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

Treatment of HIV infection in adults and children weighing at least 30 kg as part of combination antiretroviral therapy.

Pharmacological effect

Pharmacodynamics

Mechanism of action

Zidovudine and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both active substances are sequentially metabolized by intracellular kinases to 5′-triphosphates (TP). Zidovudine-TF and lamivudine-TF act as substrates and are competitive inhibitors of HIV reverse transcriptase. Their main antiviral effect is the ability to integrate in the form of monophosphate into the viral DNA chain, leading to its termination. Zidovudine and lamivudine triphosphates have significantly lower affinity for host cell DNA polymerases.

No antagonistic effects were observed in vitro with lamivudine and other antiretroviral drugs (tested substances: abacavir, didanosine, nevirapine, zalcitabine and zidovudine). Also, no antagonistic effects were observed in vitro with zidovudine and other antiretroviral drugs (tested substances: 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 monocyte-macrophage cell lines and a number of other bone marrow progenitor cells. Thus, lamivudine has a high therapeutic index in vitro.

Pharmacodynamic effects

HIV-1 resistance to lamivudine is caused by the M184V mutation in a codon located close to the active site of the HIV viral reverse transcriptase (RT). This mutation variant is observed both in vitro and in HIV-1-infected patients treated with antiretroviral therapy (APT), including lamivudine. With the M184V mutation, sensitivity to lamivudine is significantly reduced and the ability of the virus to replicate in vitro is significantly reduced. In vitro studies have shown that strains of the virus resistant to zidovudine may become susceptible to its action if these strains simultaneously develop resistance to lamivudine. However, the clinical significance of such changes has not yet been fully established.

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

Resistance to thymidine analogues (such as zidovudine) is well characterized and occurs due to 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 at codons 41 and 215 or the accumulation of at least four of the six mutations. These mutations in themselves do not cause high cross-resistance to other nucleosides, which allows the subsequent use of other registered reverse transcriptase inhibitors.

There are two models of multidrug resistance mutations, the first of which is characterized by HIV reverse transcriptase mutations at codons 62, 75, 77, 116, and 151, and the second typically involves the T698 mutation combined with a 6-bp insertion at the same position. These models lead to the development of phenotypic resistance to zidovudine, as well as to other registered nucleoside reverse transcriptase inhibitors (NRTIs). Either of these two patterns of multiple nucleoside resistance mutations significantly limits future therapeutic options.

In clinical studies, the use of lamivudine in combination with zidovudine led to a decrease in HIV-1 viral load in the blood and an increase in the number of CD4 cells. Clinical data suggest that the use of lamivudine in combination with zidovudine, either alone or as part of regimens containing zidovudine, leads to a significant reduction in the risk of HIV disease progression and mortality.

Monotherapy with zidovudine and lamivudine individually led to the emergence of clinical strains of HIV with reduced sensitivity to these drugs and HIV. The results of clinical studies have shown that in patients who have not previously received antiretroviral therapy, combination therapy with zidovudine and lamivudine slows the emergence of zidovudine-resistant strains.

In vitro tests for the sensitivity of HIV to various antiretroviral drugs have not been standardized, so their results may be influenced by various 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).

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

Suction

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

After administration of the drug with a fixed dose combination of zidovudine and lamivudine, the maximum plasma concentrations (Cmax) 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) tmax values ​​of zidovudine and lamivudine were 0.50 (0.25–2.00) hours and 0.75 (0.50–2.00) hours, respectively. The extent of absorption (AUC) of zidovudine and lamivudine and half-life values ​​after administration with food were similar to those after administration on an empty stomach, although the rate of absorption (Cmax, tmax) was reduced. The data obtained indicate the possibility of using the drug Disaverox regardless of food intake.

Taking crushed tablets with a small amount of semi-solid food or liquid is not expected to affect the pharmacological properties of the drug and, therefore, the clinical effect. These conclusions are based on the physicochemical and pharmacokinetic characteristics of the active substances and the dissolution behavior of zidovudine and lamivudine fixed-dose combination tablets in vitro in water, provided 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 range of therapeutic doses and is slightly associated with the main plasma protein albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34–38%. Thus, the interaction of zidovudine and lamivudine with other drugs through their displacement from plasma proteins is unlikely.

Available evidence suggests that zidovudine and lamivudine penetrate the central nervous system (CNS) and enter the cerebrospinal fluid (CSF). The mean ratio of zidovudine and lamivudine concentrations in the CSF to their serum concentrations 2 to 4 hours after oral administration is approximately 0.5 and 0.12, respectively. The true extent of penetration as well as the relationship to clinical efficacy are unknown.

Metabolism

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

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

Removal

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

Special patient groups

Elderly patients

The pharmacokinetics of zidovudine and lamivudine in patients over 65 years of age have not been studied.

Children

Zidovudine is well absorbed from the intestine; when used at all dosages studied in adults and children, its bioavailability is 60–74%, with an average value of 65%. The maximum concentration at steady state (CSSmax) is 4.45 µmol/L (1.19 µg/ml) after administration of zidovudine solution 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. Doses of 180 mg/m2 four times daily in children resulted in systemic exposure (AUC24 = 40.0 h×μmol/L or 10.7 h×μg/mL) similar to that of 200 mg six times daily in adults (40.7 h×μmol/L or 10.9 h×μg/mL).

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 a day and after switching to a dose of 180 mg/m2 twice a day. Systemic exposure (daily AUC and Cmax) in plasma using a twice-daily dosing regimen was equivalent to exposure using the same total daily dose divided into three divided doses.

In general, the pharmacokinetics of lamivudine in children are similar to those in adults. However, absolute bioavailability (approximately 55–65%) was lower in children under 12 years of age. In addition, systemic clearance values ​​were higher in young children and decreased as they grew older, reaching values ​​similar to those in adult patients by approximately 12 years of age. Recent evidence suggests that exposure in children aged 2 to 6 years may be reduced by approximately 30% compared with other age groups. Additional data to support this conclusion are currently awaited; Currently available data do not indicate lower efficacy of lamivudine in this age group.

Patients with impaired renal function

Studies in patients with renal impairment have shown that in patients with renal impairment, the elimination of lamivudine is impaired due to reduced renal clearance. Patients with creatinine clearance less than 50 ml/min require a dose reduction. An increase in zidovudine concentrations has also been demonstrated in patients with severe renal impairment.

Patients with liver dysfunction

Limited data obtained in patients with cirrhosis indicate the possibility of accumulation of zidovudine in patients with impaired liver function due to decreased glucuronidation. In patients with severe hepatic impairment, zidovudine dosage adjustment may be required.

Pregnancy

Pregnancy does not affect the pharmacokinetics of zidovudine and lamivudine. Lamivudine is found in the blood serum of newborns at the same concentrations as in maternal serum and umbilical cord blood, which is consistent with the idea of ​​passive transfer of lamivudine across the blood-placental barrier. The results of measuring the concentration of zidovudine in blood plasma were similar to the results obtained for lamivudine.

Special instructions

Below are special instructions for zidovudine and lamivudine. There are no additional special instructions for Disaverox.

If dose adjustment is necessary, the use of separate preparations of zidovudine and lamivudine is recommended. In such cases, your healthcare professional should refer to the separate prescribing information for these medications.

Patients should be warned about the possible consequences of simultaneous use of other drugs without a doctor’s prescription.

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

The simultaneous use of stavudine and zidovudine should be avoided.

Disaverox should not be used concomitantly with medicinal products containing lamivudine or emtricitabine.

Concomitant use of lamivudine and cladribine is not recommended.

Opportunistic infections

The use of Disaverox or any other antiretroviral drugs does not exclude the possibility of developing opportunistic infections or other complications of HIV infection, therefore patients should remain under close clinical supervision of doctors experienced in treating HIV infection.

Hematological disorders

Anemia, neutropenia and leukopenia (usually secondary to neutropenia) can be expected in patients treated with zidovudine. Most often, these phenomena develop when using higher doses of zidovudine (1200–1500 mg/day), in patients with late stage HIV infection and in patients with reduced bone marrow reserve before treatment. Therefore, patients taking Disaverox should carefully monitor hematological parameters.

These hematological disorders usually occur no earlier than 4–6 weeks after the start 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. In patients with early stage HIV infection, adverse blood reactions are uncommon. Depending on the patient’s general condition, blood tests may be performed less frequently, such as 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 less than 9 g/dL (5.59 mmol/L) or a neutrophil count less than 1.0 x 109/L, zidovudine dosage adjustment may also be required.

Since dose adjustment is not possible when using Disaverox, such patients should be prescribed zidovudine and lamivudine as separate drugs.

For more detailed information, please refer to the instructions for use of the individual preparations of 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 antiretroviral therapy or due to HIV infection. If clinical signs, symptoms or changes in laboratory parameters appear that suggest the possibility of pancreatitis, you should immediately stop taking Disaverox.

Lactic acidosis

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

Lactic acidosis has a high mortality rate and can develop in the setting of pancreatitis, liver failure, or renal failure.

Lactic acidosis usually develops after several months of treatment.

Treatment with Disaverox should be discontinued if symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly or a rapid increase in aminotransferase activity develop.

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 the use of certain drugs and alcohol consumption). Patients coinfected with hepatitis C virus and treated with interferon alfa and ribavirin may be at particular risk.

Patients at particular risk should be closely monitored.

Lipoatrophy

Treatment with zidovudine was accompanied by loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to total drug exposure. This fat loss, which is most pronounced in the face, limbs and buttocks, can only be partially reversed and improvement may only occur several months after switching to a treatment regimen that does not contain zidovudine. During therapy with zidovudine and other drugs containing zidovudine, patients should be regularly monitored for signs of lipoatrophy and, if lipoatrophy is suspected, switched to an alternative treatment regimen if possible.

Body weight and metabolic parameters

During antiretroviral therapy, weight gain and increased blood lipid and glucose concentrations may occur. Disease control and lifestyle changes may also contribute to this process. In some cases, there has been evidence that increases in lipid concentrations are related to therapy, but there is no strong evidence that weight gain is related to any specific therapy. Determination of blood lipid and glucose concentrations should be carried out in accordance with established guidelines for the treatment of HIV infection. Lipid imbalances must be corrected according to clinical manifestations.

Immune reconstitution syndrome

HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy (APT) may develop an inflammatory response in response to the activation of pathogens of asymptomatic or residual opportunistic infections, which can cause serious deterioration of the condition or aggravation of symptoms. These reactions usually occur within the first few weeks or months after starting APT. Typical examples are cytomegalovirus retinitis, generalized and/or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jirovecii (P. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Autoimmune diseases (eg, Graves’ disease, polymyositis, and Guillain-Barre syndrome) have also been observed in the setting of immune reconstitution, but the timing of initial manifestations varied and the disease could occur many months after the start of therapy and sometimes had an atypical course.

Liver diseases

When lamivudine is used concomitantly to treat HIV infection and hepatitis B virus (HBV) infection, additional information regarding the use of lamivudine for the treatment of hepatitis B infection is available in the prescribing information for lamivudine 100 mg preparations.

The efficacy and safety of Disaverox have not been established in patients with significant concomitant liver diseases.

Patients with concomitant chronic hepatitis B or C who are receiving combination antiretroviral therapy are at increased risk of developing severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, you should also read the corresponding instructions for the use of these drugs.

When discontinuing the use of Disaverox in patients with hepatitis B virus co-infection, periodic monitoring of liver function and hepatitis B virus replication markers is recommended for 4 months, since discontinuation of lamivudine may lead to exacerbation of hepatitis.

In patients with pre-existing liver dysfunction, including active chronic hepatitis, there is an increased incidence of liver dysfunction during combination antiretroviral therapy. Such patients should be monitored in accordance with standard clinical practice. Suspension or discontinuation of treatment should be considered if worsening liver disease occurs in such patients.

Concomitant viral hepatitis C

The simultaneous use of zidovudine and ribavirin is not recommended due to the increased risk of anemia.

Mitochondrial dysfunction due to in utero exposure

Analogs of nucleosides and nucleotides are capable of affecting mitochondrial function to varying degrees, which is most pronounced with the use of stavudine, didanosine and zidovudine; This mainly applies to treatment regimens that include zidovudine. The main adverse reactions were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These adverse reactions were usually transient. Rare late-onset neurological disorders (hypertension, seizures, behavioral disorders) have been reported. Whether these neurological disorders are transient or permanent is currently unknown. The possibility of mitochondrial dysfunction should be considered in any child exposed in utero to nucleoside and nucleotide analogues with significant clinical symptoms of unknown etiology, especially neurological disorders. The data presented do not affect current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV infection.

Osteonecrosis

Although the etiology of this disease is multifactorial (including the use of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most often observed in patients at an advanced stage of HIV infection and/or long-term users of combination antiretroviral therapy. Patients should consult a doctor if they experience joint pain and stiffness or difficulty moving.

Impact on the ability to drive vehicles and machinery

Special studies have not been conducted to assess the effect of zidovudine and lamivudine on the ability to drive vehicles and operate machinery. The pharmacological properties of the active substances do not allow us to predict the effect of the drug Disaverox on these types of activities. However, when assessing a patient’s ability to drive and operate machinery, his clinical condition and the adverse reaction profile of Disaverox should be taken into account.

Active ingredient

Zidovudine, Lamivudine

Composition

For 1 tablet:

active ingredients:

lamivudine – 150 mg,

zidovudine – 300 mg;

auxiliary components of the core: pregelatinized starch, magnesium stearate, Primogel, microcrystalline cellulose, Aerosil grade A-300;

film coating: copolyvidone, glyceryl caprylocaprate, titanium dioxide, hypromellose, macrogol 6000, polydextrose.

Pregnancy

Fertility

There are no data on the effect of zidovudine and lamivudine on fertility in women. Zidovudine does not affect the number, morphology and motility of sperm in men.

Pregnancy

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

A large amount 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, we can conclude that when using the drug Disaverox in humans, the risk of congenital pathologies is unlikely.

The active ingredients of Disaverox can inhibit cellular DNA replication. Zidovudine has been shown to be a transplacental carcinogen in animal studies. The clinical significance of these data is unknown.

For HIV-infected women coinfected with hepatitis virus who are being treated with a lamivudine-containing medicinal product such as Disaverox, if pregnancy occurs, the possibility of relapse of hepatitis after discontinuation of lamivudine therapy should be considered.

Mitochondrial dysfunction

In vivo and in vitro studies have demonstrated that nucleoside and nucleotide analogues are capable of causing varying degrees of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogs in utero and/or the postpartum period.

Breastfeeding period

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

Based on a study of more than 200 mother/infant pairs receiving treatment for HIV infection, lamivudine concentrations in the serum of infants breastfed by mothers receiving treatment for HIV infection are very low (<4% of maternal serum concentrations) 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 under three months of age.

After a single dose of zidovudine 200 mg in HIV-infected women, the mean concentration of zidovudine in breast milk was similar to that in serum.

Women living with HIV are not recommended to breastfeed under any circumstances to avoid transmitting HIV to their baby.

Contraindications

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

– 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 degree of liver dysfunction (for this dosage form);

– Children weighing less than 30 kg (for this dosage form).

With caution

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

Side Effects

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

There are reports of lactic acidosis, including death, usually accompanied by severe hepatomegaly with steatosis, during zidovudine therapy.

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

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

In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction may develop against the background of asymptomatic opportunistic infections or their residual effects. Cases of the development of autoimmune diseases (for example, Graves’ disease) against the background of immune restoration have also been reported, but the time of initial manifestations varied and the disease could occur many months after the start of therapy.

Cases of osteonecrosis have been reported, especially in patients with recognized risk factors, at an advanced stage of HIV infection, or during long-term combined APT. The incidence of this phenomenon is unknown.

Adverse reactions assessed as associated or possibly associated with therapy with Disaverox are listed below according to the damage to organs and organ systems and the frequency of occurrence. The frequency of occurrence is defined as follows: very common (>1/10), common (>1/100 and 1/1000 and 1/10000 and <1/1000), very rare (<1/10000, including isolated cases). Within each frequency category, adverse reactions are presented in descending order of severity.

Lamivudine

Blood and lymphatic system disorders

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

Very rare: true erythrocyte aplasia.

Metabolic and nutritional disorders

Common: hyperlactatemia.

Very rare: lactic acidosis.

Nervous system disorders

Common: headache, insomnia.

Very rare: peripheral neuropathy (or paresthesia).

Respiratory, thoracic and mediastinal disorders

Common: cough, nasal symptoms.

Gastrointestinal disorders

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

Rarely: pancreatitis, increased serum amylase activity.

Disorders of the liver and biliary tract

Uncommon: transient increase in the activity of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST).

Rarely: hepatitis.

Skin and subcutaneous tissue disorders

Common: rash, alopecia.

Rarely: angioedema.

Musculoskeletal and connective tissue disorders

Common: arthralgia, muscle disorders.

Rare: rhabdomyolysis.

General and administration site disorders

Common: 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 transfusion), neutropenia and leukopenia. These adverse reactions occur more often when using higher doses of zidovudine (1200–1500 mg per day) and in patients at advanced stages of HIV infection (especially with reduced bone marrow reserve before treatment), in particular in patients with a CD4 cell count of less than 100/mm3. In some patients, it may be necessary to reduce the dose of zidovudine or discontinue it. Neutropenia occurs more often in patients whose neutrophil count, hemoglobin concentration and serum vitamin B12 concentration are reduced at the time of initiation of treatment with zidovudine.

Blood and lymphatic system disorders

Common: anemia, neutropenia and leukopenia.

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

Rare: true erythrocyte aplasia.

Very rare: aplastic anemia.

Metabolic and nutritional disorders

Common: hyperlactatemia.

Rarely: lactic acidosis in the absence of hypoxemia, anorexia.

Mental disorders

Rarely: anxiety, depression.

Nervous system disorders

Very common: headache.

Common: dizziness.

Rarely: insomnia, paresthesia, drowsiness, decreased mental activity, convulsions.

Heart disorders

Rarely: cardiomyopathy.

Respiratory, thoracic and mediastinal disorders

Uncommon: shortness of breath.

Rarely: cough.

Gastrointestinal disorders

Common: nausea.

Uncommon: flatulence.

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

Disorders of the liver and biliary tract

Often: increased blood levels of liver enzymes and bilirubin concentrations.

Rare: liver damage such as severe hepatomegaly with stenosis.

Skin and subcutaneous tissue disorders

Uncommon: rash and itching.

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

Musculoskeletal and connective tissue disorders

Common: myalgia.

Uncommon: myopathy.

Renal and urinary tract disorders

Rarely: frequent urination.

Disorders of the genital organs and mammary glands

Rare: gynecomastia.

General and administration site disorders

Often: general malaise.

Uncommon: fever, generalized pain and asthenia.

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

Data from two clinical studies (placebo-controlled and open-label) show that the incidence of nausea and other common clinical adverse reactions decreased consistently during the first few weeks of zidovudine treatment.

Interaction

Since the drug Disaverox contains zidovudine and lamivudine, it can enter into any interactions characteristic of each of these components separately. During clinical studies, no clinically significant interactions were identified between zidovudine and lamivudine.

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

Zidovudine and lamivudine are not significantly metabolized by cytochrome P450 enzymes (for example, CYP 3A4, CYP 2C9 or CYP 2D6), and they do not inhibit or induce this enzyme system. Therefore, interactions of zidovudine and lamivudine with protease inhibitors, non-nucleoside reverse transcriptase inhibitors and other antiretroviral drugs that are metabolized by major P450 enzymes are unlikely.

Drug interaction studies have only been conducted in adult patients. The list of interactions presented below should not be considered exhaustive, but it reflects classes of drugs in which caution should be exercised.

Medicines by area of ​​application

Interaction

Geometric mean change (%)

(possible mechanism)

Recommendations for combined use

ANTIRETROVIRAL MEDICINES

Didanosine + lamivudine

The interaction has not been studied.

No dose adjustment required.

Didanosine + zidovudine

The interaction has not been studied.

Stavudine + lamivudine

The interaction has not been studied.

Combined use is not recommended.

Stavudine + zidovudine

In vitro antagonism of anti-HIV activity between stavudine and zidovudine may result in reduced effectiveness of both drugs.

ANTI-INFECTIVE DRUGS

Atovachone + lamivudine

The interaction has not been studied.

Because limited data are available, the clinical significance is unknown.

Atovachone + 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 hours)

Zidovudine: AUC ↓ 12%

Trimethoprim + sulfamethoxazole (co-trimoxazole) + 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)

With the exception of patients with impaired renal function, no dose adjustment of Disaverox is required.

If concomitant use of co-trimoxazole is warranted, patients should be under clinical supervision.

Concomitant use of high-dose trimethoprim + sulfamethoxazole for the treatment of Pneumocystis jirovecii (P. carinii) pneumonia and toxoplasmosis has not been studied and should be avoided.

Trimethoprim + sulfamethoxazole (co-trimoxazole) + zidovudine

The interaction has not been studied.

ANTIFUNGAL DRUGS

Fluconazole + lamivudine

The interaction has not been studied.

Because limited data are available, the clinical significance is unknown. Monitor for signs of zidovudine toxicity.

Fluconazole + zidovudine

(400 mg once daily +

200 mg three times a day)

Zidovudine: AUC ↑ 74%

(UDP-GT inhibition)

ANTIMYCOBACTERIAL DRUGS

Rifampicin + lamivudine

The interaction has not been studied.

There are insufficient data to recommend dose adjustment.

Rifampicin + zidovudine

(600 mg once daily +

200 mg three times a day)

Zidovudine: AUC ↓ 48%

(induction of UDP-GT)

ANTICONVIVATIVE DRUGS

Phenobarbital + lamivudine

The interaction has not been studied.

There are insufficient data to recommend dose adjustment.

Phenobarbital + zidovudine

The interaction has not been studied.

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

Phenytoin + lamivudine

The interaction has not been studied.

It is necessary to monitor the concentration of phenytoin.

Phenytoin + zidovudine

Phenytoin: AUC ↑↓

Valproic acid + lamivudine

The interaction has not been studied.

Because limited data are available, the clinical significance is unknown. Monitor for signs of zidovudine toxicity.

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

Zidovudine: AUC ↑ 80%

(UDP-GT inhibition)

H2-HISTAMINE RECEPTOR BLOCKERS

Ranitidine + lamivudine

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

No dose adjustment 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 eliminated by active tubular secretion through the organic cation transport system.

No dose adjustment required.

Cimetidine + zidovudine

The interaction has not been studied.

CYTOTOXIC DRUGS

Cladribine + lamivudine

The interaction has not been studied.

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

Therefore, concomitant use of lamivudine and cladribine is not recommended.

OPIOID DRUGS

Methadone + lamivudine

The interaction has not been studied.

Because limited data are available, the clinical significance is unknown. Monitor for signs of zidovudine toxicity. In most cases, the need for methadone dose adjustment is unlikely, but sometimes the dose may need to be titrated again.

Methadone + zidovudine

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

Zidovudine: AUC ↑ 43%

Methadone: AUC ↔

URICOSURIC DRUGS

Probenecid + lamivudine

The interaction has not been studied.

Because limited data are available, the clinical significance is unknown. Monitor for signs of zidovudine toxicity.

Probenecid + zidovudine

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

Zidovudine: AUC ↑ 106%

(UDP-GT inhibition)

Abbreviations: ↑ = increase in indicator; ↓ = decrease in indicator; ↔ = no significant changes; AUC is the area under the concentration versus time curve.

Emtricitabine

Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when these drugs are administered concomitantly. In addition, the mechanism of viral resistance to lamivudine and emtricitabine is mediated by mutation of 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 simultaneous use of zidovudine and lamivudine leads to an increase in zidovudine exposure by 13% and an increase in its maximum plasma concentration by 28%. However, the total exposure of zidovudine (AUC) does not change significantly. Zidovudine has no effect on the pharmacokinetics of lamivudine.

Other drugs

Cases of exacerbation of anemia associated with ribavirin use have been reported when zidovudine was part of an HIV treatment regimen, but the exact mechanism is currently unknown. The simultaneous use of ribavirin and zidovudine is not recommended due to the increased risk of anemia.

If a combination APT regimen containing zidovudine is used, substitution of zidovudine should be considered. This is especially important for patients with a history of anemia caused by the use of zidovudine.

Concomitant treatment, especially intensive therapy, with potentially nephrotoxic or myelosuppressive drugs (such as systemic pentamidine, 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 the drug Disaverox and any of the listed drugs is necessary, particularly careful monitoring of renal function and hematological parameters is required. If necessary, reduce the dose of one or more medications.

Limited data obtained 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 information on the interaction of lamivudine and co-trimoxazole), pentamidine in aerosol form, pyrimethamine and acyclovir in prophylactic doses.

Overdose

Symptoms

Information about cases of drug overdose is limited. There are no specific symptoms or signs of acute overdose with lamivudine or zidovudine, other than those listed in the “Side Effects” section. None of the registered cases was accompanied by death; the condition of all patients returned to normal.

Treatment

In case of overdose, the patient should be under the supervision of a physician in order to identify signs of toxic effects of the drug, and if necessary, standard supportive therapy is carried out. Because lamivudine is eliminated by dialysis, continuous hemodialysis may be used to treat overdose, but no studies have been conducted to evaluate this method. It has been established that hemodialysis and peritoneal dialysis are ineffective for the elimination of zidovudine, but accelerate the elimination of its glucuronide metabolite. Prescribers are advised to refer to the individual zidovudine and lamivudine prescribing information for more detailed information.

Storage conditions

At a temperature not exceeding 25 °C, in original packaging

Shelf life

2 years

Manufacturer

Pharmasintez JSC, Russia