Didanosine (Capsules, Powder) Instructions for Use

ATC Code

J05AF02 (Didanosine)

Active Substance

Didanosine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Antiviral agent, nucleoside reverse transcriptase inhibitor, synthetic analogue of deoxyadenosine (a purine nucleoside). Active against HIV. After didanosine penetrates the cell, it is metabolized by cellular enzymes to the active metabolite – dideoxyadenosine triphosphate, which inhibits HIV reverse transcriptase. Under the action of didanosine, the number of cells with CD4⁺ receptors increases, which is considered confirmation of antiviral action. Simultaneously, peripheral blood parameters and the content of the viral protein (P24 antigen) in the blood normalize.

Pharmacokinetics

Didanosine is rapidly degraded at acidic pH values. Therefore, all oral dosage forms contain buffering substances that increase the pH of gastric juice and thereby reduce the degradation of didanosine and enhance its absorption. C_max in plasma is reached within 0.5-1 h. Penetrates the BBB. V_d is 0.7-1 L/kg. T_1/2 is 1.5 h. Excreted in urine.

Indications

Treatment of HIV-1 infection (in combination with other antiretroviral drugs).

ICD codes

Dosage Regimen

Administer orally on an empty stomach, at least 30 minutes before or 2 hours after a meal.

Determine the dose individually based on the patient’s body weight and renal function.

For adult and adolescent patients weighing 60 kg or more, the typical dose is 400 mg once daily.

For adult and adolescent patients weighing less than 60 kg, the typical dose is 250 mg once daily.

Adjust the dose in patients with renal impairment according to creatinine clearance (CrCl).

For patients weighing ≥60 kg and CrCl 30-59 mL/min, reduce the dose to 200 mg. For CrCl 10-29 mL/min, reduce to 125 mg. For CrCl <10 mL/min, reduce to 125 mg.

For patients weighing <60 kg and CrCl 30-59 mL/min, reduce the dose to 150 mg. For CrCl 10-29 mL/min, reduce to 100 mg. For CrCl <10 mL/min, reduce to 75 mg.

When used in combination therapy with tenofovir, reduce the didanosine dose to 250 mg (for patients ≥60 kg) or 200 mg (for patients <60 kg).

Do not administer concomitantly with allopurinol or ribavirin.

Carefully monitor for signs of pancreatitis, lactic acidosis, peripheral neuropathy, and retinal changes.

Adverse Reactions

From the digestive system and liver anorexia, dyspepsia, nausea, vomiting, abdominal pain, diarrhea, increased gas formation, hepatitis, hepatic failure, portal hypertension not associated with liver cirrhosis, pancreatitis (including fatal), lactic acidosis/severe steatosis with hepatomegaly, hypertrophy of the parotid salivary gland, sialadenitis, dry mouth.

From the organ of vision dry eyes, retrobulbar neuritis, retinal depigmentation.

From the musculoskeletal system myalgia (with or without elevated creatine kinase levels), arthralgia, myopathy, rhabdomyolysis (including acute renal failure).

From the hematopoietic system anemia, granulocytopenia, leukopenia, thrombocytopenia.

From the endocrine system diabetes mellitus, hypoglycemia, hyperglycemia.

From laboratory parameters hypokalemia, hyperkalemia, hyperuricemia, increased activity of amylase, lipase, AST, ALT, ALP, hyperbilirubinemia.

Other alopecia, anaphylactoid reactions, asthenia, chills/fever, pain, redistribution/accumulation of adipose tissue.

Contraindications

Hypersensitivity to didanosine; simultaneous use with allopurinol, ribavirin; simultaneous use with stavudine; breastfeeding period.

With caution in patients with an increased risk of developing pancreatitis, with a history of pancreatitis, in patients with risk factors for the development of lactic acidosis (obesity, long-term treatment with nucleotide analogues), with progressive HIV infection, with a history of peripheral neuropathy, in patients taking neurotoxic drugs (increased risk of developing peripheral neuropathy), in elderly patients, when treating patients with impaired renal function with uncorrected doses of the drug, in patients with eye diseases (due to the risk of developing neuritis and retinal changes). Particular caution should be exercised in patients with impaired liver function due to the risk of developing severe hepatomegaly with steatosis. For patients with body weight < 60 kg and creatinine clearance < 10 ml/min, the use in the form of appropriate dosage forms is recommended.

Use in Pregnancy and Lactation

Adequate and strictly controlled studies of the safety of didanosine use during human pregnancy have not been conducted. Use during pregnancy is possible only if there are clear indications, in cases where the potential benefit of therapy for the mother outweighs the existing risk to the fetus.

It is not known whether Didanosine is excreted in breast milk. If it is necessary to use during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Caution should be exercised when using in patients with impaired liver function due to the risk of developing severe hepatomegaly with steatosis.

Use in Renal Impairment

Caution should be exercised when using in patients with impaired renal function. Dose adjustment is required.

Pediatric Use

Children should undergo periodic ophthalmological examination.

In children under 3 years of age and weighing less than 25 kg, Didanosine should be used with caution, in appropriate doses and dosage forms.

Geriatric Use

Caution should be exercised when using in elderly patients due to possible decreased renal function. It is necessary to monitor renal function and accordingly adjust didanosine doses.

Special Precautions

Didanosine should be used with caution if there is a history of pancreatitis.

During treatment, the levels of amylase, transaminases, bilirubin, peripheral blood picture, renal function parameters, and T-lymphocyte content should be regularly monitored.

When using didanosine, men and women of childbearing age should use reliable methods of contraception.

Nucleoside analogues (including Didanosine) can affect mitochondrial function to varying degrees. Therapy with didanosine is associated with severe side effects, including lactic acidosis, lipoatrophy, polyneuropathy, which are based on the development of mitochondrial toxicity.

Due to the potential risk of developing severe and/or life-threatening side effects, especially lactic acidosis, liver dysfunction, pancreatitis and peripheral neuropathy, the combined use of didanosine and stavudine is contraindicated.

When didanosine is used concomitantly with drugs that have toxic effects on the peripheral nervous system or pancreas, the risk of these toxic effects increases significantly.

When intravenous pentamidine or drugs that increase the activity of didanosine (hydroxycarbamide, allopurinol) are used concomitantly, didanosine therapy is recommended to be suspended.

Visual disturbances. Cases of retinal dysfunction and retrobulbar neuritis have been reported with the use of didanosine. It is necessary to periodically check vision and note any visual disturbances, such as altered color perception or blurred vision. Children should have their retina examined every 6 months or if any vision changes occur. The decision to change therapy can be made based on patient examination and benefit/risk assessment.

Liver disease. The efficacy and safety of didanosine in patients with a history of liver dysfunction have not been established. During combination antiretroviral therapy in such patients, including patients with active chronic hepatitis, the frequency of liver dysfunction, including severe and potentially life-threatening, increases. If the condition of such patients worsens, or if liver enzyme activity increases above a clinically significant level, didanosine therapy should be suspended or discontinued.

Hepatotoxicity and fatal liver failure have been reported in HIV-infected patients during combination antiretroviral therapy with hydroxycarbamide. Cases of fatal liver dysfunction have been reported in such patients when using the combination of hydroxycarbamide, Didanosine and stavudine, therefore the combined use of these drugs is contraindicated.

Immune reconstitution syndrome. In HIV-infected patients with severe immunodeficiency, signs of an inflammatory reaction to asymptomatic or residual opportunistic infections may occur during combination antiretroviral therapy. This syndrome was observed during the first few weeks or months after the start of antiretroviral therapy. Signs of cytomegalovirus retinitis, generalized or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii may occur. If necessary, appropriate therapy should be prescribed.

Cases of autoimmune diseases (e.g., Graves’ disease) occurring during immune reconstitution have been reported, but the time of onset of such diseases varied among patients and could occur many months after the start of therapy.

Lipoatrophy. Due to the development of mitochondrial toxicity, the use of didanosine may cause a reduction in subcutaneous adipose tissue, especially in the face, limbs, and buttocks. The extent and severity of lipoatrophy are associated with the cumulative effect of didanosine, and lipoatrophy is often irreversible even after discontinuation of didanosine. Monitoring for the development of lipoatrophy should be carried out. If symptoms of lipoatrophy develop, didanosine therapy should be discontinued.

Body weight and metabolic parameters. During antiretroviral therapy, an increase in body weight and plasma lipid and glucose concentrations may be observed; in some cases, for example, regarding lipids, this is an indicator of therapy effectiveness, regarding weight gain – there is no evidence of such a relationship.

Pancreatitis. Pancreatitis is a severe toxic effect of didanosine use. Pancreatitis of varying severity, often fatal, can develop in a patient at different stages of treatment and does not depend on whether Didanosine is used as monotherapy and in combination with other drugs, or on the degree of immunosuppression. Pancreatitis is a dose-dependent complication. Patients taking Didanosine in combination with stavudine, hydroxycarbamide, are at a higher risk of developing this side effect. The risk of developing pancreatitis increases in elderly patients, in patients with a history of pancreatitis, with impaired renal function in the absence of appropriate adjustment of the didanosine dose, as well as in patients with progressive HIV infection.

In patients with risk factors for developing pancreatitis, Didanosine should be used with caution.

If symptoms of pancreatitis appear, didanosine treatment should be suspended, and if the diagnosis is confirmed, treatment should be discontinued. If there is a clinically significant excess of biochemical markers, even in the absence of symptoms of pancreatitis, treatment should also be suspended.

Lactic Acidosis/Severe Steatosis with Hepatomegaly. Lactic acidosis/severe steatosis with hepatomegaly, including fatal cases, have been reported with the use of nucleoside reverse transcriptase inhibitors as monotherapy or in combination with other antiretroviral drugs, including Didanosine. Mainly, this side effect was observed in women. Obesity and long-term use of nucleoside reverse transcriptase inhibitors may be risk factors for this side effect. In pregnant women, the risk of fatal lactic acidosis increases when taking didanosine in combination with stavudine or other antiretroviral drugs. Particular caution should also be exercised when using didanosine in patients with a history of liver dysfunction, however, cases of lactic acidosis and steatosis have been reported in patients without any known risk factors.

If clinically confirmed symptoms of symptomatic hyperlactatemia, hepatotoxicity or lactic acidosis (which may include hepatomegaly and steatosis even in the absence of obvious signs of increased liver transaminase activity) appear, with or without changes in laboratory parameters, didanosine treatment should be suspended. If there is a significant excess of liver enzyme activity and bilirubin, treatment should be discontinued.

Portal Hypertension Not Associated with Liver Cirrhosis. Cases of portal hypertension not associated with liver cirrhosis have been reported, including cases leading to liver transplantation, as well as fatal outcomes. Portal hypertension not associated with liver cirrhosis caused by didanosine intake was confirmed in patients with unconfirmed viral hepatitis. The first signs and symptoms of portal hypertension appeared from several months to several years after the start of didanosine therapy. Common signs of portal hypertension development included increased liver enzyme activity, esophageal varices, hematemesis, ascites, splenomegaly. Patients receiving Didanosine should be regularly examined for early signs of portal hypertension. Didanosine intake should be discontinued if the patient shows signs of portal hypertension not associated with liver cirrhosis.

Peripheral Neuropathy. Peripheral neuropathy is usually accompanied by a bilateral symmetrical feeling of numbness of the extremities: tingling and pain in the feet and, less commonly, in the hands. These phenomena occur more often in the late stages of the disease, in patients with a history of neuropathy or with prior neurotoxic therapy, including stavudine. If peripheral neuropathy phenomena appear, didanosine therapy should be discontinued.

Drug Interactions

When didanosine is used in combination with other drugs with similar toxicity, the risk of developing side effects increases significantly.

Allopurinol. The risk of developing pancreatitis may increase in proportion to the increase in didanosine concentration caused by the combined use of didanosine and allopurinol. In this regard, the combined use of allopurinol and didanosine is contraindicated.

Methadone. When didanosine and methadone are used concomitantly, a decrease in the AUC value of didanosine is observed. If concomitant use of the drugs is necessary, it is recommended to use Didanosine in appropriate dosage forms. Patients should be carefully examined for the adequacy of the clinical response, including monitoring changes in HIV RNA levels.

Tenofovir disoproxil fumarate. When used concomitantly, an increase in the plasma concentration of didanosine is observed, so the dose of didanosine in capsules must be adjusted.

Increased didanosine concentration when taken concomitantly with tenofovir disoproxil fumarate may cause or enhance Didanosine-dependent side effects, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis and peripheral neuropathy. When using didanosine and tenofovir disoproxil fumarate concomitantly, caution should be exercised, and the clinical response and development of Didanosine-dependent side effects should be monitored. Didanosine intake should be suspended if the patient develops symptoms of pancreatitis, symptomatic hyperlactatemia or lactic acidosis.

Ribavirin may increase the intracellular content of didanosine triphosphate and potentially increase the risk of side effects. When didanosine was used concomitantly with ribavirin in combination with stavudine or without it, cases of fatal liver failure, as well as cases of pancreatitis, peripheral neuropathy and symptomatic hyperlactatemia/lactic acidosis, have been reported. In this regard, the combined use of didanosine and ribavirin is contraindicated.

Drugs with neurotoxic effects. When used concomitantly with didanosine, caution should be exercised due to an increased risk of developing neuropathy.

Drugs with pancreatotoxic effects. When used concomitantly with didanosine, particular caution should be exercised due to an increased risk of developing pancreatitis. If the use of such drugs is necessary, the use of didanosine should be suspended.

Nelfinavir. No clinically significant changes in the pharmacokinetic parameters of nelfinavir were observed when taken 1 hour after didanosine intake.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

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