Zovilam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOVILAM (ZOVILAM)

Composition:

Active substances: lamivudine, zidovudine;

One tablet contains 150 mg of lamivudine and 300 mg of zidovudine;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, film coating: "Opadry White" 03H58736 (hypromellose, titanium dioxide (E 171), propylene glycol, purified water).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white capsule-shaped tablets, film-coated, with a break line on one side and the imprint "M103" on the other.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of HIV infection, combinations. Zidovudine and lamivudine. ATC code J05AR01.

Pharmacological Properties

Pharmacodynamics. Lamivudine and zidovudine are potent selective inhibitors of HIV-1 and HIV-2.

Lamivudine is highly synergistic with zidovudine in inhibiting HIV replication in cell culture. Both drugs are sequentially metabolized intracellularly by kinases to their 5-triphosphate (TP) forms. Lamivudine-TP and zidovudine-TP are competitive inhibitors of human immunodeficiency virus reverse transcriptase. However, the primary mechanism of antiviral activity is incorporation as a monophosphate into the viral DNA chain, resulting in chain termination. The triphosphates of lamivudine and zidovudine exhibit significantly lower affinity for host cell DNA polymerase.

In vitro, lamivudine demonstrates low cytotoxicity toward peripheral lymphocytes, lymphocytic and monocytic-macrophage cell lines, and various other bone marrow progenitor cells. Thus, lamivudine has a high in vitro therapeutic index.

Zidovudine and stavudine retain their antiretroviral activity against lamivudine-resistant HIV-1.

Clinical evidence confirms that the combination of lamivudine and zidovudine reduces HIV viral load and increases CD4 cell counts. Recent clinical data indicate that lamivudine, either in combination with zidovudine or as part of other zidovudine-containing regimens, significantly reduces the risk of disease progression and mortality.

In some patients, treatment with lamivudine and zidovudine may lead to the emergence of HIV isolates with reduced in vitro susceptibility to nucleoside analogs to which they have been exposed. Clinical data suggest that lamivudine, when used in combination with zidovudine, delays the development of zidovudine resistance in antiretroviral-naïve patients.

Lamivudine and zidovudine are widely used as components of antiretroviral therapy, in combination with other antiretroviral agents of the same class (nucleoside reverse transcriptase inhibitors) or other classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).

Combination antiretroviral therapy containing lamivudine is effective in both antiretroviral-naïve patients and patients with the M184V viral mutation.

Prophylaxis of potential exposure

International guidelines (Centers for Disease Control and Prevention, June 1998) recommend immediate administration (within 1–2 hours) of a combination of zidovudine and lamivudine following accidental exposure to HIV-infected blood, such as needlestick injury. In cases of high risk of infection, a protease inhibitor should be added to the regimen. Antiretroviral prophylaxis should be continued for 4 weeks. Despite prompt initiation of antiretroviral therapy, seroconversion remains possible.

Pharmacokinetics.

Absorption

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

Bioequivalence of the drug was evaluated compared to the combination of lamivudine 150 mg and zidovudine 300 mg; additionally, the effect of food on the extent and rate of absorption was studied. Bioequivalence between the drug and the separate 150 mg lamivudine and 300 mg zidovudine tablets administered fasting was demonstrated. After administration of the drug, maximum concentrations of lamivudine and zidovudine are 1.5 (1.3–1.8) mg/mL and 1.8 (1.5–2.2) mg/mL, respectively. The median time to peak concentration (t_max) for lamivudine and zidovudine is 0.75 (0.50–2.00) hours and 0.50 (0.25–2.00) hours, respectively.

The extent of absorption and elimination half-life of lamivudine and zidovudine are similar when administered with food compared to fasting, although the rate of absorption (C_max, t_max) is reduced. Based on these data, the drug can be administered independently of food intake.

Administration of crushed tablets mixed with a small amount of food or liquid does not affect the pharmaceutical quality of the drug and therefore does not impact its clinical efficacy. This conclusion is based on physicochemical and pharmacokinetic properties of the active ingredients and dissolution profile data of lamivudine- and zidovudine-containing tablets in water, provided the patient ingests 100% of the crushed tablet immediately after crushing.

Distribution

Following intravenous administration, the mean volume of distribution for lamivudine and zidovudine is 1.3 L/kg and 1.6 L/kg, respectively. At therapeutic doses, lamivudine exhibits linear pharmacokinetics and binds minimally to major plasma proteins (less than 36% to serum albumin in vitro). Protein binding of zidovudine to plasma proteins ranges from 34% to 38%. The drug does not participate in drug interactions involving displacement from protein-binding sites.

Lamivudine and zidovudine penetrate into the central nervous system (CNS) and reach cerebrospinal fluid (CSF). The mean CSF/serum concentration ratios for lamivudine and zidovudine 2–4 hours after oral administration are approximately 0.12 and 0.5, respectively. The actual extent of CNS penetration and its correlation with clinical efficacy remain unknown.

Metabolism

Lamivudine is primarily eliminated unchanged via renal excretion. The potential for metabolic interaction with other drugs is low due to limited hepatic metabolism (5–10%) and low plasma protein binding.

50–80% of zidovudine is excreted renally as its major metabolite, 5-glucuronide-zidovudine, which is detectable in both urine and plasma. Following intravenous administration, 3’-amino-3’-deoxythymidine has been identified as a metabolite of zidovudine.

Elimination

The elimination half-life of lamivudine ranges from 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, with renal excretion (via the organic cation transport system) accounting for over 70% of elimination. Studies show that lamivudine clearance is reduced in patients with renal impairment; therefore, dosage adjustment of lamivudine is required when creatinine clearance is ≤50 mL/min (see section "Dosage and Administration").

Limited data suggest that in patients with hepatic impairment, accumulation of zidovudine may occur due to reduced glucuronidation. Dose reduction of zidovudine may be necessary in patients with severe hepatic impairment.

Clinical characteristics.

Indications.

Treatment of HIV infection.

Contraindications.

The use of the medicinal product Zovirax is contraindicated in patients with known hypersensitivity to lamivudine, zidovudine, or any component of the product.

Zidovudine is contraindicated in patients with neutrophil counts below 0.75 × 10⁹/L or hemoglobin levels below 7.5 g/dL or 4.65 mmol/L; therefore, Zovilam is contraindicated in this patient group (see section "Special precautions").

Interaction with other medicinal products and other types of interactions.

The medicinal product Zovilam contains lamivudine and zidovudine; therefore, any interactions characteristic of each of these agents will also apply to Zovilam. Clinical studies have shown that there are no clinically significant interactions between lamivudine and zidovudine.

Zidovudine is primarily metabolized by UDP-GT enzymes; concomitant administration of inducers or inhibitors of UDP-GT enzymes may alter zidovudine exposure. Lamivudine is eliminated by the kidneys. Active renal secretion of lamivudine into urine occurs via organic cation transporters (OCT); co-administration of lamivudine with OCT inhibitors or nephrotoxic agents may increase lamivudine exposure.

Lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes (such as CYP3A4, CYP2C9, or CYP2D6), and they do not inhibit or induce this enzyme system. Therefore, interactions with antiretroviral protease inhibitors, non-nucleosides, and other medicinal products that are primarily metabolized by P450 enzymes are unlikely.

Interaction studies have been conducted only in adults. The interactions described below are not exhaustive but include the studied classes of medicinal products.

Abbreviations: ↑ – increase; ↓ – decrease; ↔ – no significant changes; AUC – area under the pharmacokinetic concentration-time curve; Cmax – maximum observed concentration; CL/F – apparent clearance after oral administration.

Exacerbation of anaemia associated with the use of ribavirin has been observed in patients receiving zidovudine as part of a combination antiretroviral therapy for HIV, although the exact mechanism remains unclear. Concomitant use of ribavirin and zidovudine is not recommended due to an increased risk of developing anaemia (see section "Special precautions for use").

Consideration should be given to replacing zidovudine in such combination antiretroviral regimens. This is particularly important for patients with a history of zidovudine-induced anaemia.

Concomitant use, primarily in acute cases, with drugs that are potentially nephrotoxic or have myelosuppressive properties (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon, vincristine, vinblastine, and doxorubicin) may also increase the risk of zidovudine-related adverse reactions. If concomitant administration of Zovilam and any of these medicinal products is necessary, renal function and haematological parameters should be monitored and dosage of one or more components of therapy should be reduced as needed.

Limited clinical study data suggest no significant increase in the risk of interaction between zidovudine and co-trimoxazole (see above information on interaction concerning lamivudine and co-trimoxazole), aerosolized pentamidine, pyrimethamine, or acyclovir when used at prophylactic doses.

Special precautions for use.

Although effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to avoid transmission should be implemented according to national guidelines.

This section includes specific warnings and precautions applicable to both lamivudine and zidovudine. Additional precautions and warnings specific to the combined drug Zovilam are not available.

When dose adjustments of the active substances are required, it is recommended to use separate formulations of lamivudine and zidovudine (see section "Method of administration and dosage"). In such cases, physicians should refer to the instructions for medical use of these drugs.

Concomitant use of stavudine and zidovudine should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Opportunistic infections. Opportunistic infections and other complications of HIV infection may continue to develop in patients receiving Zovilam or any other antiretroviral therapy. Therefore, these patients should remain under continuous clinical supervision by physicians experienced in the treatment of HIV infection.

Hematological adverse reactions. Anemia, neutropenia, and leukopenia (usually secondary to neutropenia) may occur in patients treated with zidovudine. These are most commonly observed when high doses of zidovudine (1200–1500 mg per day) are used in patients with advanced stages of HIV infection and in individuals who had reduced bone marrow reserve prior to treatment. Therefore, hematological parameters must be closely monitored in patients receiving this drug (see section "Contraindications"). These hematological changes are usually not observed during the first 4–6 weeks of therapy. Patients with advanced HIV are advised to have blood tests at least once every 2 weeks during the first 3 months of treatment and at least once a month thereafter.

Hematological adverse reactions occur rarely in patients with early-stage HIV infection. Depending on the patient's general condition, blood tests may be performed less frequently, e.g., once every 1–3 months. In cases of severe anemia or myelosuppression during treatment with Zovilam, or in patients with already compromised bone marrow (i.e., hemoglobin < 9 g/dL (5.59 mmol/L) or neutrophil count < 1.0 × 10⁹/L), dose adjustment of zidovudine may be required (see section "Method of administration and dosage"). Since dose reduction is not possible with the fixed-dose combination, separate formulations of zidovudine and lamivudine should be prescribed. Physicians should consult the instructions for medical use of these drugs.

Pancreatitis. Isolated cases of pancreatitis have been reported in patients treated with lamivudine and zidovudine. However, it remains unclear whether these cases are related to drug use or are a consequence of the disease itself. If a patient presents clinical signs or symptoms suggestive of pancreatitis or elevated biochemical markers, pancreatitis should be suspected and the drug should be discontinued immediately.

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

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

Lactic acidosis usually develops after several months or more of treatment.

If symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels occur, zidovudine treatment must be discontinued.

Zidovudine should be prescribed with caution for any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain drugs and alcohol). A high-risk group includes patients co-infected with hepatitis C and those receiving alpha-interferon and ribavirin.

Patients at increased risk require ongoing monitoring.

Mitochondrial dysfunction following in utero exposure. Nucleoside and nucleotide analogs may cause mitochondrial dysfunction of varying degrees, particularly pronounced with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogs during the prenatal and/or postnatal period; primarily involving treatment regimens containing zidovudine. The main adverse reactions reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events were often transient. Neurological disorders (hypertonia, seizures, behavioral disturbances) have been rarely reported and may manifest later. Whether such neurological disorders are transient or permanent is currently unknown. These disorders should be considered in any child exposed to nucleoside and nucleotide analogs in utero or presenting with severe clinical disorders of unknown etiology, particularly neurological ones. These data do not affect current recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical transmission of HIV.

Lipoatrophy. Treatment with zidovudine is associated with loss of subcutaneous fat, linked to mitochondrial toxicity. The frequency and severity of lipoatrophy depend on cumulative exposure. Such fat loss, most evident in the face, limbs, and buttocks, may be irreversible even after switching to a zidovudine-free treatment regimen. Patients should be regularly assessed for signs of lipoatrophy during zidovudine and zidovudine-containing drug therapy. If lipoatrophy is suspected, therapy should be changed to an alternative regimen.

Body weight and metabolic parameters. Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Factors influencing these levels may also include disease control and lifestyle changes. In some cases, there is evidence supporting the impact of treatment on increased lipid levels, whereas increased body weight lacks such confirmation. Monitoring of lipid and glucose levels should be performed according to established HIV treatment protocols. Treatment for lipid abnormalities should be initiated based on clinical indications.

Immune reconstitution syndrome. In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur during combined antiretroviral therapy (cART), potentially causing severe clinical conditions or symptom exacerbation. Such reactions typically occur within the first few weeks or months of cART. Examples include cytomegalovirus-induced retinitis, generalized and/or focal mycobacterial infections, or Pneumocystis jirovecii-induced pneumonia (formerly known as Pneumocystis pneumonia). Any inflammatory symptoms should be promptly investigated and treated if necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; although their onset is more variable and may occur several months after starting treatment.

Liver disease. If lamivudine is used concomitantly for the treatment of HIV infection and hepatitis B virus, additional information on the use of lamivudine for hepatitis B treatment is available in the lamivudine product information.

The safety and efficacy of zidovudine in patients with severe hepatic impairment have not been established.

In patients with chronic hepatitis B or C undergoing combined antiretroviral therapy, there is an increased risk of severe and potentially fatal hepatic adverse reactions. When antiviral drugs for hepatitis B or C are used concomitantly, the product information for these drugs should be consulted.

If treatment with Zovilam is discontinued in patients co-infected with hepatitis B virus, liver function tests and markers of hepatitis B virus replication should be monitored periodically for 4 months, as discontinuation of lamivudine may lead to hepatitis flare.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk of hepatic impairment during combined antiretroviral therapy and should be monitored according to standard practice. In case of signs indicating worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Patients co-infected with hepatitis C virus. Concomitant use of ribavirin and zidovudine is not recommended due to an increased risk of anemia (see section "Interaction with other medicinal products and other forms of interaction").

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index), cases have been reported particularly in patients with advanced HIV disease and/or long-term combined antiretroviral therapy (cART). Patients experiencing joint pain, stiffness, or impaired joint mobility should seek medical consultation.

Zovilam should not be prescribed with other medicinal products containing lamivudine or with drugs containing emtricitabine.

Combination of lamivudine with cladribine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use in patients with moderate renal impairment.

In patients with creatinine clearance of 30–49 mL/min receiving Zovilam, lamivudine exposure (AUC) may be 1.6–3.3 times higher than in patients with creatinine clearance ≥ 50 mL/min. Safety data from randomized controlled trials comparing Zovilam with its individual components in patients with creatinine clearance of 30–49 mL/min who received lamivudine dose adjustment are lacking. In original registration studies of lamivudine in combination with zidovudine, higher lamivudine exposure was associated with increased frequency of hematological toxicity (neutropenia and anemia), although discontinuation due to neutropenia or anemia occurred in < 1% of patients. Other lamivudine-related adverse effects (such as gastrointestinal and hepatic disorders) may also occur.

Patients with stable creatinine clearance values of 30–49 mL/min receiving Zovilam should be monitored for lamivudine-related adverse effects, particularly hematological toxicity. If neutropenia or anemia develops or worsens, lamivudine dose adjustment should be performed according to the lamivudine product information, which cannot be achieved with Zovilam. Zovilam should be discontinued and separate component drugs prescribed to construct a treatment regimen.

Excipients.

Sodium: this medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Fertility

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