Disaverox, 300 mg+150 mg 60 pcs

Pharmacodynamics

Mechanism of action

Zidovudine and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both active agents are sequentially metabolized by intracellular kinases to 5′-triphosphate (TF). Zidovudine-TF and lamivudine-TF act as substrates and are competitive inhibitors of HIV reverse transcriptase. Their main antiviral effect lies in their ability to be incorporated into the viral DNA chain in monophosphate form, leading to its breakage. Zidovudine and lamivudine triphosphates have much less affinity to ‑host cell DNA polymerases.‑

No in vitro antagonistic effects were observed with lamivudine and other antiretroviral drugs (substances studied: abacavir, didanosine, nevirapine, zalcitabine and zidovudine). There were also no antagonistic effects under in vitro conditions with zidovudine and other antiretrovirals (substances studied: abacavir, didanosine, lamivudine and interferon alfa).

In in vitro studies, lamivudine has a weak cytotoxic effect on peripheral blood lymphocytes as well as on lymphocytic and monocytic-macrophage cell lines and several other bone marrow progenitor cells. Thus, lamivudine has a high therapeutic index in vitro.

Pharmacodynamic effects

The HIV-1 resistance to lamivudine is due to an M184V mutation in a codon close to the active center of HIV viral reverse transcriptase (RT). This mutation variant is observed in both in vitro and HIV-1-infected patients who have received antiretroviral therapy (APT) that includes lamivudine. The M184V mutation significantly reduces sensitivity to lamivudine and significantly reduces the ability of the virus to replicate in vitro. In vitro studies have shown that zidovudine-resistant strains of the virus can become susceptible to its action if these strains simultaneously develop lamivudine resistance. However, the clinical significance of such changes has not yet been conclusively established.

The M184V mutation in the reverse transcriptase codon results in HIV cross-resistance only to antiretroviral drugs from the nucleoside inhibitor class. Zidovudine and stavudine retain activity against lamivudine-resistant HIV-1 strains. Abacavir retains antiretroviral activity against lamivudine-resistant HIV-1 strains with only the M184V mutation. HIV strains with the M184V mutation in the reverse transcriptase codon have no more than a 4-fold decrease in sensitivity to didanosine and zalcitabine; the clinical significance of these phenomena has not been established.

Resistance to thymidine analogues (such as zidovudine) is well characterized and occurs through 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 a combination of mutations in codons 41 and 215 or an accumulation of at least four of the six mutations. These mutations alone do not cause high cross-resistance to other nucleosides, allowing other reported reverse transcriptase inhibitors to be used subsequently.

There are two models of multiple drug resistance mutations, the first characterized by HIV reverse transcriptase mutations in codons 62, 75, 77, 116, and 151, and the second typically involves a T698 mutation combined with a 6-nucleotide pair insertion at the same position. The above models lead to the development of phenotypic resistance to zidovudine as well as to other reported nucleoside reverse transcriptase inhibitors (NRTIs). Either of these two multiple nucleoside resistance mutation patterns significantly limits future therapy options.

In clinical trials, use of lamivudine in combination with zidovudine resulted in a lower HIV-1 viral load in the blood and an increased CD4 cell count. Clinical evidence suggests that lamivudine in combination with zidovudine, either alone or as part of therapy regimens that include zidovudine, results in a significant reduction in risk of HIV progression and mortality.

Monotherapy with zidovudine and lamivudine alone resulted in clinical strains of HIV with reduced sensitivity to these drugs and UIGO. The results of clinical trials have shown that in patients who have not previously received antiretroviral therapy, combination therapy with zidovudine and lamivudine delays the emergence of zidovudine-resistant strains.

Tests of HIV sensitivity to different antiretrovirals in vitro have not been standardized, so results may be affected by different methodological factors. Evaluation of the relationship between HIV sensitivity to zidovudine and/or lamivudine in vitro and clinical response to therapy is under investigation.

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

The combination antiretroviral therapy including lamivudine has been shown to be effective against HIV strains with M184V mutations, as well as in patients who have not previously received antiretroviral therapy.

Pharmacokinetics

Intake

Zidovudine and lamivudine are well absorbed from the gut. The absolute bioavailability of zidovudine and lamivudine in adults after oral administration is usually 60-70% and 80-85%, respectively.

After use with a fixed-dose combination of zidovudine and lamivudine, the maximum plasma concentrations (C_max) of zidovudine and lamivudine (95% confidence interval) were 1.8 (1.5-2.2) µg/mL and 1.5 (1.3-1.8) µg/mL, respectively. The median (range) t_max values for zidovudine and lamivudine were 0.50 (0.25-2.00) h and 0.75 (0.50-2.00) h, respectively. The absorption rate (AUC) of zidovudine and lamivudine and elimination half-life values after ingestion with food were similar to those after fasting, although the absorption rate (C_max, t_max) was reduced. The findings indicate that Dizaverox can be administered independently of food intake.

The intake of crushed tablets with small amounts of semisolid food or liquid is not expected to affect the pharmacological properties of the drug and hence the clinical effect. These conclusions are based on the physicochemical and pharmacokinetic characteristics of the active ingredients and the in vitro dissolution pattern of fixed-dose combination zidovudine and lamivudine tablets in water, assuming that the patient crushes and immediately takes 100% of the crushed tablet.

Distribution

Lamivudine is characterized by a linear change in pharmacokinetic parameters over the entire therapeutic dose range and binds only slightly to the major plasma protein albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34-38%. Thus, interaction of zidovudine and lamivudine with other drugs through their displacement from binding to plasma proteins is unlikely.

The available data indicate that zidovudine and lamivudine penetrate the central nervous system (CNS) and enter the cerebrospinal fluid (CSF). The average ratio of zidovudine and lamivudine concentration in the CSF to their concentration in blood serum in 2-4 hours after oral administration is approximately 0.5 and 0.12, respectively. The true degree of penetration, as well as the relationship to clinical efficacy, is unknown.

Metabolism

Lamivudine is practically not metabolized and is mainly excreted unchanged by the kidneys. Metabolic interactions for lamivudine are unlikely due to minor metabolism in the liver (5-10%) and low degree of binding to blood plasma proteins.

The 5′-glucuronide of zidovudine is the major metabolite in both plasma and urine, with approximately 50-80% of the accepted dose of zidovudine excreted by renal excretion. 3′-amino-3′-deoxythymidine (AMT) has been identified as the metabolite of zidovudine following intravenous administration.

The elimination half-life of lamivudine is 5-7 h. Average systemic clearance of lamivudine is approximately 0.32 l/h/kg, most of it is renal clearance (more than 70%), which is carried out by active tubular secretion through the system of transport of organic cations. Renal clearance of zidovudine is 0.34 l/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys.

Particular patient groups

Patients in the elderly

The pharmacokinetics of zidovudine and lamivudine have not been studied in patients older than 65 years.

Children

Zidovudine is well absorbed from the gut, with a bioavailability of 60-74% when used in all doses studied in adults and children, with a mean of 65%. The maximum equilibrium concentration (C_SSmax) is 4.45 μmol/L (1.19 μg/mL) after administration of zidovudine in solution form at a dose of 120 mg/m² body surface area and 7.7 μmol/L (2.06 μg/mL) after administration of zidovudine at a dose of 180 mg/m² body surface area. Administration at a dose of 180 mg/m² four times daily in children resulted in systemic exposure (AUC₂₄ = 40.0 h×mc/mL or 10.7 h×mcg/mL) similar to that in adults (40.7 h×mc/mL or 10.9 h×mcg/mL) when administered at a dose of 200 mg six times daily.

In six HIV-infected children aged 2 to 13 years, the plasma pharmacokinetics of zidovudine were assessed after administration at a dose of 120 mg/m² three times daily and after switching to a dose of 180 mg/m² twice daily. Systemic exposure (daily AUC and C_max) in plasma using the twice-daily dosing regimen was equivalent to exposure using the same total daily dose divided into three doses.

In general, the pharmacokinetics of lamivudine in children is similar to that in adults. However, the absolute bioavailability (approximately 55-65%) was lower in children younger than 12 years of age. In addition, systemic clearance values were higher in young children and decreased with increasing age, reaching values similar to those in adult patients by about 12 years of age. Recent data suggest that exposure in children aged 2 to 6 years may be reduced by approximately 30% compared to other age groups. Additional data are currently pending to support this conclusion; currently available data do not indicate a lower efficacy of lamivudine in this age group.

Patients with impaired renal function

In studies involving patients with impaired renal function, lamivudine excretion has been shown to be impaired with impaired renal function due to decreased renal clearance. Patients with creatinine clearance less than 50 ml/min should reduce the dose of the drug. Increased concentration of zidovudine has also been demonstrated in patients with severe renal impairment.

Patients with impaired liver function

Limited data obtained in patients with cirrhosis indicate the possibility of accumulation of zidovudine in patients with impaired liver function due to reduced glucuronidation. In patients with severe hepatic impairment, the dose of zidovudine may need to be adjusted.

Pregnancy

Pregnancy does not affect the pharmacokinetics of zidovudine and lamivudine. Lamivudine is detected in the serum of newborns in the same concentrations as in the mother’s serum and umbilical cord blood, which is consistent with the notion of passive transfer of lamivudine through the hematoplacental barrier. The results of zidovudine plasma concentrations were similar to those obtained for lamivudine.

Indications

Active ingredient

Composition

How to take, the dosage

The drug Disaverox is taken orally, regardless of meals.

Therapy with Dizaverox should be started and monitored by a doctor with experience in treating HIV infection.

To ensure accurate dosing, the tablet must be swallowed whole without breaking. To treat patients who have difficulty swallowing, the tablets can be crushed and added to a small amount of semi-solid food or liquid. The entire resulting mixture should be taken orally immediately.

If a dose reduction or withdrawal of one component of Diziverox (zidovudine or lamivudine) is necessary, separate preparations of zidovudine and lamivudine should be used.

Particular groups of patients

Adults and children with a body weight of at least 30 kg

The recommended dose of Dizaverox is 1 tablet twice daily.

Patients in the elderly

There are no specific data on the use of Dizaverox in elderly patients, but special caution should be exercised when treating elderly patients because of age-related changes, such as impaired renal function and altered hematologic parameters.

Patients with impaired renal function

Patients with a creatinine clearance of less than 50 mL/min require correction of the lamivudine dose, so separate preparations of zidovudine and lamivudine are recommended in these patients.

Patients with impaired liver function

Limited data obtained in patients with cirrhosis indicate the possibility of cumulation of zidovudine in patients with impaired liver function due to decreased glucuronide formation rate. The data obtained when using lamivudine in patients with moderate to severe hepatic impairment indicate that hepatic impairment does not significantly affect the pharmacokinetics of lamivudine. Nevertheless, it may be necessary to adjust the dose of zidovudine, therefore in patients with severe hepatic impairment the use of separate preparations of zidovudine and lamivudine is recommended. Treating physicians should refer to the instructions for medical use for these drugs.

Patients with hematologic adverse reactions

. If hemoglobin concentrations fall below 9 g/dL (5.59 mmol/L) or neutropenia (neutrophil count less than 1.0×109/L), a dose adjustment of zidovudine may be required. Since it is not possible to adjust the dose of Dizaverox, separate preparations of zidovudine and lamivudine should be used.

Interaction

Because Dizaverox contains zidovudine and lamivudine, it can enter into any of the interactions characteristic of each of these components individually. No clinically significant interactions between zidovudine and lamivudine have been found in clinical studies.

Zidovudine is primarily metabolized by uridine diphosphate-glucuronyl transferase (UDF-GT) enzymes; co-administration of UDF-GT enzyme inducers or inhibitors may affect zidovudine exposure. Lamivudine is excreted by the kidneys. Active renal secretion of lamivudine into the urine occurs through the organic cation transport system (OCT). Concomitant use of lamivudine with OST inhibitors or nephrotoxic drugs may increase lamivudine exposure.

Zidovudine and lamivudine are not significantly metabolized by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6), nor do they inhibit or induce this enzyme system. Thus, interactions of zidovudine and lamivudine with protease inhibitors, non-nucleoside reverse transcriptase inhibitors and other antiretroviral drugs that are metabolized by key P450 enzymes are unlikely.

Drug interactions studies have only been conducted with adult patients. The following list of drug interactions should not be considered exhaustive, but does reflect the classes of drugs with which caution should be exercised.

Drugs by area of use

Interactions

Geometric mean change (%)

(possible mechanism)

Recommendations for co-administration

ANTIRETROVIRUS MEDICINARY PREPARATIONS

Didanosine + lamivudine

A interaction has not been studied.

Dose adjustment is not required.

Didanosine + zidovudine

The interaction has not been studied.

Stavudine + lamivudine

The interaction has not been studied.

Co-use is not recommended.

Stavudine + zidovudine

In vitro antagonism of HIV activity between stavudine and zidovudine may lead to decreased efficacy of both drugs.

Antiviral drugs

Atovahon + lamivudine

The interaction has not been studied.

Because limited data are available, clinical significance is unknown.

Atovahon + zidovudine

(750 mg twice daily with meals + 200 mg three times daily)

Zidovudine: AUC ↑ 33%

Atovahon: AUC

Clarithromycin + lamivudine

The interaction has not been studied.

The interval between taking Disaverox and clarithromycin should be at least 2 hours.

Clarithromycin + zidovudine

(500 mg twice daily +

100 mg every 4 h)

Zidovudine: AUC ↓ 12%

Trimethoprim + sulfamethoxazole (cotrimoxazole) + lamivudine (160 mg + 800 mg once daily for 5 days + 300 mg once)

Lamivudine: AUC ↑ 40%

Trimethoprim: AUC ↔

Sulfamethoxazole: AUC

(inhibition of the organic cation transport system)

Except in patients with impaired renal function, no dose adjustment of Disaverox is necessary.

If concomitant use of cotrimoxazole is warranted, patients should be kept under clinical observation.

The co-administration with high doses of trimethoprim + sulfamethoxazole to treat pneumonia caused by Pneumocystis jirovecii (P. carinii) and toxoplasmosis has not been studied and should be avoided.

Trimethoprim + sulfamethoxazole (cotrimoxazole) + zidovudine

The interaction has not been studied.

Antihypertensive drugs

Fluconazole + lamivudine

The interaction has not been studied.

Because limited data are available, clinical significance is unknown. Signs of zidovudine toxicity should be monitored.

Fluconazole + zidovudine

(400 mg once daily +

200 mg three times daily)

Zidovudine: AUC ↑ 74%

(UDF-GT inhibition)

ANTIMICOBACTERIAL PREPARATES

Rifampicin + lamivudine

A interaction has not been studied.

There is insufficient data to recommend dose adjustment.

Rifampicin + zidovudine

(600 mg once daily +

200 mg three times daily)

Zidovudine: AUC ↓ 48%

(induction of UDF-GT)

Antiviral medicines

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Phenobarbital + lamivudine

A interaction has not been studied.

There is insufficient data to recommend dose adjustment.

Phenobarbital + zidovudine

The interaction has not been studied.

There may be a slight decrease in the plasma concentration of zidovudine through induction of UDF-GT.

Phenytoin + lamivudine

The interaction has not been studied.

Phenytoin concentration should be monitored.

Phenytoin + zidovudine

Phenytoin: AUC ↑↓

Valproic acid + lamivudine

The interaction has not been studied.

Because limited data are available, clinical significance is unknown. Signs of zidovudine toxicity should be monitored.

Valproic acid + zidovudine (250 mg or 500 mg three times daily + 100 mg three times daily)

Zidovudine: AUC ↑ 80%

(UDF-GT inhibition)

H2 blockers.-HISTAMIN RECEPTORS

Ranitidine + lamivudine

A interaction has not been studied. A clinically significant interaction is unlikely. Ranitidine is partially excreted by active tubular secretion through the organic cation transport system.

Dose adjustment is not required.

Ranitidine + zidovudine

The interaction has not been studied.

Cimetidine + lamivudine

The interaction has not been studied. A clinically significant interaction is unlikely. Cimetidine is partially excreted by active tubular secretion through the organic cation transport system.

Dose adjustment is not required.

Cimetidine + zidovudine

The interaction has not been studied.

Cytotoxic medicines

Cladribine + lamivudine

The interaction has not been studied.

In vitro, lamivudine inhibits intracellular phosphorylation of cladribine, leading to a possible risk of loss of cladribine efficacy if combined in a clinical setting. Some clinical data also support a possible interaction between lamivudine and cladribine.

Thus, co-administration of lamivudine and cladribine is not recommended.

OPIOID PREPARATES

Methadone + lamivudine

The interaction has not been studied.

Because limited data are available, clinical significance is unknown. Signs of zidovudine toxicity should be monitored. In most cases, the need for methadone dose adjustment is unlikely, but re-titration of the dose may sometimes be necessary.

Methadone + zidovudine

(30 to 90 mg once daily + 200 mg every 4 h)

Zidovudine: AUC ↑ 43%

Methadone: AUC

URICOZURIC PREPARATES

Probenecid + lamivudine

The interaction has not been studied.

Because limited data are available, clinical significance is unknown. Signs of zidovudine toxicity should be monitored.

Probenecid + zidovudine

(500 mg four times daily + 2 mg/kg three times daily)

Zidovudine: AUC ↑ 106%

(UDFGT inhibition)

Abbreviations: ↑ = increase in index; ↓ = decrease in index; ↔ = no significant change; AUC – area under the concentration-time curve.

Emtricitabine

Lamivudine can inhibit intracellular phosphorylation of emtricitabine when these drugs are used simultaneously. In addition, the mechanism of viral resistance to lamivudine and emtricitabine is mediated by a mutation in the same viral reverse transcriptase gene (M184V), so the therapeutic effectiveness of these drugs in combination therapy may be limited.

The use of lamivudine in combination with emtricitabine or fixed-dose combinations containing emtricitabine is not recommended.

Lamivudine

The concomitant use of zidovudine and lamivudine results in a 13% increase in zidovudine exposure and a 28% increase in its maximum plasma concentration. However, total zidovudine exposure (AUC) does not change significantly. Zidovudine has no effect on the pharmacokinetics of lamivudine.

Other drugs

There have been reported cases of worsening anemia associated with the use of ribavirin when zidovudine was part of the HIV treatment regimen, but the exact mechanism is currently unknown. Concomitant use of ribavirin and zidovudine is not recommended because of the increased risk of anemia.

If a combination APT regimen containing zidovudine is used, consideration should be given to replacing zidovudine. This is especially important for patients with a history of anemia caused by zidovudine.

The concomitant treatment, especially intensive therapy, with potentially nephrotoxic or myelosuppressive medications (such as: pentamidine for systemic use, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to zidovudine. If concomitant use of Dizaverox and any of the listed drugs is necessary, especially careful monitoring of renal function and hematologic parameters is required. If necessary, the dose of one or more drugs should be reduced.

Limited data from clinical studies do not indicate a significant increase in the risk of adverse reactions to zidovudine when used concomitantly with co-trimoxazole (see above for interaction of lamivudine and co-trimoxazole), pentamidine aerosol, pyrimethamine and acyclovir at preventive doses.

Special Instructions

The following are special indications for zidovudine and lamivudine. There are no additional Special Indications related to Dizaverox.

When dose adjustments are necessary, separate medications for zidovudine and lamivudine are recommended. In such cases, the treating physician should refer to the separate instructions for use for these medications.

Patients should be cautioned about the possible effects of concomitant use of other medications without a prescription.

While effective suppression of the virus with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission of HIV to others, the risk cannot be completely eliminated. Patients should take precautions to prevent HIV transmission in accordance with national guidelines.

The concomitant use of stavudine and zidovudine should be avoided.

Diziverox should not be used concomitantly with medicines containing lamivudine or emtricitabine.

The concomitant use of lamivudine and cladribine is not recommended.

Opportunistic infections

The use of Dizaverox or any other antiretroviral drug does not rule out the possibility of opportunistic infections or other complications of HIV infection, so patients should remain under close clinical observation by physicians experienced in treating HIV infection.

Hematologic disorders

The development of anemia, neutropenia, and leukopenia (usually secondary to neutropenia) can be expected in patients treated with zidovudine. These phenomena most often develop with higher doses of zidovudine (1200-1500 mg/day), in patients with advanced HIV infection and in patients with reduced bone marrow reserve prior to treatment. Therefore, hematologic parameters should be carefully monitored in patients taking Dizaverox.

These hematologic abnormalities usually do not occur until 4-6 weeks after initiation of therapy. For symptomatic patients with advanced HIV infection, blood tests are recommended at least every two weeks for the first three months of therapy and at least once a month thereafter. Adverse blood reactions are uncommon in patients with early HIV infection. Depending on the overall condition of the patient, blood tests may be performed less frequently, e.g., every 1 to 3 months.

If severe anemia or myelosuppression develops during treatment with Disaverox or in patients with pre-existing bone marrow dysfunction, such as a hemoglobin concentration of less than 9 g/dL (5.59 mmol/L) or a neutrophil count of less than 1.0×10

(sup>).sup>9/L, a dose adjustment of zidovudine may also be required.

Because dose adjustment is not possible with Dizaverox, these patients should be treated with zidovudine and lamivudine as separate drugs.

For more information, please refer to the instructions for use for the individual drugs zidovudine and lamivudine.

Pancreatitis

Rare cases of pancreatitis have been reported in patients treated with zidovudine and lamivudine, but it is unclear whether these cases are due to the effects of antiretroviral therapy or due to HIV infection. Disaverox should be discontinued immediately if there are clinical signs, symptoms, or changes in laboratory values suggestive of pancreatitis.

Lactoacidosis

Cases of lactoacidosis, usually with hepatomegaly and steatosis of the liver, have been reported when using zidovudine. Early symptoms (symptomatic hyperlactatemia) include minor digestive symptoms (nausea, vomiting and abdominal pain), nonspecific general malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).

Lactoacidosis has a high mortality rate and may develop against a background of pancreatitis, liver failure or renal failure.

Lactoacidosis usually develops after several months of treatment.

The treatment with Disaverox should be discontinued if symptomatic hyperlactatemia and metabolic acidosis/lactoacidosis develop, progressive hepatomegaly or rapid increase in aminotransferase activity.

Caution should be exercised when using Disaverox to treat any patient (especially obese women) with hepatomegaly, hepatitis or other known risk factors for liver damage and hepatic steatosis (including use of certain medications and alcohol consumption). Patients with hepatitis C co-infection treated with interferon alfa and ribavirin may represent a special risk group.

Patients at high risk should be closely monitored.

Lipoatrophy

The treatment with zidovudine was accompanied by loss of subcutaneous fatty tissue. The incidence and severity of lipoatrophy were related to total drug exposure. This loss of fatty tissue, which is most pronounced in the face, extremities, and buttocks, may be only partially reversible, and improvement may not occur until several months after switching to a treatment regimen that does not contain zidovudine. During therapy with zidovudine and other zidovudine-containing drugs, patients should be regularly evaluated for signs of lipoatrophy, and if lipoatrophy is suspected, switch to an alternative therapy regimen if possible.

Body weight and metabolic parameters

At the time of antiretroviral therapy, increases in body weight, lipid concentrations and blood glucose may occur. Disease control and lifestyle changes can also contribute to this process. In some cases, there has been evidence to link increases in lipid concentrations to therapy, but there is no strong evidence to link weight gain to any particular therapy. Blood lipid and glucose concentrations should be determined in accordance with established guidelines for the treatment of HIV infection. Lipid metabolism disorders should be corrected according to clinical manifestations.

Contraindications

– Hypersensitivity to zidovudine, lamivudine or any other drug component;

– Severe neutropenia (neutrophil count less than 0.75×109/L) or anemia (hemoglobin less than 7.5 g/dL or 4.65 mmol/L).

– Impaired renal function with creatinine clearance less than 50 ml/min (for this dosage form);

– Severe hepatic impairment (for this dosage form);

– Children with a body weight less than 30 kg (for this dosage form).

Cautions

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

Side effects

Adverse reactions have been described in patients with HIV infection treated with zidovudine and lamivudine as monotherapy or in combination. For many adverse reactions, it remains unclear whether they are related to the use of zidovudine, lamivudine, or other drugs used to treat HIV infection, or whether they result from the underlying disease. Since Dizaverox contains zidovudine and lamivudine, adverse reactions of the type and severity described below can be expected to be associated with each of these components. There is currently no evidence that the combination of zidovudine and lamivudine has increased toxicity.

There have been reports of the development of lactoacidosis, including fatal, usually accompanied by severe hepatomegaly with steatosis, during therapy with zidovudine.

The zidovudine treatment was accompanied by loss of subcutaneous fat, which was most pronounced in the face, limbs and buttocks. During therapy with Dizaverox, patients should be regularly evaluated for signs of lipoatrophy, and if lipoatrophy is suspected, Dizaverox therapy should be discontinued.

Body weight and serum lipid and blood glucose concentrations may increase during antiretroviral therapy.

In HIV-infected patients with severe immunodeficiency at the time of initiation of combined antiretroviral therapy, an inflammatory reaction may develop with asymptomatic opportunistic infections or their residual effects. There have also been cases of autoimmune diseases (e.g., Graves’ disease) developing against a background of immune reconstitution, but the timing of the initial manifestations varied and the disease could occur many months after initiation of therapy.

Cases of osteonecrosis have been reported, particularly in patients with established risk factors, in advanced HIV infection or with long-term combined APT. The incidence of this phenomenon is unknown.

The adverse reactions evaluated as related or possibly related to therapy with Disaverox are listed below according to organ and organ system involvement and frequency of occurrence. The frequency is defined as follows: very common (>1/10), common (>1/100 and < 1/10), infrequent (>1/1000 and < 1/100), rare (>1/10000 and < 1/1000), very rare (< 1/10000, including individual cases). Within each frequency category, adverse reactions are presented in descending order of severity.

Lamivudine

Disorders of the blood and lymphatic system

Infrequent: neutropenia and anemia (sometimes severe), thrombocytopenia.

Very rare: true erythrocytic aplasia.

Metabolic and nutritional disorders

Often: hyperlactatemia.

Very rarely: lactoacidosis.

Nervous system disorders

Often: headache, insomnia.

Very rarely: peripheral neuropathy (or paresthesias).

Respiratory system, chest and mediastinal disorders

Often: cough, nasal symptoms.

Gastrointestinal disorders

Often: nausea, vomiting, abdominal pain or colic, diarrhea.

Rarely: pancreatitis, increased serum amylase activity.

Liver and biliary tract disorders

Infrequent: transient increase of liver enzymes activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT).

Rarely: hepatitis.

Dermal and subcutaneous tissue disorders

Often: rash, alopecia.

Rarely: angioedema.

Muscular and connective tissue disorders

Often: arthralgia, muscle disorders.

Rarely: rhabdomyolysis.

General disorders and disorders at the site of administration

Often: fatigue, general malaise, fever.

Zidovudine

The profile of adverse reactions does not differ between adults and adolescents. The most serious adverse reactions are anemia (which may require blood transfusions), neutropenia, and leukopenia. These adverse reactions are more common with higher doses of zidovudine (1200-1500 mg daily) and in patients at advanced stages of HIV infection (especially with reduced bone marrow reserve prior to treatment), particularly in patients with CD4 cell counts less than 100/mm3. In some patients it may be necessary to reduce the dose of zidovudine or withdraw it. Neutropenia occurs more often in patients whose neutrophil count, hemoglobin concentration, and serum vitamin B12 concentrations are reduced at the start of treatment with zidovudine.

Blood and lymphatic system disorders

Often: anemia, neutropenia and leukopenia.

Infrequent: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).

Rare: true erythrocytic aplasia.

Very rare: aplastic anemia.

Metabolic and nutritional disorders

Often: hyperlactatemia.

Rarely: lactoacidosis in the absence of hypoxemia, anorexia.

Mental disorders

Rarely: anxiety, depression.

Nervous system disorders

Very common: headache.

Often: dizziness.

Rarely: insomnia, paresthesias, somnolence, decreased mental activity, seizures.

Cardiac disorders

Rarely: cardiomyopathy.

Respiratory system, thorax and mediastinum disorders

Infrequently: dyspnea.

Rarely: cough.

Gastrointestinal disorders

Often: nausea.

Infrequent: flatulence.

Rarely: pigmentation of the oral mucosa, perversion of taste, dyspepsia, pancreatitis.

Liver and biliary tract disorders

Often: increased liver enzymes activity and bilirubin concentration in blood.

Rarely: liver damage, such as marked hepatomegaly with stenosis.

Skin and subcutaneous tissue disorders

Infrequent: rash and itching.

Rarely: pigmentation of the nails and skin, urticaria and sweating.

Muscular and connective tissue disorders

Often: myalgia.

Infrequent: myopathy.

Rare: Renal and urinary tract disorders

Rarely: frequent urination.

Gender and mammary gland disorders

Rarely: gynecomastia.

General disorders and disorders at the site of administration

Often: general malaise.

Infrequent: fever, generalized pain syndrome and asthenia.

Rarely: chills, chest pain and flu-like syndrome.

The data from two clinical trials (placebo-controlled and open-label) show that the incidence of nausea and other common clinical adverse reactions decreases steadily during the first few weeks of treatment with zidovudine.

Overdose

Symptoms

There are limited reports of overdose with the drug. No specific symptoms or signs of acute overdose with lamivudine or zidovudine have been identified other than those listed under “Side effects”. None of the reported cases were fatal, and all patients recovered normally.

Treatment

In case of overdose the patient should be under medical supervision in order to detect signs of toxic effect of the drug; if necessary the standard supportive therapy is carried out. Since lamivudine is excreted by dialysis, continuous hemodialysis may be used to treat overdose, but there have been no studies to evaluate the use of this method. Hemodialysis and peritoneal dialysis have been found to be ineffective in excretion of zidovudine, but accelerate excretion of its glucuronide metabolite. Treating physicians are advised to refer to the instructions for use of the individual drugs zidovudine and lamivudine for more detailed data.

Pregnancy use

Fertility

There are no data on the effect of zidovudine and lamivudine on fertility in women. Zidovudine has no effect on the number, morphology and motility of sperm in men.

Pregnancy

In general, data from animal studies as well as clinical experience in pregnant women should be considered when making a decision to use antiretroviral drugs to treat HIV infection in pregnant women and, consequently, to reduce the risk of vertical transmission of HIV infection to the newborn. In this case, the use of zidovudine in pregnant women followed by therapy in newborn infants showed a decrease in the rate of mother-to-fetus HIV transmission.

The large number of data on the use of zidovudine or lamivudine in pregnant women does not indicate the development of congenital pathology in the fetus (for each of the drugs, more than 3000 outcomes after exposure when used during the first trimester, of which more than 2000 outcomes after exposure when both drugs were used simultaneously). Based on the above data, it can be concluded that the risk of congenital abnormalities in humans is unlikely with the use of Disaverox.

The active ingredients in Disaverox can inhibit cellular DNA replication. In an animal study, zidovudine has been shown to be a transplacental carcinogen. The clinical significance of these data is unknown.

For HIV-infected women co-infected with hepatitis virus who are being treated with a lamivudine-containing drug such as Dizaverox, the possibility of hepatitis recurrence after discontinuation of lamivudine therapy should be considered if pregnancy occurs.

Mitochondrial dysfunction

It has been demonstrated in in vivo and in vitro studies that nucleoside and nucleotide analogs can cause varying degrees of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and/or during the postpartum period.

Breastfeeding

Zidovudine and lamivudine are excreted in breast milk at concentrations similar to those found in serum.

Based on a study of more than 200 mother-infant pairs receiving HIV therapy, lamivudine concentrations in the serum of breastfed infants of mothers receiving HIV therapy are very low (<4% of maternal serum concentration) and gradually decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data on the safety of lamivudine in children younger than three months.

After a single administration of zidovudine at a dose of 200 mg in HIV-infected women, the average concentration of zidovudine in maternal milk was similar to that in serum.

Breastfeeding is never recommended for HIV-infected women to avoid transmitting HIV to the baby.

Similarities