Dizaverox^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AR01 (Zidovudine and Lamivudine)

Active Substances

Zidovudine (Rec.INN registered by WHO)

Lamivudine (Rec.INN registered by WHO)

Dosage Form

Dizaverox®

Film-coated tablets, 300 mg+150 mg: 20, 30, 60, or 100 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
60 pcs. – jars (1) – cardboard packs.
10 pcs. – blister packs (10) – cardboard packs.
100 pcs. – jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; combinations of antiviral agents for the treatment of HIV infections

Pharmacological Action

Antiviral combination drug. Lamivudine and Zidovudine are highly effective selective inhibitors of HIV-1 and HIV-2. Lamivudine is a synergist of zidovudine in inhibiting HIV replication. Both components of the drug are sequentially metabolized by intracellular kinases to triphosphate derivatives. Lamivudine triphosphate and zidovudine triphosphate are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of lamivudine and zidovudine is mainly due to the incorporation of their monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine and zidovudine triphosphates have significantly less affinity for human cell DNA polymerases.

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

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

Pharmacokinetics

Well absorbed from the gastrointestinal tract (in adults, the bioavailability of lamivudine is 80-85%, zidovudine is 60-70%). Both components of the drug are weakly bound to plasma proteins. They penetrate the central nervous system and cerebrospinal fluid. Lamivudine is excreted from the body mainly by the kidneys unchanged. T_1/2 is 5-7 hours. Zidovudine is metabolized in the liver, where it undergoes conjugation with glucuronic acid. It is excreted by the kidneys mainly as a glucuronide. The T_1/2 of zidovudine is about 1 hour.

Special patient groups

Elderly patients: pharmacokinetics have not been studied in patients over 65 years of age.

Children: in children older than 5-6 months, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine is well absorbed from the intestine after administration at all studied doses in adults and children; its bioavailability is 64-70%, on average 65%. The maximum steady-state concentration is 4.45 µM (1.19 µg/ml) after administration of 120 mg/m² zidovudine as a solution and 7.7 µM (2.06 µg/ml) after a dose of 180 mg/m². A dose of 180 mg/m² four times a day leads to the same systemic exposure in children (area under the concentration-time curve from 0 to 24 hours after drug administration (AUC₂₄) is 10.7×µg/ml) as a dose of 200 mg six times a day in adults (AUC₂₄ 10.9×µg/ml).

In general, the pharmacokinetics of lamivudine in children are similar to those in adult patients. However, the absolute bioavailability (approximately 55-56%) 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 adult levels by 12 years of age. Taking these differences into account, the recommended dose of lamivudine in children (aged 3 months to 12 years with a body weight of 6 kg to 40 kg) is 8 mg/kg/day. After administration of this dose, AUC_0-12 reaches 3800-5300 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.

Patients with impaired renal function: due to reduced renal clearance, the elimination of lamivudine is impaired in renal failure. Dose reduction of lamivudine is recommended in patients with a creatinine clearance of 50 ml/min. Plasma concentrations of zidovudine are also increased in patients with severe renal impairment.

Hepatic impairment: 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 renal impairment.

Pregnancy: Pregnancy does not affect the pharmacokinetics of lamivudine and zidovudine. Lamivudine and Zidovudine are detected in the child’s serum at birth in the same concentrations as in the maternal serum and umbilical cord blood at delivery, confirming the theory of passive passage through the hematoplacental barrier.

Indications

• HIV infection in children over 12 years of age and adults with progressive immunodeficiency (CD4+ cell count less than 500/µl).

ICD codes

Dosage Regimen

Orally, regardless of food intake, for adults and children over 12 years of age and weighing at least 30 kg, 1 tablet twice a day.

In chronic renal failure (with CC less than 50 ml/min), hepatic impairment, with hemoglobin concentration less than 9 g/dl or 5.59 mmol/l, neutropenia below 1,000/µl, it is necessary to use Lamivudine and Zidovudine as separate drugs in order to individually select the dose of lamivudine and zidovudine.

Children weighing less than 30 kg: separate preparations of lamivudine and zidovudine should be used.

Elderly patients: there are no specific data on the use of the drug Dizaverox^® in the elderly. However, when treating elderly patients, special caution is recommended, taking into account age-related changes, such as changes in hematological parameters and impaired renal function.

Adverse Reactions

The adverse reactions described below have been observed during the treatment of HIV infection with lamivudine and zidovudine as monotherapy or in combination. For many adverse reactions, it is unclear whether they are caused by lamivudine, zidovudine, the wide range of other drugs used to treat HIV infection, or are complications of HIV infection itself. The drug Dizaverox^® contains Lamivudine and Zidovudine, and therefore it can cause side effects characteristic of each of these components. There are currently no data indicating that the combination of lamivudine and zidovudine has additive toxicity.

The following classification of adverse reactions by frequency of occurrence is used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10000, including isolated cases).

Lamivudine

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

Metabolism and nutrition disorders: common – hyperlactatemia; rare – lactic acidosis.

Nervous system disorders: common – headache; rare – paresthesia, peripheral neuropathy.

Gastrointestinal disorders: common – nausea, vomiting, epigastric pain, diarrhea; rare – pancreatitis, increased serum amylase activity.

Hepatobiliary disorders: uncommon – transient increase in liver enzyme activity (ALT, AST); rare – hepatitis.

Skin and subcutaneous tissue disorders: rash, alopecia.

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

General disorders: fatigue, fever, malaise, redistribution/accumulation of adipose tissue.

Zidovudine

Blood and lymphatic system disorders: common – anemia (may require blood transfusion), neutropenia and leukopenia; uncommon – thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rare – pure red cell aplasia; very rare – aplastic anemia.

Metabolism and nutrition disorders: common – hyperlactatemia; rare – lactic acidosis, anorexia.

Psychiatric disorders: rare – anxiety, depression.

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

Cardiac disorders: rare – cardiomyopathy.

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

Gastrointestinal disorders: common – nausea, vomiting, stomach pain, diarrhea; uncommon – flatulence; rare – pigmentation of the oral mucosa, taste perversion, dyspepsia, pancreatitis.

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

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

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

Renal and urinary disorders: rare – frequent urination.

Reproductive system and breast disorders: rare – gynecomastia.

General disorders: malaise, fever, generalized pain syndrome and asthenia, chills, chest pain and flu-like syndrome, redistribution/accumulation of adipose tissue.

Contraindications

• Hypersensitivity to zidovudine and lamivudine and other components of the drug;
• Neutrophil count (less than 750/µl);
• Anemia (hemoglobin less than 7.5 g/dl or 4.65 mmol/l);
• Children under 12 years of age and body weight less than 30 kg;
• Lactation period.

With caution

Hepatomegaly, hepatitis, liver cirrhosis, obesity, risk factors predisposing to liver damage.

Use in Pregnancy and Lactation

Dizaverox^® can be prescribed to pregnant women only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Women taking the drug are not recommended to breastfeed.

Use in Hepatic Impairment

In case of hepatic impairment, it is necessary to use Lamivudine and Zidovudine as separate drugs in order to individually select the dose of lamivudine and zidovudine.

Use in Renal Impairment

In chronic renal failure (with CC less than 50 ml/min), it is necessary to use Lamivudine and Zidovudine as separate drugs in order to individually select the dose of lamivudine and zidovudine.

Pediatric Use

The drug is contraindicated in children under 12 years of age and weighing less than 30 kg.

Geriatric Use

There are no specific data on the use of the drug Dizaverox^® in the elderly. However, when treating elderly patients, special caution is recommended, taking into account age-related changes, such as changes in hematological parameters and impaired renal function.

Special Precautions

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

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

Patients should be informed that treatment with antiretroviral drugs, such as Dizaverox^®, reduces 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 Dizaverox^® with other drugs when taken concomitantly.

Hematological disorders

Anemia, neutropenia and leukopenia (the latter is usually secondary to neutropenia) may develop in patients receiving Zidovudine. These phenomena are more often observed when prescribing high doses of zidovudine (1200-1500 mg/day) in patients with late stages of HIV infection with reduced bone marrow reserve before starting treatment. Therefore, patients receiving Dizaverox^® should be carefully monitored for hematological parameters. These hematological changes usually appear no earlier than 4-6 weeks after the start of therapy. In patients with late-stage clinically significant HIV infection, blood tests are recommended to be monitored at least once every 2 weeks for the first three months of therapy, and then at least once a month.

In patients with early-stage HIV infection, side effects from the blood system are rare. Blood tests can be done less frequently, depending on the general condition of the patients, for example, once every 1-3 months. Special selection of zidovudine may be required in case of severe anemia or myelosuppression during treatment with Dizaverox^®, as well as in patients with pre-existing bone marrow suppression, for example, with a hemoglobin concentration of less than 9 g/dl (5.59 mmol/l) or a neutrophil count of less than 1.0 × 10%. Since it is impossible to individually select the dose of Dizaverox^®, it is recommended to use separate preparations of lamivudine and zidovudine.

Pancreatitis

Cases of pancreatitis have been described in patients taking Lamivudine and Zidovudine. However, it has not been established whether this complication is caused by the drugs or the underlying disease – HIV infection. Treatment with Dizaverox^® should be discontinued immediately if clinical symptoms or laboratory data appear indicating the development of pancreatitis (abdominal pain, nausea, vomiting, or increased biochemical markers).

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (for example, taking glucocorticosteroids, alcohol consumption, severe immunosuppression, increased body mass index play an important role in the development of this complication), such cases have been reported, especially in patients with advanced HIV infection and/or those receiving long-term antiretroviral therapy. Patients should consult their doctor if symptoms such as lethargy, stiffness, joint pain, or difficulty moving occur.

Lactic acidosis/severe hepatomegaly with steatosis

Rare but potentially fatal cases of lactic acidosis and severe hepatomegaly with fatty liver have been reported in patients taking antiretroviral nucleoside analogues as monotherapy or in combination, including Lamivudine and Zidovudine. Most cases were reported in women.

Clinical symptoms of lactic acidosis include general weakness, loss of appetite and sudden unexplained weight loss, gastrointestinal and respiratory disorders (shortness of breath and tachypnea).

Dizaverox^® should be used with caution in patients with risk factors for liver damage. The drug should be discontinued in patients with clinical and laboratory symptoms of lactic acidosis or hepatotoxicity (including hepatomegaly and steatosis even in the absence of increased transaminase activity).

Redistribution of adipose tissue

Some patients receiving combined antiretroviral therapy experience redistribution/accumulation of adipose tissue, including central obesity, dorsocervical fat accumulation (“buffalo hump”), peripheral and facial wasting, breast enlargement, and increased serum lipid and glucose levels. These symptoms may occur together or separately in patients.

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 in the protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor (NRTI) classes, data suggest that there are differences between individual representatives of these drug classes in their ability to cause side effects.

It should also be noted that the 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 glucose levels should be determined. Lipid metabolism disorders should be treated according to their clinical manifestations.

Mitochondrial dysfunction

In vitro and in vivo, nucleotide and nucleoside analogues have been shown to cause mitochondrial damage of varying degrees. There are reports of mitochondrial dysfunction in HIV-negative children exposed to nucleoside analogues in utero or immediately after birth. The main manifestations of mitochondrial dysfunction, often transient, were anemia, neutropenia, hyperlactatemia and increased plasma lipase activity. Later manifestations of this disorder have also been noted: muscle hypertonia, convulsions, and behavioral abnormalities.

Immune reconstitution syndrome

At the beginning of treatment with antiretroviral drugs in HIV-infected patients with severe immunodeficiency, an exacerbation of the inflammatory process against the background of asymptomatic or residual opportunistic infection may occur, which can lead to a serious deterioration in condition or worsening of symptoms. Such reactions are usually observed within the first weeks or months after starting antiretroviral therapy. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection, and Pneumocystis pneumonia. Any symptoms of inflammation should be identified immediately and treatment initiated if necessary. Autoimmune diseases (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have been observed in the context of immune reconstitution, but the time of initial manifestations varied, and the disease could occur many months after the start of therapy and have an atypical course.

Patients with liver disease

In patients with previously identified liver diseases (including chronic hepatitis), the frequency of liver function disorders increases when using combined antiretroviral therapy. Dizaverox^® should be used with caution in this category of patients. Patients should be carefully monitored; if signs of worsening liver function appear, the possibility of discontinuing therapy should be considered.

Patients with chronic hepatitis B or C

The risk of hepatotoxic effects of antiretroviral drugs in patients co-infected with HIV and hepatitis B or C virus is higher than in the presence of HIV infection alone. Therefore, patients with chronic hepatitis B or C who are simultaneously taking antiretroviral drugs are at an increased risk of adverse effects on the liver with a possible fatal outcome. Such patients should be closely monitored, both clinically and laboratory.

Concomitant viral hepatitis B

Dizaverox^® should be used with caution in patients co-infected with HIV and hepatitis B virus, since after discontinuation of lamivudine therapy, clinical or laboratory signs of hepatitis exacerbation may appear, which can have serious consequences in case of liver function decompensation. After completion of therapy with Dizaverox^® in patients infected with HIV and hepatitis B virus, it is necessary to monitor biochemical parameters of liver function and markers of hepatitis B virus replication.

Concomitant viral hepatitis C

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

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 operate machinery. The pharmacological properties of these drugs indicate a low probability 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.

Overdose

Symptoms no specific dose-dependent symptoms have been identified in acute overdose of lamivudine or zidovudine other than those listed in the Side Effects section.

Treatment monitoring of the patient’s condition and standard supportive therapy, continuous hemodialysis are recommended.

Drug Interactions

Since Dizaverox^® contains Lamivudine and Zidovudine, it can enter into any interactions characteristic of each of the components. The likelihood of metabolic interactions with lamivudine is low, since only a small part of the administered drug is metabolized and binds to plasma proteins, and the drug is almost completely excreted 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, can potentially inhibit the metabolism of zidovudine. Below are some drugs representing classes of drugs that should be used with caution during therapy with Dizaverox^®.

Interactions involving lamivudine

Lamivudine is primarily excreted via the cationic transport system; accordingly, the possibility of interaction of Dizaverox^® with drugs that have the same excretion pathway should be kept in mind.

Trimethoprim/sulfamethoxazole simultaneous administration of lamivudine and the combination of trimethoprim and sulfamethoxazole (160 mg+800 mg, co-trimoxazole) leads to a 40% increase in lamivudine plasma concentration when this drug is taken at therapeutic doses. However, patients with normal renal function do not require lamivudine dose adjustment. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Caution should be exercised when co-administering co-trimoxazole and Dizaverox^® in patients with renal failure. The effect of co-administration of lamivudine and high doses of co-trimoxazole for the treatment of pneumocystis pneumonia and toxoplasmosis has not been studied. Zalcitabine: Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when taken simultaneously. Thus, the use of Dizaverox^® in combination with zalcitabine is not recommended.

Interactions involving zidovudine

AtovaquoneZidovudine 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 maximum plasma concentration of the glucuronide decreases by 19%). When prescribing zidovudine at doses of 500-600 mg/day and a concomitant 3-week course of treatment for acute pneumocystis pneumonia with atovaquone, an increase in the frequency of side effects associated with increased plasma concentrations of zidovudine is unlikely. If longer combined use of these drugs is necessary, careful monitoring of the patient’s clinical condition is recommended.

Clarithromycin the absorption of zidovudine is reduced when taken simultaneously with clarithromycin tablets. The interval between taking zidovudine and clarithromycin should be at least 2 hours.

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

Phenytoin 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 Dizaverox^® and phenytoin.

Probenecid according to some data, probenecid increases the average half-life 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.

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

StavudineZidovudine may inhibit the process of intracellular phosphorylation of stavudine when taken simultaneously. Thus, the combined use of stavudine and Dizaverox^® is not recommended.

Other drugs acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex may alter the metabolism of zidovudine as a result of competitive inhibition of the formation of its glucuronide. Before prescribing these drugs in combination with Dizaverox^®, especially for long-term treatment, possible drug interactions should be assessed.

Combination with nephrotoxic and myelosuppressive drugs (pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the likelihood of zidovudine side effects. When prescribing Dizaverox^® simultaneously with any of these drugs, renal function and hematological parameters should be carefully monitored and, if necessary, the dose of one or more drugs should be reduced.

Ribavirin blocks the antiviral activity of zidovudine.

Co-trimoxazole, aerosolized pentamidine, pyrimethamine, and acyclovir are used for the prevention of opportunistic infections. Limited clinical trial data indicate no significant increase in the frequency of zidovudine side effects when used simultaneously with these drugs.

Storage Conditions

Store in the original manufacturer’s packaging at a temperature not exceeding 25°C (77°F), in a place inaccessible to children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

By prescription.

Important Safety Information

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