4 hours. Thus, even if the concentration of abacavir in the CSF 4 hours after its administration at a dose of 600 mg twice a day does not reach a maximum, it exceeds the IC50 (0.8 mcg/ml or 0.6 µmol/l) by approximately 9 times.

Abacavir is predominantly metabolized in the liver, only 2% of the administered dose is excreted unchanged by the kidneys. In humans, abacavir is metabolized mainly by alcohol dehydrogenase to form 5′-carboxylic acid and by conjugation with glucuronic acid to form 5′-glucuronide, which account for about 66% of the total amount of the drug excreted by the kidneys.

Lamivudine is excreted unchanged by renal excretion.

Zidovudine is mainly metabolized in the liver. The main metabolite of zidovudine in plasma and urine is zidovudine 5′-glucuronide, which is excreted by the kidneys and accounts for approximately 50-80% of the administered dose. Another metabolite of zidovudine upon parenteral administration is 3′-amino-3′-deoxythymidine (AMT).

The T_1/2 of lamivudine is 5-7 hours. The average systemic clearance of lamivudine is about 0.32 l/h kg, most of which is renal clearance (more than 70%), carried out through the organic cation transport system. Studies involving patients with renal failure have shown that impaired renal function affects the excretion of lamivudine.

In patients with severe renal impairment, the plasma concentration of zidovudine is increased.

The average T_1/2 of abacavir is about 1.5 hours. After repeated administration of abacavir at a dose of 300 mg orally twice a day, no significant accumulation is observed. The elimination of abacavir is carried out through metabolism in the liver followed by excretion of metabolites mainly by the kidneys. About 83% of the administered dose of abacavir is excreted by the kidneys as metabolites and unchanged, the remaining amount is excreted through the intestines.

Studies involving patients with renal failure have shown that impaired renal function affects the excretion of lamivudine due to decreased renal clearance. It has also been shown that in patients with severe renal impairment, the plasma concentration of zidovudine is increased. Abacavir is metabolized mainly in the liver, less than 2% is excreted by the kidneys unchanged. The pharmacokinetics of abacavir in patients with end-stage renal failure is similar to that in patients with normal renal function.

Abacavir is metabolized mainly in the liver. The pharmacokinetics of abacavir was studied in patients with mild hepatic impairment (5-6 points on the Child-Pugh scale). The results of the study indicate an increase in the AUC of abacavir by an average of 1.89 times and an increase in the T_1/2 of abacavir by 1.58 times. Impaired liver function does not affect the AUC value of abacavir metabolites, but the rate of their formation and excretion is reduced.

Indications

Treatment of HIV infection in adults and children over 12 years of age as part of antiretroviral therapy.

ICD codes

Dosage Regimen

For oral administration. A single dose of the combined medicinal product is taken twice a day.

If the body weight of an adolescent or adult is below 40 kg, this combination is not used, since the dose of each active substance is fixed and it is impossible to reduce the dose for each active substance separately.

In case of impaired liver and/or kidney function, dosage adjustment is required.

Adverse Reactions

Symptoms of hypersensitivity reaction (HSR)

From the hematopoietic system: lymphopenia.

From the nervous system: headache, paresthesia.

From the respiratory system: shortness of breath, cough, sore throat, respiratory distress syndrome, respiratory failure.

From the digestive system: nausea, vomiting, diarrhea, abdominal pain, mouth ulcers, increased liver function tests, liver failure.

From the urinary system: increased creatinine concentration, renal failure.

From the skin and subcutaneous tissue: rash (maculopapular or urticarial).

From the musculoskeletal system: myalgia, rarely – myolysis, arthralgia, increased CPK activity.

Other: increased body temperature, feeling of fatigue, malaise, edema, lymphadenopathy, decreased blood pressure, conjunctivitis, anaphylaxis.

If any of the listed symptoms appear, a thorough examination of the patient is necessary to exclude a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, re-prescription of the abacavir+Lamivudine+Zidovudine combination or other drugs containing abacavir is strictly contraindicated.

Definition of frequency of adverse reactions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).

Abacavir

From the immune system: common – hypersensitivity reactions.

From the nervous system: common – headache.

From the digestive system: common – anorexia, nausea, vomiting, diarrhea; rare – pancreatitis.

From the metabolism: common – hyperlactatemia; rare – lactic acidosis.

From the skin and subcutaneous tissue: common – rash (without systemic symptoms); very rare – exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Other: common – increased body temperature, apathy, feeling of fatigue.

Lamivudine

From the hematopoietic system: uncommon – neutropenia, anemia, thrombocytopenia; very rare – pure red cell aplasia.

From the metabolism: common – hyperlactatemia; rare – lactic acidosis.

From the nervous system: common – headache; very rare – paresthesia, peripheral neuropathy.

From the digestive system: common – nausea, vomiting, pain in the upper abdomen, diarrhea; uncommon – temporary increase in AST, ALT; rare – increased serum amylase activity, pancreatitis.

From the skin and subcutaneous tissue: common – rash, alopecia.

From the musculoskeletal system: common – arthralgia, muscle damage; rare – rhabdomyolysis.

Other: common – feeling of fatigue, malaise, fever.

Some patients receiving combined antiretroviral therapy have experienced redistribution/accumulation of adipose tissue in the body. The frequency of this phenomenon depends on many factors, including the combination of antiretroviral drugs.

Zidovudine

From the hematopoietic system: common – anemia (may require blood transfusion), neutropenia and leukopenia. These side effects occur more often when using zidovudine in high doses (1200-1500 mg/day), in patients with late stages of HIV infection (especially with reduced bone marrow reserve before starting treatment) and, in particular, in patients with a CD4⁺ cell count of less than 100/µl. In some patients, it is necessary to reduce the dose of zidovudine up to discontinuation. Neutropenia occurs more often in those patients who have a reduced number of neutrophils, hemoglobin level and serum vitamin B₁₂ level at the start of zidovudine treatment. Uncommon – thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rare – pure red cell aplasia; very rare – aplastic anemia.

From the metabolism: common – hyperlactatemia; rare – lactic acidosis, anorexia; redistribution/accumulation of adipose tissue (the frequency of this side effect depends on many factors, including the specific combination of antiretroviral drugs).

From the psyche: rare – anxiety and depression.

From the nervous system: very common – headache; common – dizziness; rare – insomnia, paresthesia, drowsiness, decreased mental activity, convulsions.

From the organ of vision: frequency unknown – macular edema, amblyopia, photophobia.

From the organ of hearing: vertigo, hearing loss.

From the cardiovascular system: rare – cardiomyopathy.

From the respiratory system: uncommon – shortness of breath; rare – cough.

From the digestive system: very common – nausea; common – vomiting, abdominal pain and diarrhea, increased activity of liver enzymes and bilirubin concentration; uncommon – flatulence; rare – pigmentation of the oral mucosa, dysgeusia, dyspepsia, pancreatitis, liver damage, such as severe hepatomegaly with steatosis.

From the skin and subcutaneous tissue: uncommon – rash and itching; rare – pigmentation of nails and skin, sweating.

From the musculoskeletal system: common – myalgia; uncommon – myopathy.

From the urinary system: rare – frequent urination.

From the reproductive system and mammary gland: rare – gynecomastia.

Allergic reactions: rare – urticaria.

Other: common – general malaise; uncommon – fever, generalized pain syndrome and asthenia; rare – chills, chest pain, flu-like syndrome.

Contraindications

Moderate and severe hepatic failure (class B and C according to the Child-Pugh scale); mild hepatic failure (class A according to the Child-Pugh scale); impaired renal function (CrCl <50 ml/min); pronounced decrease in neutrophil count (less than 0.75×10⁹/l) or hemoglobin concentration (less than 7.5 g/dl, or 4.65 mmol/l) due to the content of zidovudine; age under 12 years (due to the inability to adjust the dose); body weight less than 40 kg.

With caution

Bone marrow hematopoiesis suppression (with hemoglobin concentration less than 9 g/l (5.59 mmol/l) or neutrophil count in the blood less than 1.0×10⁹/l) may require adjustment of the zidovudine dose (if these adverse reactions develop, abacavir, Zidovudine and Lamivudine are used as separate drugs); pancreatitis (including in the anamnesis); hepatomegaly, hepatitis, any risk factors for liver disease; presence of risk factors for coronary artery disease; elderly patients.

Use in Pregnancy and Lactation

The safety of using this combination in women during pregnancy has not been studied to date. There are research data on the effect of abacavir, lamivudine and zidovudine on fetal development in animals. Therefore, during pregnancy, drugs containing this combination are used only if the intended benefit to the mother outweighs the risk to the fetus.

The effect of abacavir, lamivudine and zidovudine on fertility in women has not been studied to date. Regarding zidovudine, it has been shown that its use in men does not affect the number, morphology and motility of spermatozoa.

Experts do not recommend breastfeeding for HIV-infected patients to avoid transmission of HIV infection to the child. Since abacavir, its metabolites and HIV penetrate into breast milk, breastfeeding is contraindicated.

Use in Hepatic Impairment

The use of the drug is contraindicated in moderate and severe hepatic impairment.

Use in Renal Impairment

In patients with impaired renal function, the dose of lamivudine should be reduced in proportion to the decrease in CrCl. In this regard, the use of the drug is not recommended for CrCl less than 50 ml/min.

Pediatric Use

Contraindicated for use in children under 12 years of age due to the inability to adjust the dose.

Special Precautions

The use of drugs containing this combination is associated with the risk of developing a hypersensitivity reaction (HSR), characterized by the appearance of fever and/or rash and other symptoms indicating multiorgan damage. HSR can be life-threatening and in rare cases, if appropriate treatment is not provided, can lead to death. The risk of developing HSR when using this combination is significantly increased in patients with a positive test for the presence of the HLA-B*5701 allele. However, HSR to abacavir has been noted with a lower frequency in patients who are not carriers of this allele.

Before starting therapy with the combination, testing for the presence of the HLA-B*5701 allele should be performed and also before resuming therapy with this combination in patients with unknown HLA-B*5701 allele status who previously tolerated abacavir therapy well.

Use is not recommended in patients with the HLA-B*5701 allele, or in patients in whom hypersensitivity reaction was suspected during the use of any other medicinal product containing abacavir, regardless of HLA-B*5701 allele status.

In all patients receiving therapy with this combination, the clinical diagnosis of a suspected hypersensitivity reaction should remain the basis for clinical decision-making.

If a hypersensitivity reaction is suspected, therapy with this combination must be discontinued immediately even in the absence of the HLA-B*5701 allele. Delaying discontinuation of therapy with this combination after the occurrence of a hypersensitivity reaction may lead to a life-threatening situation.

Resumption of the use of medicinal products containing abacavir after a suspected abacavir hypersensitivity reaction may lead to a rapid return of symptoms within hours, which may include life-threatening arterial hypotension and death.

When considering resuming abacavir therapy after discontinuation of any product containing abacavir for any reason, the reason for discontinuing therapy must be established regardless of the patient’s carriage of the HLA-B*5701 allele. If a hypersensitivity reaction cannot be ruled out, the use of medicinal products containing this combination, as well as any other medicinal products containing abacavir, must not be resumed.

If a hypersensitivity reaction is ruled out, resumption of therapy with this combination is possible. In rare cases, patients who discontinued abacavir for reasons other than symptoms of a hypersensitivity reaction have also experienced life-threatening reactions within hours of resuming abacavir therapy. Resumption of therapy with this combination or other medicinal products containing abacavir should only be undertaken if rapid access to medical care is available.

There have been reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, due to antiretroviral therapy with nucleoside analogues as individual drugs, including abacavir, Lamivudine and Zidovudine, or their combinations. These events have been observed mainly in women.

Caution should be exercised when using this combination, especially in patients with hepatomegaly, hepatitis, or other risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C virus and patients receiving treatment with alpha-interferon and ribavirin may constitute a special risk group. The use of this combination should be suspended if clinical or laboratory signs of lactic acidosis with or without hepatitis (which include hepatomegaly and steatosis, even in the absence of a significant increase in aminotransferase activities), symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or a rapid increase in aminotransferase activity appear.

In vitro and in vivo studies have shown that nucleoside and nucleotide analogues can cause varying degrees of mitochondrial damage. Cases of mitochondrial dysfunction have been reported in HIV-negative children who were exposed to nucleoside analogues in utero and/or postnatally. The main adverse reactions were hematological disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These adverse reactions are often transient. Some late-onset neurological disorders (increased muscle tone, convulsions, behavioral disorders) have been registered. Whether these neurological disorders are transient or permanent is currently unknown. Any child, even HIV-negative, who has been exposed in utero to nucleoside and nucleotide analogues should undergo clinical and laboratory examination to rule out mitochondrial dysfunction if relevant signs or symptoms are identified. These data do not affect current national recommendations for the use of ART in pregnant women for the prevention of vertical transmission of HIV infection.

Treatment with zidovudine has been associated with loss of subcutaneous adipose tissue. The frequency and severity of lipoatrophy are related to the total exposure. Such loss of adipose tissue, which is most pronounced on the face, limbs, and buttocks, may be only partially reversible, and improvement may occur only several months after switching to a treatment regimen not containing Zidovudine. During therapy with zidovudine and other products containing Zidovudine, patients should be regularly examined for signs of lipoatrophy, and if lipoatrophy is suspected, switching to an alternative treatment regimen should be considered if possible.

Serum lipid and blood glucose concentrations may increase during antiretroviral therapy. Disease control and lifestyle changes may also contribute to this process. The need to determine serum lipid and blood glucose concentrations should be considered. Lipid metabolism disorders should be treated based on their clinical manifestations.

Hematological parameters should be carefully monitored during treatment.

If symptoms or laboratory signs of pancreatitis appear, treatment should be discontinued immediately.

In patients with pre-existing impaired liver function, including active chronic hepatitis, an increased frequency of liver function disorders has been observed with combination ART. Such patients should be monitored in accordance with standard clinical practice. If liver function worsens in such patients, the possibility of suspending or discontinuing this combination should be considered.

Patients with chronic hepatitis B or C receiving combination ART are at an increased risk of developing serious and fatal liver adverse reactions. In case of concomitant use of antiviral therapy for hepatitis B or C, the prescribing information for these medicinal products should be consulted. When discontinuing treatment in patients with concomitant viral hepatitis B, liver function tests should be monitored and viral load should be regularly determined, as a recurrence of hepatitis may occur after discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease.

Results from clinical studies and post-marketing surveillance data indicate that in some patients with chronic hepatitis B, clinical and laboratory signs of hepatitis recurrence may occur upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If this combination is discontinued in patients with concomitant viral hepatitis B, the possibility of periodic monitoring of liver function and markers of hepatitis B virus replication should be considered.

Cases of exacerbation of anemia during ribavirin administration have been reported with the use of zidovudine as part of HIV infection treatment regimens; the exact mechanism of this phenomenon remains unknown. In this regard, the concomitant use of zidovudine with ribavirin is not recommended. If Zidovudine is already included in a combined antiretroviral therapy regimen, the possibility of replacing it should be considered. This is especially important for patients with a history of zidovudine-induced anemia.

In HIV-infected patients with severe immunodeficiency who have asymptomatic opportunistic infections or their residual manifestations at the start of antiretroviral therapy, its administration may activate the inflammatory process and lead to an increase in the symptoms of opportunistic infections or other serious consequences. These reactions usually occur within the first weeks or months after starting antiretroviral therapy.

Autoimmune diseases (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have been observed in the context of immune reconstitution; however, the timing of initial manifestations varied, and the disease could occur many months after starting therapy and have an atypical course.

The use of this combination or other antiretroviral drugs does not preclude the possibility of developing opportunistic infections or other complications of HIV infection, so patients should remain under the supervision of a physician experienced in treating these diseases.

Although the etiology of osteonecrosis is multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high BMI), cases of osteonecrosis have been most frequently reported in patients with advanced HIV infection and/or those receiving long-term combination ART. Patients should consult a doctor if they experience joint pain and stiffness or difficulty moving.

Patients should be warned that treatment with antiretroviral drugs does not prevent the risk of transmitting HIV to others through sexual contact or blood contamination. Therefore, patients must take appropriate precautions.

Antiretroviral therapy including abacavir should be prescribed with caution to patients with a possible risk of coronary artery disease. All measures should be taken to minimize modifiable risk factors (such as hypertension, hyperlipidemia, diabetes mellitus, and smoking).

Patients should be cautioned against self-treatment with any drugs.

This combination should not be used with medicinal products containing Lamivudine or emtricitabine.

Concomitant use of stavudine and zidovudine should be avoided.

The use of lamivudine with cladribine is not recommended.

Drug Interactions

Drug interactions due to the presence of abacavir

The metabolism of abacavir is impaired when taken concomitantly with ethanol, leading to an increase in the AUC of abacavir by approximately 41%. Given the safety profile of abacavir, these data are not considered clinically significant. Abacavir does not affect the metabolism of ethanol.

In a pharmacokinetic study of drugs with concomitant administration of abacavir (at a dose of 600 mg twice daily) and methadone, a 35% decrease in the C_max of abacavir and a decrease in the time to reach C_max by 1 hour were observed, but the AUC remained unchanged. The changes in the pharmacokinetics of abacavir were not considered clinically significant. In this study, abacavir increased the mean total clearance of methadone by 22%. This change was not considered clinically significant in most patients, but sometimes a methadone dose adjustment may be necessary.

Drug interactions due to the presence of lamivudine

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg (co-trimoxazole) causes an increase in lamivudine exposure by 40%, which is due to the presence of trimethoprim. However, except in patients with renal failure, no dose adjustment of lamivudine is required.

Lamivudine may suppress the intracellular phosphorylation of zalcitabine when these drugs are taken concomitantly. Therefore, use in combination with zalcitabine is not recommended.

Interactions due to the presence of zidovudine

Zidovudine does not affect the pharmacokinetics of atovaquone. However, pharmacokinetic data indicate that atovaquone reduces the degree of metabolism of zidovudine to its glucuronide (at steady state, the AUC of zidovudine increases by 33%, and the C_max of the glucuronide in plasma decreases by 19%). When zidovudine is prescribed 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 adverse reactions associated with increased plasma concentrations of zidovudine is unlikely. If longer-term combined use of these drugs is necessary, careful monitoring of the patient’s clinical condition is recommended.

The absorption of zidovudine is reduced when taken concomitantly with clarithromycin in tablet form. An interval of at least 2 hours between clarithromycin and zidovudine administration should be observed.

In some patients receiving Zidovudine in combination with phenytoin, a decrease in phenytoin blood concentrations was detected, and in one case an increase in phenytoin concentration was noted. These observations indicate the need to monitor phenytoin blood concentrations in patients who are simultaneously taking the Zidovudine+Lamivudine combination and phenytoin.

According to some data, probenecid increases the mean T_1/2 and AUC of zidovudine 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.

Limited data show that with the combined use of zidovudine and rifampicin, the AUC of zidovudine decreases by 48±34%. However, the clinical significance of this observation is unknown.

Zidovudine may inhibit the intracellular phosphorylation process of stavudine when they are used concomitantly. Thus, the concomitant use of stavudine and the Zidovudine+Lamivudine combination is not recommended.

Nucleoside analogues that impair DNA replication, such as ribavirin, may in vitro reduce the antiviral activity of zidovudine. The concomitant use of such medicinal products with zidovudine is not recommended. An increase in ribavirin-induced anemia was observed when zidovudine was included in the complex therapy of HIV infection. The use of Zidovudine in combination with ribavirin is not recommended due to the increased risk of anemia.

Concomitant use of zidovudine and doxorubicin is not recommended due to mutual weakening of the activity of each of the medicinal products in vitro.

When used concomitantly with fluconazole, an increase in the AUC of zidovudine by 74% is observed due to inhibition of UDP-glucuronosyltransferase. Given the limited data, the clinical significance is unknown. Monitoring for toxic effects of zidovudine is necessary.

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

Acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex can alter the metabolism of zidovudine as a result of competitive inhibition of the glucuronidation process or direct suppression of zidovudine metabolism by hepatic microsomal enzymes. Before prescribing these drugs in combination with the Zidovudine+Lamivudine combination, especially for long-term treatment, possible drug interactions should be assessed.

Concomitant use, especially for the therapy 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, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse effects of zidovudine. When prescribing the Zidovudine+Lamivudine combination concomitantly with any of these drugs, renal function and hematological parameters should be carefully monitored and the dose of one or more drugs should be reduced if necessary.

Since some patients may develop opportunistic infections despite the use of the combination, additional therapy may be required to prevent infections. For such prophylaxis, co-trimoxazole, aerosolized pentamidine, pyrimethamine, and acyclovir are used. Limited data from clinical studies indicate no significant increase in the frequency of adverse effects of zidovudine when used concomitantly with these drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.