Disaverox pills 300mg + 150mg 60pcs

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 brand A-300; film shell: copolividone, glyceryl caprylocaprate, titanium dioxide, hypromellose, macrogol 6000, polydextrose.

Pharmacological action

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 (TF). Zidovudine-TF and lamivudine-TF act as substrates and are competitive HIV reverse transcriptase inhibitors. Their main antiviral effect is the ability to integrate in the form of monophosphate into the viral DNA chain, leading to its breakage. 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, salzitabine and zidovudine). Also, no antagonistic effects were observed in vitro when using zidovudine and other antiretroviral drugs (tested substances: abacavir, didanosine, lamivudine and interferon alpha).

In vitro studies, lamivudine has a weak cytotoxic effect on peripheral blood lymphocytes, as well as on lymphocytic and monocytic-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 an 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 who have received antiretroviral therapy (APT), including lamivudine. The M184V mutation significantly reduces the 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 resistance to lamivudine. However, the clinical significance of such changes has not yet been definitively established.

The M184V mutation in the reverse transcriptase codon results in HIV cross-resistance only against antiretroviral drugs from the nucleoside inhibitor class. Zidovudine and stavudine remain active against lamivudine-resistant HIV-1 strains. Abacavir retains its antiretroviral activity against lamivudine-resistant HIV-1 strains with 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 salzitabine is determined; the clinical significance of these phenomena has not been established.

Resistance to thymidine analogs (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 analogs as a result of a combination of mutations in codons 41 and 215 or the accumulation of at least four of the six mutations. These mutations alone 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 multi-drug resistance mutations, the first of which is characterized by HIV reverse transcriptase mutations at codons 62,75,77,116 and 151, and the second usually includes the T 698 mutation in combination with the insertion of 6 pairs of nucleotides in 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 models of multiple nucleoside resistance mutations significantly limits future treatment options.

In clinical studies, the use of lamivudine in combination with zidovudine resulted in a decrease in the viral load of HIV-1 in the blood and an increase in the number of CD4 cells. Clinical evidence suggests that lamivudine in combination with zidovudine alone or as part of treatment regimens that include zidovudine significantly reduces the risk of HIV infection progression and mortality.

Monotherapy with zidovudine and lamivudine alone resulted in the development of clinical HIV strains with reduced sensitivity to these drugs and UIGO. 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 appearance of zidovudine-resistant strains.

Tests for HIV sensitivity to various antiretroviral drugs in vitro have not been standardized, so their results may be influenced by various methodological factors. The relationship between HIV sensitivity to zidovudine and / or lamivudine in vitro and clinical response to therapy is currently 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).

Combined 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

Absorption

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

After using 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) mcg/ml and 1.5 (1.3–1.8) mcg/ml, respectively. The median (range) t_{max values} of zidovudine and lamivudine were 0.50 (0.25–2.00) hours and 0.75 (0.50–2.00) hours, respectively. The degree of absorption (AUC) of zidovudine and lamivudine and the values of the half-life after food intake were similar to those after fasting, although the rate of absorption (_cmax, tmax) was reduced. The data obtained indicate the possibility of using the drug Disaverox regardless of food intake.

It is not expected that taking crushed tablets with a small amount of semi-solid food or liquid will affect the pharmacological properties of the drug and, therefore, the clinical effect. These conclusions are based on the physico-chemical and pharmacokinetic characteristics of the active ingredients and the nature of the dissolution of tablets with a fixed dose combination of zidovudine and lamivudine in vitro in water, provided that the patient grinds 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 slightly binds to 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 by displacing them from binding to plasma proteins is unlikely.

Available evidence suggests that zidovudine and lamivudine enter the central nervous system (CNS) and enter the cerebrospinal fluid (CSF). The average ratio of CSF concentrations of zidovudine and lamivudine to their serum concentrations 2-4 hours after oral use is approximately 0.5 and 0.12, respectively. The true extent of penetration, as well as the relationship with 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 low liver metabolism (5-10%) and low binding to plasma proteins.

Zidovudine 5′ – glucuronide is the main metabolite in both blood plasma and urine, with approximately 50-80% of the zidovudine dose taken being eliminated by renal excretion. 3′ – amino-3′ – deoxythymidine (AMT) was identified as a metabolite of zidovudine after intravenous use.

Deduction

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, which indicates 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 in all studied dosages in adults and children, its bioavailability is 60-74%, with an average value of 65%. The maximum concentration at steady state (C_SSmax) is 4,45 µmol/l (of 1.19 mcg/ml) after use of zidovudine in the form of a solution in a dose of 120 mg/m 2 of the body surface area and 7.7 mmol/l (of 2.06 µg/ml) after use of zidovudine dose of 180 mg/m 2 of the body surface area. The application of the dose of 180 mg/m2 four times daily in children resulted in a systemic exposure (AUC₂₄ = 40,0 h×mmol/l or 10.7 h×µg/ml), similar to that when used in a dose of 200 mg six times per day in adults (40,7 h×mmol/l or 10.9 h×µg/ml).

In six HIV-infected children aged 2 to 13 years, the pharmacokinetics of zidovudine in blood plasma were evaluated after use 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 blood plasma when using the twice-daily dosage regimen was equivalent to exposure when using the same total daily dose divided into three 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 with 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 can be reduced by about 30% compared to other age groups. Additional data are currently expected to support this conclusion; currently available data do not indicate lower efficacy of lamivudine in this age group.

Patients with impaired renal function

In studies involving patients with impaired renal function, it has been shown that when renal function is impaired, lamivudine excretion is impaired due to reduced renal clearance. Patients with creatinine clearance less than 50 ml/min should reduce the dose of the drug. An increase in zidovudine concentrations 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. Patients with severe hepatic impairment may need to adjust the dose of zidovudine.

Pregnancy

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

Indications

Treatment of HIV infection in adults and children with a body weight of at least 30 kg as part of combined antiretroviral therapy.

Use during pregnancy and lactation

Fertility

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

Pregnancy

Generally, when deciding whether to use antiretroviral drugs for the treatment of HIV infection in pregnant women and, as a result, to reduce the risk of vertical transmission of HIV infection to the newborn, data from animal studies, as well as clinical experience of use in pregnant women, should be taken into account. In this case, the use of zidovudine in pregnant women with subsequent treatment of newborn children 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 with simultaneous use of both drugs). Based on the above data, it can be concluded 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. In an animal study, zidovudine was shown to be a transplacental carcinogen. The clinical significance of these data is unknown.

For HIV-infected women with hepatitis co-infection who are being treated with a lamivudine-containing drug, such as Disaverox, the possibility of hepatitis recurrence after discontinuation of lamivudine therapy should be considered in the event of pregnancy.

Mitochondrial dysfunction

In vivo and in vitro studies have shown that analogues of nucleosides and nucleotides can cause various degrees of mitochondrial damage. Mitochondrial dysfunction has been reported in HIV-negative children exposed to nucleoside analogues in utero and / or in the postpartum period.

Breast-feeding period

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

Based on the results of a study of more than 200 mother/child couples treated for HIV infection, the concentration of lamivudine in the blood serum of children who are breastfed by mothers treated for HIV infection is very low ( There are no data on the safety of lamivudine use in children under three months of age.

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

Under no circumstances should HIV-infected women be encouraged to breastfeed to avoid transmission of HIV to their child.

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 liver function impairment (for this dosage form);

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

With caution

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

Side effects

Adverse reactions have been reported in the treatment of patients with HIV infection with zidovudine and lamivudine alone or in combination. For many adverse reactions, it remains unclear whether their occurrence is due to the use of zidovudine, lamivudine or other medications used to treat HIV infection, or whether they are the result of an underlying disease. Since Dizaverox contains both zidovudine and lamivudine, the following adverse reactions of the specified type and severity associated with each of these components can be expected. Currently, there is no evidence that the combination of zidovudine and lamivudine has increased toxicity.

Lactic acidosis, including fatal lactic acidosis usually associated with severe hepatomegaly with steatosis, has been reported during zidovudine therapy.

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

Body weight and serum lipids 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 against the background of asymptomatic opportunistic infections or their residual phenomena. Cases of autoimmune diseases (for example, Graves ‘ disease) have also been reported during immune recovery, 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 generally recognized risk factors, at an advanced stage of HIV infection, or with prolonged combined APT. The frequency of occurrence of this phenomenon is unknown.

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

Lamivudine

Disorders of the blood and lymphatic system

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

Very rarely: true erythrocytic aplasia.

Metabolic and nutritional

disorders are common: hyperlactatemia.

Very rarely: lactic acidosis.

Nervous system disorders

are Common: headache, insomnia.

Very rarely: peripheral neuropathy (or paresthesia).

Respiratory, thoracic, and mediastinal

disorders are common: cough, nasal symptoms.

Gastrointestinal disorders

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

Rarely: pancreatitis, increased serum amylase activity.

Liver and biliary tract disorders

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

Rarely: hepatitis.

Skin and subcutaneous tissue disorders

are common: rash, alopecia.

Rarely: angioedema.

Musculoskeletal and connective tissue

disorders are common: arthralgia, muscle disorders.

Rarely: rhabdomyolysis.

General disorders and disorders at the injection site

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 a blood transfusion), neutropenia, and leukopenia. These adverse reactions are more likely to occur when using higher doses of zidovudine (1200-1500 mg per day) and in patients with 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 cancel it. Neutropenia occurs more frequently in patients whose neutrophil count, hemoglobin concentration, and serum vitamin B12 concentrations are reduced at the time of initiation of zidovudine treatment.

Disorders of the blood and lymphatic system

are common: anemia, neutropenia and leukopenia.

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

Rarely: true erythrocytic aplasia.

Very rarely: aplastic anemia.

Metabolic and nutritional

disorders are common: hyperlactatemia.

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

Mental disorders

Rarely: anxiety, depression.

Nervous system disorders

Very often: headache.

Often: dizziness.

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

Cardiac disorders

Rarely: cardiomyopathy.

Respiratory, thoracic and mediastinal disorders

Infrequently: shortness of breath.

Rarely: cough.

Gastrointestinal disorders

are Common: nausea.

Infrequently: flatulence.

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

Liver and biliary tract disorders

are common: increased blood activity of liver enzymes and bilirubin concentration.

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

Skin and subcutaneous tissue disorders

Infrequently: rash and itching.

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

Musculoskeletal and connective tissue

disorders are common: myalgia.

Infrequently: myopathy.

Kidney and urinary tract disorders

Rarely: frequent urination.

Violation of the genitals and mammary glands

Rarely: gynecomastia.

General disorders and disorders at the injection site

Often: general malaise.

Infrequently: fever, generalized pain syndrome, and asthenia.

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

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

Interaction

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

Zidovudine is primarily metabolized by uridine diphosphate glucuronyltransferase (UDP-GT) enzymes; co – use of inducers or inhibitors of UDP-GT enzymes 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 (OST). 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 (e. g., CYP 3A4, CYP 2C9, or CYP 2D6), nor do they inhibit or induce this enzyme system. Thus, the interaction of zidovudine and lamivudine with protease inhibitors, non-nucleoside reverse transcriptase inhibitors and other antiretroviral drugs that are metabolized by the main P 450 enzymes is unlikely.

Drug interaction studies were conducted only with adult patients. The list of interactions presented below should not be considered exhaustive, but it reflects the classes of drugs that should be used with caution.

Medicinal products by application area	Interaction Geometric mean change (%) (possible mechanism)	Recommendations for the combined use
of ANTIRETROVIRAL DRUGS
Didanosine + lamivudine	The interaction has not been studied.	No dose adjustment is required.
Didanosine + zidovudine	The interaction has not been studied.
Stavudine + lamivudine	The interaction has not been studied.	Joint use is not recommended.
Stavudine + zidovudine	In vitro antagonism of anti-HIV activity between stavudine and zidovudine may lead to a decrease in the effectiveness of both drugs.
ANTI-INFECTIVE DRUGS
Atovahone + lamivudine	The interaction has not been studied.	Because limited data are available, clinical significance is unknown.
Atovahone + 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 the concomitant use of co‑trimoxazole is justified, patients should be under clinical supervision. Co-use with high doses of trimethoprim + sulfamethoxazole for the treatment of pneumonia caused by Pneumocystis jirovecii (P. carinii )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, clinical significance is unknown.Signs of zidovudine toxicity should be monitored.
Fluconazole + zidovudine (400 mg once a day + 200 mg three times a day)	Zidovudine: AUC ↑ 74% (inhibition of UDP-HT)
ANTIMYCOBACTERIAL DRUGS
Rifampicin + lamivudine	The 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% (inducing UDP-HT)
ANTICONVULSANTS
Phenobarbital + lamivudine	The interaction has not been studied.	There is insufficient data to recommend dose adjustment.
Phenobarbital + zidovudine	The interaction has not been studied. It is possible to slightly reduce the concentration of zidovudine in blood plasma by inducing UDP-HT.
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, clinical significance is unknown. Signs of zidovudine toxicity should be monitored.
Valproic acid + zidovudine (250 mg or 500 mg three times a day + 100 mg three times a day)	Zidovudine: AUC ↑ 80% (UDP-HT 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 is 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 is required.
Cimetidine + zidovudine	The interaction has not been studied.
CYTOTOXIC DRUGS
Cladribine + lamivudine	The interaction has not been studied. In vitro, lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a possible risk of loss of effectiveness of cladribine in the case of combination in clinical practice. Some clinical data also support a possible interaction between lamivudine and cladribine.	Therefore, the combined use of lamivudine and cladribine is not recommended.
OPIOID MEDICATIONS
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, it is unlikely that a dose adjustment of methadone will be necessary, but sometimes it may be necessary to re-titrate the dose.
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, clinical significance is unknown. Signs of zidovudine toxicity should be monitored.
Probenecid + zidovudine (500 mg four times a day + 2 mg / kg three times a day)	Zidovudine: AUC ↑ 106% (inhibition of UDP-HT)

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

Emtricitabine

Lamivudine may inhibit intracellular phosphorylation of emtricitabine when these drugs are co-administered. 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

Concomitant use of zidovudine and lamivudine resulted in a 13% increase in zidovudine exposure and a 28% increase in its maximum plasma concentration. However, the total zidovudine exposure (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Other medications

Cases of acute anemia associated with ribavirin use have been reported 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 due to the increased risk of anemia.

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

Concomitant treatment, especially intensive care, 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 the concomitant use of Disaverox and any of the listed medications is necessary, especially careful monitoring of renal function and hematological parameters is required. If necessary, reduce the dose of one or more medications.

Limited data obtained in clinical trials do not indicate a significant increase in the risk of adverse reactions to zidovudine when co-administered with co-trimoxazole (see above for information on the interaction of lamivudine and co-trimoxazole), pentamidine in aerosol form, pyrimethamine and acyclovir in preventive doses.

How to take, course of use and dosage

The drug Disaverox is taken orally, regardless of food intake.

Therapy with Disaverox should be initiated and supervised by a doctor who has experience in the treatment of HIV infection.

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

If it is necessary to reduce the dose or cancel one of the components of the drug Disaverox (zidovudine or lamivudine), separate preparations of zidovudine and lamivudine should be used.

Special patient groups

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

The recommended dose of Disaverox is 1 tablet twice a day.

Elderly patients

There are no specific data on the use of Disaverox in the elderly, but special care should be taken when treating elderly patients, taking into account age-related changes, such as impaired renal function and changes in hematological parameters.

Patients with impaired renal function

Patients with creatinine clearance less than 50 ml/min require dose adjustment of lamivudine, so the use of separate drugs zidovudine and lamivudine is recommended in these patients.

Patients with impaired liver function

Limited data obtained in patients with cirrhosis of the liver indicate the possibility of accumulation of zidovudine in patients with impaired liver function due to a decrease in the rate of formation of glucuronide. Data obtained from the use of lamivudine in patients with moderate to severe hepatic impairment indicate that impaired liver function does not significantly affect the pharmacokinetics of lamivudine. However, it may be necessary to adjust the dose of zidovudine, so in patients with severe hepatic impairment, the use of separate drugs zidovudine and lamivudine is recommended. Treating physicians should refer to the instructions for medical use for these medications.

Patients with hematological adverse reactions

If the hemoglobin concentration is reduced to less than 9 g / dl (5.59 mmol / L) or if neutropenia occurs (neutrophil count is less than 1.0×109/L), zidovudine dose adjustment may be required. Since dose adjustment of Disaverox is not possible, separate zidovudine and lamivudine preparations should be used.

Overdose

Symptoms

Information on overdose cases is limited. No specific symptoms or signs of acute overdose with lamivudine or zidovudine have been identified, other than those listed in the “Side Effects”section. None of the reported cases was accompanied by a fatal outcome, the condition of all patients returned to normal.

Treatment

In case of overdose, the patient should be monitored by a doctor in order to detect signs of toxic effects of the drug, if necessary, standard maintenance therapy is carried out. Since lamivudine is eliminated by dialysis, continuous hemodialysis can be used to treat overdose, but no studies have been conducted to evaluate the use of this method. It was found that hemodialysis and peritoneal dialysis are ineffective for the elimination of zidovudine, but accelerate the elimination of its glucuronide metabolite. Treating physicians are advised to refer to the instructions for use of individual medications zidovudine and lamivudine for more detailed information.

Special instructions

Special instructions for zidovudine and lamivudine are given below. There are no additional special instructions related to the drug Disaverox.

If dose adjustment is necessary, the use of separate drugs zidovudine and lamivudine is recommended. In such cases, the attending physician should refer to the separate instructions for use for these medications.

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

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

Concomitant use of stavudine and zidovudine should be avoided.

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

Simultaneous use of lamivudine and cladribine is not recommended.

Opportunistic infections

The use of Dizaverox or any other antiretroviral drugs does not exclude the possibility of developing opportunistic infections or other complications of HIV infection, so patients should remain under close clinical supervision of doctors who have experience in treating HIV infection.

Hematological disorders

Patients treated with zidovudine may be expected to develop anemia, neutropenia, and leukopenia (usually secondary to neutropenia). Most often, these phenomena develop with the use of higher doses of zidovudine (1200-1500 mg / day), in patients with late-stage HIV infection and in patients with reduced bone marrow reserve before starting treatment. Therefore, in patients taking the drug Disaverox, it is necessary to carefully monitor hematological parameters.

These hematological disorders usually occur no earlier than 4-6 weeks after the start of therapy. For patients with late-stage HIV infection with symptoms, it is recommended that a blood test be performed at least every two weeks during 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 general condition of the patient, a blood test can be performed less frequently, for example, every 1-3 months.

If severe anemia or myelosuppression develops during treatment with Disaverox, as well as in patients with pre-existing bone marrow dysfunction, for example, with a hemoglobin concentration of less than 9 g/dl (5.59 mmol/L) or a neutrophil count of less than 1.0×109/L, zidovudine dose adjustment may also be required.

Since no dose adjustment is possible when using the drug Disaverox, such patients should be prescribed zidovudine and lamivudine as separate drugs.

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

Lactic acidosis

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

Lactic acidosis is characterized by high mortality and can develop on the background of pancreatitis, liver failure or kidney failure.

Lactic acidosis usually develops after several months of treatment.

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

Caution should be exercised when using Disaverox for the treatment of any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver damage and hepatic steatosis (including the use of certain medications and alcohol consumption). Patients with hepatitis C virus co-infection treated with interferon alpha and ribavirin may be particularly at risk.

Patients in the high-risk group should be carefully monitored.

Lipoatrophy

Treatment with zidovudine was accompanied by loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to the total drug exposure. This loss of fat, which is most pronounced in the face, limbs, and buttocks, can only be partially reversed, and improvement may occur only a few months after switching to a zidovudine-free treatment regimen. During therapy with zidovudine and other drugs containing zidovudine, patients should be regularly examined for signs of lipoatrophy, and if lipoatrophy is suspected, they should switch to an alternative therapy regimen if possible.

Body weight and metabolic parameters

During antiretroviral therapy, an increase in body weight, an increase in the concentration of lipids and blood glucose may occur. Disease control and lifestyle changes can also contribute to this process. In some cases, data have been obtained indicating an association of increased lipid concentrations with therapy, but there is no strong evidence for an association of increased body weight with any particular therapy. Determination of blood lipids and glucose should be carried out in accordance with established guidelines for the treatment of HIV infection. Violations of lipid metabolism should be corrected in accordance with the clinical manifestations.

Immune recovery 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 lead to a serious deterioration of the condition or aggravation of symptoms. These reactions usually occur within the first few weeks or months after the start of 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 (such as Graves ‘ disease, polymyositis, and Guillain-Barre syndrome) They were also observed against the background of restoring immunity, but the time of primary manifestations varied, and the disease could occur many months after the start of therapy and sometimes had an atypical course.

Liver diseases

If lamivudine is used simultaneously for the treatment of 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 instructions for medical use for lamivudine preparations in a dosage of 100 mg.

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

Patients with concomitant chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of developing severe and potentially fatal adverse liver reactions. In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the relevant instructions for the use of these medications.

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

Patients with pre-existing hepatic impairment, including active chronic hepatitis, show an increased incidence of hepatic impairment during combination antiretroviral therapy. Such patients should be monitored in accordance with standard clinical practice. Consideration should be given to suspending or discontinuing treatment in the event of worsening liver disease in such patients.

Concomitant viral hepatitis C

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

Mitochondrial dysfunction as a result of intrauterine exposure

Analogues of nucleosides and nucleotides can affect mitochondrial function to varying degrees, which is most pronounced when using 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, hyperlipazemia). 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 probability of mitochondrial dysfunction should be considered in any child exposed to intrauterine exposure to nucleoside and nucleotide analogues, with severe clinical symptoms of unclear etiology, especially neurological disorders. These data do not affect the current national guidelines for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV infection.

Osteonecrosis

Despite the fact that 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 taking long-term combination antiretroviral therapy. Patients should consult a doctor if they experience joint pain and stiffness or difficulty moving.

Influence on the ability to drive vehicles and mechanisms

Special studies to assess the effect of zidovudine and lamivudine on the ability to drive vehicles and work with mechanisms have not been conducted. The pharmacological properties of the active ingredients do not allow predicting the effect of the drug Disaverox on these activities. However, when assessing the patient’s ability to drive vehicles and work with mechanisms, it is necessary to take into account his clinical condition and the profile of adverse reactions of the drug Disaverox.

Storage conditions

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

Shelf life

2 years

Active ingredient

: Zidovudine, Lamivudine

Conditions of release from pharmacies

By prescription

Dosage form

Tablets