Lami-Zidox^® (Tablets) Instructions for Use

Marketing Authorization Holder

NANOLEK LLC (Russia)

ATC Code

J05AR01 (Zidovudine and Lamivudine)

Active Substances

Zidovudine (Rec.INN registered by WHO)

Lamivudine (Rec.INN registered by WHO)

Dosage Form

Lami-Zidox®

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

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, oval, biconvex, with an engraving “C” and “60” on one side and smooth on the other side.

Excipients: microcrystalline cellulose (Avicel PH101) – 114.5 mg, sodium carboxymethyl starch – 10 mg.

Composition of the tablet core granule coating: sodium carboxymethyl starch – 5 mg, microcrystalline cellulose (Avicel PH101) – 130 mg, colloidal silicon dioxide (Aerosil 200) – 8 mg, magnesium stearate – 7.5 mg.
Composition of the tablet coating: Opadry white 13B58802 – 15 mg (hypromellose – 59.75%, titanium dioxide – 31.25%, macrogol – 8%, polysorbate 80 – 1%).

60 pcs. – polyethylene jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

A combined antiviral drug containing Lamivudine and Zidovudine, which are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. 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.

HIV-1 resistance to lamivudine is caused by a mutation in codon 184 (M184V), located near the active site of HIV reverse transcriptase. These viral variants occur both in vitro and in HIV-1-infected patients receiving antiretroviral therapy regimens including Lamivudine.

Viral strains with the M184V mutation show a significant decrease in sensitivity to lamivudine and have lower replicative activity in vitro. In vitro studies have shown that Zidovudine-resistant virus isolates can regain sensitivity to zidovudine if resistance to lamivudine develops simultaneously. The clinical significance of this phenomenon is unclear.

Mutations at the M184V site lead to HIV cross-resistance only to drugs from the nucleoside reverse transcriptase inhibitor group. Zidovudine and stavudine remain active against Lamivudine-resistant HIV-1 strains. Abacavir retains antiretroviral activity against Lamivudine-resistant HIV-1 strains with only the M184V mutation. Strains of HIV with M184V mutations show no more than a 4-fold decrease in sensitivity to didanosine and zalcitabine; the clinical significance of this phenomenon has not been established.

Resistance to thymidine analogues (such as Zidovudine) is well studied and occurs as a result of the gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. Viruses acquire phenotypic resistance to thymidine analogues as a result of combined mutations at codons 41 and 215 or the accumulation of at least four of the six mutations. These thymidine analogue resistance mutations themselves do not cause high cross-resistance to other nucleoside analogues, allowing for the subsequent use of other approved reverse transcriptase inhibitors.

Two types of mutations lead to the development of multidrug resistance.

In one case, mutations occur at positions 62, 75, 77, 116 and 151 of HIV reverse transcriptase, and in the second case, it is the T69S mutation with an insertion of six base pairs at this position, which is accompanied by the appearance of phenotypic resistance to zidovudine, as well as to other nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit therapeutic options for HIV infection.

In clinical studies, the use of the combination of lamivudine and zidovudine led to a decrease in HIV-1 viral load and an increase in CD4⁺ cell count. Clinical data indicate that the use of the combination of lamivudine and zidovudine or the 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.

Tests for HIV sensitivity to drugs in vitro have not been standardized, so their results can be influenced by various methodological factors. Currently, the relationship between in vitro sensitivity to lamivudine and/or zidovudine and the clinical effect of therapy has not been studied.

Lamivudine and Zidovudine are widely used as components of combined antiretroviral therapy along with other antiretroviral drugs of the same class or other classes (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors and fusion inhibitors).

Combined antiretroviral therapy regimens including Lamivudine are effective in treating patients who have not previously received antiretroviral drugs and patients from whom HIV strains with the M184V mutation have been isolated.

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). In case of high risk of infection, a drug from the protease inhibitor group should be included in the antiretroviral therapy regimen. Prophylactic treatment is recommended for 4 weeks. Data on the effectiveness of prophylactic treatment after accidental HIV infection are insufficient; no controlled studies have been conducted. Despite the rapid initiation of treatment with antiretroviral drugs, the possibility of seroconversion cannot be ruled out.

Pharmacokinetics

Administration of the combined Lamivudine/Zidovudine drug is equivalent to taking lamivudine and zidovudine separately on an empty stomach.

Lamivudine and Zidovudine are well absorbed from the gastrointestinal tract. In adults after oral administration, the bioavailability of lamivudine is 80-85%, and that of zidovudine is 60-70%.

After oral administration of the Lamivudine/Zidovudine combination, C_max of lamivudine and zidovudine were noted at 0.75 (0.5-2) h and 0.5 (0.25-2) h and amounted to 1.5 (1.3-1.8) mg/ml and 1.8 (1.5-2.2) mg/ml, respectively. The extent of absorption of lamivudine and zidovudine (based on AUC value) and T_1/2 after food intake were similar to the values after fasting, although the rate of absorption was somewhat slowed.

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

With IV administration, the mean V_d for lamivudine and zidovudine is 1.3 and 1.6 l/kg, respectively. Lamivudine has linear pharmacokinetics when used at therapeutic doses and is limitedly bound to plasma albumin (less than 36% of serum albumin in vitro). Zidovudine is bound to plasma proteins by 34-38%. Thus, interaction of lamivudine and zidovudine with other drugs through displacement from protein binding sites is unlikely.

Lamivudine and Zidovudine have been shown to penetrate the CNS and cerebrospinal fluid. At 2-4 hours after oral administration, the ratio between the concentration of lamivudine and zidovudine in the CSF and in the blood serum averages 0.12 and 0.5, respectively.

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

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

T_1/2 of lamivudine is 5-7 h. The systemic clearance of lamivudine is approximately 0.32 l/h×kg, with renal clearance accounting for more than 70% involving the cationic transport system.

With IV administration of zidovudine, the mean T_1/2 is 1.1 h, and the mean systemic clearance is 1.6 l/h×kg. The renal clearance of zidovudine is 0.34 l/h×kg via glomerular filtration and active tubular secretion.

Pharmacokinetics in special clinical cases

In children over 5-6 months of age, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine is well absorbed from the intestine after drug administration at all studied doses in adults and children; its bioavailability is 60-74%, on average 65%. C_max is 4.45 µM (1.19 µg/ml) after taking 120 mg/m² of zidovudine in solution form and 7.7 µM (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 h×µg/ml) as taking 200 mg 6 times/day in adults (AUC₂₄ 10.9 h×µg/ml).

A study in six HIV-infected children aged 2 to 13 years evaluated the pharmacokinetics of zidovudine after taking 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, the 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 taking this dose, AUC_0-12 reaches 3800-5300 ng×h/ml. Recent data indicate that exposure in children aged 2 to 6 years may be reduced by 30% compared to other age groups.

Due to reduced renal clearance, the elimination of lamivudine is impaired in renal failure. A dose reduction of lamivudine is recommended in patients with CC less than 50 ml/min. The plasma concentration of zidovudine also increases in patients with severe renal failure.

Reduced glucuronidation in patients with impaired liver function due to liver cirrhosis may lead to accumulation of zidovudine. Dose adjustment is required in patients with severe hepatic insufficiency.

Indications

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

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals.

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

Treatment with the drug should be carried out by a physician experienced in the therapy of HIV infection.

The recommended dose of the drug for adults and adolescents weighing at least 30 kg is 1 tab. 2 times/day; for children weighing from 21 to 30 kg – 0.5 tab. in the morning plus 1 tab. in the evening; for children weighing from 14 to 21 kg – 1/2 tab. 2 times/day.

For children weighing less than 14 kg, as well as in cases where it is necessary to reduce the dose of the drug or discontinue one of its components (Lamivudine or Zidovudine), separate preparations of lamivudine and zidovudine should be used.

Since patients with impaired renal function (CC less than 50 ml/min) require individual dose selection of lamivudine and zidovudine, it is recommended to prescribe them separate preparations of lamivudine and zidovudine.

In patients with severe hepatic impairment, it is recommended to use separate preparations of lamivudine and zidovudine. In patients with mild to moderate hepatic impairment, the drug should be used with caution.

If hemoglobin decreases to less than 9 g/dl (5.59 mmol/l) or neutropenia (neutrophil count less than 1.0×10⁹/l), adjustment of the zidovudine dose may be required. When using the combined drug, it is impossible to individually select doses of lamivudine and zidovudine; it is recommended to use separate preparations of lamivudine and zidovudine.

Adverse Reactions

Treatment of HIV infection with lamivudine and zidovudine as monotherapy or as a 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 underlying disease. The drug contains Lamivudine and Zidovudine, so it can cause side effects characteristic of each of these components.

Definition of frequency of adverse reactions: 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 (<1/10,000, including isolated cases).

Lamivudine

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

Allergic reactions rare – angioedema.

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

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

From the respiratory system common – cough.

From the digestive system: common – nausea, vomiting, epigastric pain, diarrhea; uncommon – transient increase in liver enzyme activity (ALT, AST); rare – pancreatitis, increased serum amylase activity, hepatitis.

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

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

Other: common – fatigue, malaise, fever.

Zidovudine

From the hematopoietic system common – anemia (may require blood transfusion), neutropenia and leukopenia. These side effects occur more often when zidovudine is used in high doses (1200-1500 mg/day), in patients with advanced 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 whose neutrophil count, hemoglobin level and serum vitamin B₁₂ level are reduced at the start of zidovudine treatment. Uncommon – thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rare – pure red cell aplasia; very rare – aplastic anemia.

From 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 acuity, 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 – dyspnea; rare – cough.

From the digestive system very common – nausea; common – vomiting, abdominal pain and diarrhea, increased liver enzyme activity 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 rarely – urticaria.

Other frequently – general malaise; infrequently – fever, generalized pain syndrome and asthenia; rarely – chills, chest pain, flu-like syndrome.

Contraindications

Severe neutropenia (neutrophil count less than 0.75×10⁹/L) or anemia (hemoglobin less than 75 g/L or 4.65 mmol/L); hypersensitivity to lamivudine, zidovudine or any other component of the drug.

Use in Pregnancy and Lactation

The drug is not recommended during the first 3 months of pregnancy, except in cases where the intended 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 fetus. No such data are available for lamivudine. Therefore, the drug should be prescribed to pregnant women only in cases where the expected benefit to the mother outweighs the possible risk to the fetus.

Newborns and infants exposed to nucleoside reverse transcriptase inhibitors during maternal pregnancy or childbirth have shown a slight transient increase in blood lactate concentration. There are also rare reports of cases of developmental delay, seizures and other neurological pathology.

In general, for children whose mothers took nucleoside reverse transcriptase inhibitors during pregnancy, the benefit of reducing the risk of vertical HIV transmission clearly outweighs the danger associated with the side effects of these drugs.

HIV-infected mothers are not recommended to breastfeed in order to prevent vertical transmission of HIV. Since Lamivudine, Zidovudine and HIV penetrate into breast milk, breastfeeding is prohibited.

Use in Hepatic Impairment

In patients with severe hepatic impairment, it is recommended to use separate preparations of lamivudine and zidovudine. In patients with mild to moderate hepatic impairment, the drug should be used with caution.

Use in Renal Impairment

Since patients with impaired renal function (CrCl less than 50 ml/min) require individual dose adjustment of lamivudine and zidovudine, it is recommended to prescribe them separate preparations of lamivudine and zidovudine.

Pediatric Use

Children weighing less than 14 kg should use separate preparations of lamivudine and zidovudine.

Special Precautions

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

Despite taking the Zidovudine+Lamivudine combination or any other antiretroviral drug, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should be under constant supervision of a physician experienced in the treatment of HIV infection.

Patients should be informed that treatment with antiretroviral drugs, including the Zidovudine+Lamivudine combination, does not prevent the risk of transmitting HIV to others through sexual contact or transfusion of infected blood, so patients should take appropriate precautions.

Patients should be warned about the possible interaction of the drug with other drugs when taken concomitantly.

In patients receiving Zidovudine, anemia, neutropenia and leukopenia (usually secondary to neutropenia) may develop. These phenomena are more often observed when zidovudine is prescribed in high doses (1200-1500 mg/day) in patients with late stages of HIV infection with reduced bone marrow reserve before starting treatment. Therefore, careful monitoring of hematological parameters is necessary during treatment with the drug. These hematological changes usually appear no earlier than 4-6 weeks after the start of therapy.

In patients with late-stage clinically pronounced HIV infection, blood counts are recommended to be monitored at least once every 2 weeks for the first 3 months of therapy, and then at least once a month. In patients with early-stage HIV infection, side effects from the blood system are rare. In this situation, a complete blood count can be done less frequently, guided by the general condition of the patients, for example, once every 1-3 months. Special dose adjustment of zidovudine may be required in case of severe anemia or myelosuppression during treatment with the drug, 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/L. Since it is impossible to individually adjust the dose of the drug, it is recommended to use separate preparations of lamivudine and zidovudine.

If clinical symptoms or laboratory data appear indicating the development of pancreatitis (abdominal pain, nausea, vomiting, or increased activity of biochemical markers), treatment with the drug should be stopped immediately.

Nucleoside analogues should be used with caution in all patients (especially obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain drugs and ethanol). Patients with hepatitis C co-infection receiving therapy with interferon alfa and ribavirin are at increased risk. The use of nucleoside analogues should be discontinued if clinical or laboratory signs of lactic acidosis or hepatotoxicity (including hepatomegaly and steatosis, even in the absence of a significant increase in aminotransferase activity) appear.

Some patients receiving combined antiretroviral therapy experience redistribution/accumulation of adipose tissue, including central obesity, dorsocervical fat deposition (“buffalo hump”), reduction of subcutaneous fat on the face and extremities, breast enlargement, and increased serum lipid and blood glucose concentrations. These symptoms may be observed in patients together or separately. Although one or more of the above side effects, associated with a general syndrome often referred to as lipodystrophy, can be caused by all drugs belonging to protease inhibitors and nucleoside reverse transcriptase inhibitors, data indicate that there are differences between individual representatives of these classes of drugs in their ability to cause these side effects. It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, older age and the duration of antiretroviral therapy play an important, possibly synergistic role. The long-term consequences of these side effects are currently unknown. Clinical examination of patients should include an assessment of physical signs of adipose tissue redistribution. Serum lipid and blood glucose concentrations should be determined. Lipid metabolism disorders should be treated based on their clinical manifestations.

When using the Zidovudine+Lamivudine combination and other antiretroviral therapy, the possibility of developing opportunistic infections remains. Therefore, patients should be under the supervision of an HIV infection treatment specialist. At the start of antiretroviral treatment of HIV-infected patients with severe immunodeficiency, an exacerbation of the inflammatory process against the background of asymptomatic or residual opportunistic infection is possible, which may cause a serious deterioration in condition or worsening of symptoms. Such reactions are usually observed within the first weeks or months after the start of antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and/or focal infection caused by mycobacteria, and Pneumocystis pneumonia. The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

In the context of immune reconstitution syndrome, the formation of autoimmune diseases (Graves’ disease, polymyositis, Guillain-Barré syndrome) is also possible. The time of initial manifestations varied, and the disease could occur many months after the start of therapy and have an atypical course. In case of muscle weakness, trembling, tremor, hyperactivity, patients are recommended to immediately notify their doctor.

The drug should be used with caution in patients with decompensated liver cirrhosis due to chronic hepatitis B, since in rare cases, exacerbation of hepatitis is possible upon discontinuation of lamivudine. Monitoring of liver function and markers of hepatitis B virus replication should be carried out for 4 months after discontinuation of the drug.

The risk of serious, including fatal, liver complications is increased in patients with hepatitis B or C. Patients with pre-existing liver disease, including chronic active hepatitis, have an increased risk of liver dysfunction during combined antiretroviral therapy and require monitoring in accordance with accepted standards. In case of obvious worsening of liver disease in this group of patients, a decision should be made to interrupt or discontinue therapy.

Worsening of anemia has been observed with concomitant use of ribavirin and zidovudine, although the mechanism of this phenomenon remains unclear. Thus, concomitant use of ribavirin and zidovudine is not recommended, especially in patients with a history of Zidovudine-induced anemia. In these cases, it is recommended to consider the possibility of changing the antiretroviral regimen in order to discontinue zidovudine.

The development of osteonecrosis is due to the action of multiple factors (including taking corticosteroids, alcohol abuse, severe immunosuppression, high BMI), in particular, cases of osteonecrosis have been registered in patients with late stages of HIV and/or long-term combined antiretroviral therapy. This category of patients should be advised to consult a specialist if joint pain, stiffness and limited joint mobility appear.

Nucleotide and nucleoside analogues have the ability to cause mitochondrial damage in vitro and in vivo. There is evidence of the development of mitochondrial dysfunctions in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally. The following adverse events have been recorded: hematological disorders – anemia, neutropenia; metabolic disorders – increased lactate and lipase concentrations. These phenomena were mainly transient. Long-term neurological manifestations (hypertonia, convulsive syndrome, behavioral disorders) were noted. It is currently unknown whether neurological disorders are permanent or transient. Children exposed to nucleotide and nucleoside analogues in utero, in cases of manifestation of corresponding symptoms, need clinical observation and examination to diagnose mitochondrial dysfunction.

Effect on ability to drive vehicles and mechanisms

No special studies have been conducted on the effect of lamivudine and zidovudine on the ability to drive a car and work with machinery. The pharmacological properties of these drugs indicate a low likelihood of such an effect. The clinical condition of the patient, as well as the nature of the side effects of lamivudine and zidovudine, should be taken into account.

Drug Interactions

Since the drug contains Lamivudine and Zidovudine, it can enter into any interaction characteristic of each of its components. The likelihood of metabolic interaction with lamivudine is low, since only a small part of the administered drug is metabolized and binds to plasma proteins, and the drug is almost completely excreted by the kidneys unchanged. Zidovudine also binds to plasma proteins to a small extent, but is eliminated primarily through hepatic metabolism to an inactive glucuronide. Drugs with predominant hepatic metabolism, especially through glucuronidation, may potentially inhibit the metabolism of zidovudine.

Concomitant administration of zidovudine and lamivudine leads to a 13% increase in the exposure time of zidovudine and a 28% increase in its C_max in plasma. However, the total exposure of zidovudine (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Interaction due to the presence of lamivudine

Lamivudine is primarily excreted via the organic cation transport system; accordingly, the possibility of interaction of the Zidovudine+Lamivudine combination with drugs that have the same excretion pathway should be kept in mind.

Concomitant administration of lamivudine and trimethoprim (one of the components of the drug co-trimoxazole) leads to a 40% increase in the plasma concentration of lamivudine when this drug is taken in therapeutic doses. However, patients with normal renal function do not require individual dose adjustment of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Caution should be exercised when co-administering co-trimoxazole and the Zidovudine+Lamivudine combination in patients with renal failure. Concomitant use of lamivudine and high-dose co-trimoxazole for the treatment of Pneumocystis pneumonia and toxoplasmosis has not been studied and should be avoided.

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

Due to the similarity of lamivudine to emtricitabine, the use of this combination of drugs for the treatment of HIV infection is not recommended.

Clinically significant interaction with ranitidine is unlikely. Ranitidine is only partially excreted by the renal organic cation transport system. Dose adjustment of the drugs is not required.

In vitro, Lamivudine inhibits the process of intracellular phosphorylation of cladribine, thus, there is a risk of reduced efficacy of cladribine when used concomitantly with lamivudine in clinical practice. Some clinical findings also confirm the possibility of interaction between lamivudine and cladribine. Concomitant use of lamivudine and cladribine is not recommended.

Interaction 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%, the C_max of the glucuronide in plasma 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. If longer concomitant 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 taking clarithromycin and zidovudine 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 average T_1/2 of zidovudine and AUC as a result of inhibition of glucuronide formation. In the presence of probenecid, the renal excretion of the glucuronide and possibly zidovudine itself is reduced.

Limited data show that when zidovudine and rifampicin are taken together, the AUC of zidovudine decreases by 48±34%. However, the clinical significance of this observation is unknown.

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

Nucleoside analogues that disrupt DNA replication, such as ribavirin, may in vitro reduce the antiviral activity of zidovudine. Concomitant use of such drugs 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 developing anemia.

Concomitant use of zidovudine and doxorubicin is not recommended due to mutual weakening of the activity of each of the drugs 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 side effects of zidovudine. When prescribing the Zidovudine+Lamivudine combination and any of these drugs concomitantly, renal function and hematological parameters should be carefully monitored and, if necessary, the dose of one or more drugs should be reduced.

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

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.