Videx^® (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 drug active against HIV. Didanosine (2′,3′-dideoxyinosine or ddI) is a synthetic nucleoside analogue of deoxyadenosine that suppresses HIV replication in cultured human cells and in cell lines in vitro.

After entering the cell, didanosine is converted by cellular enzymes into the active metabolite dideoxyadenosine triphosphate (ddATP). During viral nucleic acid replication, the incorporation of 2′,3′-dideoxynucleoside inhibits chain growth and thereby suppresses viral replication. In addition, ddATP inhibits the activity of HIV reverse transcriptase by competing with deoxyadenosine 5-triphosphate (dATP) for binding to the active sites of the enzyme, preventing the synthesis of proviral DNA.

Pharmacokinetics

Absorption

The AUC of didanosine in plasma and the C_max in plasma when taking capsules and tablets are equal. Compared to tablets, the absorption rate of the drug from capsules is lower, the C_max value when taking capsules is 60% of the C_max value when taking tablets. T_max is approximately 2 hours for capsules and 0.67 hours for tablets.

Tablets and powder for oral solution for children should be taken at least 30 minutes before or 2 hours after a meal. If the drug is taken earlier than 2 hours after a meal, C_max and AUC values decrease by approximately 55%. When the drug is taken with food, the bioavailability of didanosine decreases by approximately 50%.

Capsules should be taken on an empty stomach, at least 1.5 hours before or 2 hours after a meal. When capsules are taken with a fatty meal, C_max and AUC values decrease by 46% and 19%, respectively.

Metabolism

The metabolism of didanosine in humans has not been studied. Based on animal studies, it is assumed that in humans it occurs via the metabolic pathway of endogenous purines.

Excretion

After oral administration, the T_1/2 of the drug averages 1.6 hours, and approximately 20% of the administered dose is found in the urine. Renal clearance is 50% of the total clearance (800 ml/min), indicating active tubular secretion during the renal excretion of didanosine along with glomerular filtration.

Pharmacokinetics in special clinical cases

After oral administration, T_1/2 increases on average from 1.4 hours in patients with normal renal function to 4.1 hours in patients with severe renal impairment. Didanosine is not detected in peritoneal dialysis fluid, while during hemodialysis after 3-4 hours, didanosine concentrations are 0.6-7.4% of the administered dose. The absolute bioavailability does not change in patients with severe renal impairment compared to patients with normal renal function; however, the clearance of didanosine decreases in proportion to the creatinine clearance.

The metabolism of didanosine depends on the degree of liver dysfunction.

During a pharmacokinetic study in children aged 1 to 17 years, the absorption of didanosine varied widely. Despite this, C_max and AUC values increased proportionally with the dose. The absolute bioavailability of didanosine after oral administration was approximately 36% after the first dose and 47% at steady state.

T_1/2 averages about 0.8 hours. After the first oral dose, urinary concentrations of didanosine were 18% and 21% at steady state. Renal clearance is about 243 ml/m²/min, which was 46% of the total body clearance. As in adults, active tubular secretion was observed in children. No accumulation of didanosine was observed in children after oral administration for 26 days.

Indications

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

ICD codes

Dosage Regimen

Powder

The drug is administered orally.

Capsules

The recommended daily dose depends on body weight.

Capsules should be swallowed whole, without chewing, on an empty stomach.

Chewable tablets or tablets for oral suspension and powder for oral solution for children

The recommended daily dose depends on body weight. Tablets or powder are taken 1-2 times/day. When taking the drug twice daily, the interval between doses should be 12 hours.

The required dose can be selected by combining tablets of different strengths, avoiding possible overdose of antacids or phenylalanine contained in the tablets. Each dose of the drug should consist of at least 2 tablets, but no more than 4 tablets, in total not exceeding the recommended dose. Children under 1 year of age should receive 1 tablet per dose, which would provide a sufficient amount of antacids for this age group.

For children under 3 years of age, tablets are recommended to be administered only as a suspension. Tablets should be taken at least 30 minutes before or 2 hours after a meal. The tablet should be thoroughly chewed or dissolved in at least 30 ml of water, stirring thoroughly until a homogeneous suspension is obtained. For children, the recommended dose, equal to 1 tablet, is dissolved in 15 ml of water. To improve the taste, about 30 ml (for adults) or 15 ml (for children) of clear apple juice can be added.

After preparation, the resulting suspension should be stirred and drunk entirely. The resulting suspension is stable for 1 hour when stored at room temperature (17-23°C (63-73°F)).

For newborns and children under 8 months, the daily dose is calculated based on body surface area and is 100 mg/m² twice daily with a 12-hour interval.

For children over 8 months, the daily dose is 120 mg/m² twice daily with a 12-hour interval.

Powder for oral solution for children

The powder should be taken at least 30 minutes before or 2 hours after a meal only in mixture with antacids containing aluminum and magnesium hydroxides (oxides). Antacid preparations are divided into three groups (A, B and C) depending on their content of these active substances. The first column indicates the content of magnesium hydroxide (oxide) (in mg) per 5 ml of the preparation, the second – the amount of aluminum hydroxide that should be contained in the preparation, the third – the group to which the preparation belongs.

Before preparing the solution, it should be determined which group the patient’s antacid preparation belongs to.

* – if the magnesium hydroxide content falls between the indicated values, the preparation can be used provided that the minimum aluminum hydroxide content compensates for the reduced magnesium hydroxide content.

• For example, if a preparation contains 325 mg of magnesium hydroxide and a sufficient amount of aluminum hydroxide, then the preparation belongs to group A. The minimum aluminum hydroxide content is calculated as follows: a decrease in magnesium hydroxide content by 1 mg requires an increase in aluminum hydroxide content by at least 0.5 mg. In our example: a decrease in magnesium hydroxide content by 75 mg (from 400 mg to 325 mg) requires a minimum increase in aluminum hydroxide content by 37.5 mg (if rounded – 38 mg). Therefore, the aluminum hydroxide content in the preparation must be at least 438 mg.
• For example, if a preparation contains 175 mg of magnesium hydroxide and a sufficient amount of aluminum hydroxide, the preparation belongs to group B. The minimum aluminum hydroxide content is calculated as follows: a decrease in magnesium hydroxide content by 1 mg requires an increase in aluminum hydroxide content by at least 0.25 mg. In our example: a decrease in magnesium hydroxide content by 75 mg (from 250 mg to 175 mg) requires a minimum increase in aluminum hydroxide content by 18.75 mg (if rounded – 19 mg). Therefore, the aluminum hydroxide content in the preparation must be at least 219 mg.
• For example, if a preparation contains 85 mg of magnesium hydroxide and a sufficient amount of aluminum hydroxide, the preparation belongs to group C. The minimum aluminum hydroxide content is calculated as follows: a decrease in magnesium hydroxide content by 1 mg requires an increase in aluminum hydroxide content by at least 0.25 mg. In our example: a decrease in magnesium hydroxide content by 40 mg (from 125 mg to 85 mg) requires a minimum increase in aluminum hydroxide content by 10 mg. Therefore, the aluminum hydroxide content in the preparation must be at least 110 mg.

** – if the preparation contains aluminum oxide, its content is recalculated to aluminum hydroxide: 1 mg of aluminum oxide corresponds to 1.53 mg of aluminum hydroxide.

Preparation of solution with group A preparations

Add 100 ml of water up to the 100 ml mark on the bottle label, resulting in a solution with a didanosine concentration of 20 mg/ml. Mix well. Add the antacid suspension up to the 200 ml mark on the bottle label. The concentration of didanosine in the suspension is 10 mg/ml. Mix well.

Preparation of solution with group B preparations

Add 100 ml of antacid suspension up to the 100 ml mark on the bottle label, resulting in a suspension with a didanosine concentration of 20 mg/ml. Mix well. Add the antacid suspension up to the 200 ml mark on the bottle label. The concentration of didanosine in the suspension is 10 mg/ml. Mix well.

Preparation of solution with group C preparations

Add 100 ml of antacid suspension up to the 100 ml mark on the bottle label. Mix well. Add the antacid suspension up to the 200 ml mark on the bottle label. Mix well. Transfer the resulting suspension to a glass or plastic bottle of suitable size and add another 200 ml of antacid suspension to it. The concentration of didanosine in the resulting suspension is 5 mg/ml; the resulting suspension will last half as many days as when using group A and B antacids.

Store the prepared mixture in a tightly closed bottle in the refrigerator (from 2°C (35.6°F) to 8°C (46.4°F)) for no more than 30 days. Shake before use. Unused drug should be discarded after 30 days of storage.

For adults with impaired renal function, a dose reduction and/or an increase in the intervals between doses is recommended depending on creatinine clearance (CrCl).

^a – each dose of the drug should consist of at least 2 tablets, but no more than 4 tablets, in total not exceeding the recommended dose. The dose can be selected by combining tablets of different strengths.

^b– patients with body weight < 60 kg and CrCl < 10 ml/min should be prescribed another dosage form.

Patients on dialysis should take the daily dose of the drug after dialysis. There is no need for an additional dose of the drug.

For children with impaired renal function, there are no precise recommendations for adjusting the drug dose. A dose reduction and/or an increase in the interval between doses of the drug is possible.

For elderly patients, careful dose selection is necessary due to possible reduced renal function. Renal function should be monitored and the drug dose adjusted accordingly.

For patients with impaired liver function, a reduction in the drug dose may be required. There are no precise recommendations for changing the drug dose in case of impaired liver function. During treatment with the drug, liver enzyme levels should be examined. If liver enzyme levels are clinically significantly elevated, treatment with the drug should be suspended. With a rapidly increasing level of aminotransferases, it may be necessary to discontinue or suspend treatment with any nucleoside analogues.

Capsules

The drug is administered orally.

Capsules

The recommended daily dose depends on body weight.

Capsules should be swallowed whole, without chewing, on an empty stomach.

Chewable tablets or tablets for oral suspension

The recommended daily dose depends on body weight. Tablets are taken 1-2 times/day. When taking the drug twice daily, the interval between doses should be 12 hours.

The required dose can be selected by combining tablets of different strengths, avoiding possible overdose of antacids or phenylalanine contained in the tablets. Each dose of the drug should consist of at least 2 tablets, but no more than 4 tablets, in total not exceeding the recommended dose. Children under 1 year of age should receive 1 tablet per dose, which would provide a sufficient amount of antacids for this age group.

For children under 3 years of age, tablets are recommended to be administered only as a suspension. Tablets should be taken at least 30 minutes before or 2 hours after a meal. The tablet should be thoroughly chewed or dissolved in at least 30 ml of water, stirring thoroughly until a homogeneous suspension is obtained. For children, the recommended dose, equal to 1 tablet, is dissolved in 15 ml of water. To improve the taste, about 30 ml (for adults) or 15 ml (for children) of clear apple juice can be added.

After preparation, the resulting suspension should be stirred and drunk entirely. The resulting suspension is stable for 1 hour when stored at room temperature (17-23°C (63-73°F)).

For newborns and children under 8 months, the daily dose is calculated based on body surface area and is 100 mg/m² twice daily with a 12-hour interval.

For children over 8 months, the daily dose is 120 mg/m² twice daily with a 12-hour interval.

For adults with impaired renal function, a dose reduction and/or an increase in the intervals between doses is recommended depending on CrCl.

^a – each dose of the drug should consist of at least 2 tablets, but no more than 4 tablets, in total not exceeding the recommended dose. The dose can be selected by combining tablets of different strengths.

^b– patients with body weight < 60 kg and CrCl < 10 ml/min should be prescribed another dosage form.

For patients on dialysis, the drug is prescribed in the daily dose after dialysis. There is no need for an additional dose of the drug.

For children with impaired renal function, there are no precise recommendations for adjusting the drug dose. A dose reduction and/or an increase in the interval between doses of the drug is possible.

For elderly patients, careful dose selection is necessary due to possible reduced renal function. It is necessary to monitor renal function and adjust the drug doses accordingly.

For patients with impaired liver function, a reduction in the drug dose may be required. There are no precise recommendations for changing the drug dose in case of impaired liver function. During treatment with the drug, liver enzyme levels should be examined. If liver enzyme levels are clinically significantly elevated, treatment with the drug should be suspended. With a rapidly increasing level of aminotransferases, it may be necessary to discontinue or suspend treatment with any nucleoside analogues.

Adverse Reactions

Pancreatitis is a severe toxic effect of the drug.

Pancreatitis of varying severity, often fatal, may develop in a patient at different stages of treatment and does not depend on whether the drug is used as monotherapy or in combination with other drugs, or on the degree of immunosuppression.

Pancreatitis is a dose-dependent complication.

When using the suspension, data on the increase in pancreatic markers to a clinically significant level even in the absence of symptoms should be taken into account.

Lactic Acidosis/Severe Steatosis with Hepatomegaly, including fatal cases, have been reported with the use of nucleoside analogues as monotherapy or in combination with other antiviral drugs, including Didanosine.

This side effect was observed mainly in women.

Obesity and long-term use of nucleosides may be risk factors for this side effect.

Treatment with the drug should be discontinued if patients develop clinical or laboratory signs of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in transaminase activity).

Peripheral Neuropathy is usually accompanied by bilateral symmetric numbness of the extremities: tingling and pain in the feet (and, to a lesser extent, in the hands).

In the early stages of the disease, these phenomena are less frequent.

There is information that the course of peripheral neuropathy may be aggravated by the concomitant use of antiretroviral drugs, including Didanosine, and hydroxycarbamide.

From the Digestive System dry mouth, anorexia, nausea, vomiting, abdominal pain, diarrhea and flatulence, hepatitis, pancreatitis, increased activity of hepatic transaminases and alkaline phosphatase, hyperbilirubinemia, hypertrophy of the parotid salivary gland.

From the Nervous System paresthesia, pain in the hands and feet, headache.

From the Organ of Vision: dry eyes, optic neuritis, retinal depigmentation.

From the Musculoskeletal System: myalgia, arthralgia, myopathy, sialadenitis, rhabdomyolysis.

From the Hematopoietic Organs anemia, granulocytopenia, leukopenia, thrombocytopenia.

Laboratory Parameters hypo- and hyperkalemia, hyperuricemia, increased concentration of amylase and lipase, hypo- and hyperglycemia.

Other alopecia, anaphylactoid/allergic reactions, asthenia, chills, pruritus, skin rash, lipodystrophy, lipoatrophy.

Children

The side effects of the drug in children and adult patients are similar.

Development of pancreatitis in children is observed in 3% of cases when taken in doses not exceeding the recommended ones, and in 13% – when treated with the drug in increased doses.

Visual disturbances are rarely observed in children and are characterized by changes in the retina and optic neuritis.

Contraindications

• Children under 3 years of age (for capsules, contraindication due to the method of administration);
• Phenylketonuria;
• Lactation period;
• Hypersensitivity to didanosine and/or any of the excipients of the drug.

The drug should be used with caution in patients with an increased risk of developing pancreatitis, with a history of pancreatitis, with progressive HIV infection, in elderly patients, when treating patients with impaired renal function with uncorrected doses of the drug.

With special caution should be used in patients with impaired liver function.

Use in Pregnancy and Lactation

Adequate and controlled studies in pregnant women have not been conducted.

Videx^® should be used during pregnancy only if there are strict indications and only in cases where the potential benefit to the mother outweighs the possible risk to the fetus.

Breastfeeding should be discontinued during treatment with the drug.

Pediatric Use

Contraindication: children under 3 years of age (for capsules, contraindication due to the method of administration).

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

The relationship between HIV sensitivity to didanosine in vitro and the clinical response to treatment has not been established.

The results of in vitro sensitivity determination vary widely.

A positive in vivo correlation has been established between measurements of viral activity (e.g., by RNA polymerase chain reaction methods) and clinical disease progression.

Chewable tablets or tablets for preparation of oral suspension in children under 3 years of age are recommended to be used only as a suspension.

With simultaneous use of the drug Videx^® with drugs with known toxic effects on the peripheral nervous system or pancreas, the risk of manifestation of these toxic effects increases significantly.

With simultaneous administration of intravenous pentamidine or drugs that increase the activity of didanosine (hydroxycarbamide, allopurinol), it is recommended to use Videx^® in the form of a suspension.

It is necessary to periodically check vision and note any visual disturbances, such as altered color perception or blurred vision.

Children should be examined for retinal changes every 6 months or if any changes in vision occur.

Didanosine is rapidly destroyed in the acidic environment of gastric juice.

Therefore, to reduce acidity, antacids are included in the tablets.

The powder for preparation of oral solution for children should be taken only mixed with antacids.

In capsules, Didanosine is contained in the form of granules coated with an enteric coating, which increases the absorption of the drug in the intestine.

In HIV-infected patients with severe immunodeficiency during combined antiretroviral therapy, signs of an inflammatory reaction to asymptomatic or residual opportunistic infections may occur.

This syndrome was observed during the first few weeks or months after the initiation of antiretroviral therapy.

The occurrence of signs of cytomegalovirus retinitis, generalized or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci is possible.

If symptoms of pancreatitis appear, treatment with the drug should be suspended, and if the diagnosis is confirmed, treatment should be discontinued.

If there is a clinically significant excess of biochemical parameters even in the absence of symptoms of pancreatitis, the drug should be prescribed in the form of a suspension.

If clinically confirmed symptoms of hepatotoxicity or lactic acidosis appear (even if hepatic transaminases are slightly above the upper limit of normal), treatment with the drug should be suspended.

If these parameters are significantly above normal, treatment should be discontinued.

The absorption of didanosine, regardless of the dosage form, in the presence of food is reduced by an average of 50%.

Tablets and powder for preparation of oral solution for children should be taken 30 minutes before or 2 hours after meals, capsules should be taken on an empty stomach.

When prescribing the drug to patients with impaired renal function, it should be taken into account that each tablet contains 8.6 mEq of magnesium.

When prescribing the drug to patients with phenylketonuria, it should be taken into account that each 100 mg tablet contains 36.5 mg of phenylalanine as part of aspartame.

Capsules and powder for preparation of oral solution for children do not contain phenylalanine.

When prescribing the drug to patients on a salt-restricted diet, it should be taken into account that 100 mg of the capsule contents contain at least 0.424 mg of sodium.

Tablets do not contain sodium salts.

The powder for preparation of oral solution for children does not contain sodium salts.

However, the sodium content should be taken into account when selecting and calculating the amount of antacids.

The dosage forms do not contain sucrose, so there are no restrictions on the use of the drug in patients with diabetes mellitus.

Overdose

There is no antidote for didanosine overdose.

Symptoms pancreatitis, peripheral neuropathy, hyperuricemia, impaired liver function.

Treatment: Didanosine is not removed from the body by peritoneal dialysis and very little by hemodialysis.

During hemodialysis sessions lasting 3-4 hours, approximately 25-30% of didanosine is removed from the total concentration of didanosine circulating in the blood at the start of hemodialysis.

Drug Interactions

When using the drug Videx^® in combination with other drugs with similar toxicity (for example, with stavudine), the risk of developing the described side effects increases significantly.

Allopurinol is not recommended to be used simultaneously with the drug Videx^®.

The risk of developing pancreatitis increases in proportion to the increase in the concentration of the drug Videx^®.

When using the drug Videx^® in the form of tablets or powder for preparation of oral solution for children in patients with opioid dependence during long-term treatment with methadone, a decrease in the AUC of didanosine (by 57%) is observed.

With simultaneous use of the drugs, the dose of Videx^® should be increased.

When used concomitantly with tenofovir, a decrease in the plasma concentration of didanosine is observed, so the dose of the drug must be adjusted.

Delavirdine or indinavir should be taken 1 hour before taking the drug Videx^® in the form of tablets or powder for preparation of oral solution for children.

In the presence of the drug Videx^®, the AUC of delavirdine or indinavir increases significantly.

No drug interaction between indinavir and the drug Videx^® in capsules has been identified.

In special studies of multiple doses of the drug Videx^® simultaneously with nevirapine, rifabutin, foscarnet, ritonavir, stavudine and zidovudine and a single dose of the drug Videx^® simultaneously with loperamide, metoclopramide, ranitidine, sulfamethoxazole, trimethoprim, no drug interaction was identified.

Ketoconazole or itraconazole, the absorption of which when taken orally is affected by gastric acidity, should be taken 2 hours before taking the drug Videx^® in the form of tablets or powder for preparation of oral solution for children.

Videx^® capsules do not contain antacids, so there is no risk of interaction with these drugs.

When taking the drug Videx^® in the form of tablets or powder for preparation of oral solution for children 2 hours before or simultaneously with ganciclovir, the steady-state AUC of didanosine increases on average up to 111%.

A slight decrease in the steady-state AUC (by 21%) of ganciclovir was noted in cases where patients took Videx^® 2 hours before ganciclovir.

No changes in renal clearance were observed for either of these two drugs.

It is unknown whether these changes are associated with changes in the safety of Videx^® or the efficacy of ganciclovir.

There are no data confirming the enhancement of the myelosuppressive effects of ganciclovir by didanosine.

The plasma concentrations of tetracycline antibiotics and some fluoroquinolone antibiotics (e.g., ciprofloxacin) are reduced in the presence of antacids because they form chelate compounds.

Therefore, Videx^® tablets containing antacids, or powder for preparation of oral solution for children dissolved in an antacid suspension, should be taken at least 6 hours before or 2 hours after taking ciprofloxacin.

Videx^® capsules do not contain antacids, so there is no risk of interaction with tetracycline and fluoroquinolone antibiotics.

Ribavirin may increase the level of intracellular didanosine triphosphates and potentially increase the risk of side effects.

Cases of fatal hepatic failure, as well as cases of pancreatitis, peripheral neuropathy and systemic hyperlactatemia/lactic acidosis have been reported with the concomitant use of didanosine with ribavirin in combination with stavudine or without it.

Concomitant use of didanosine and ribavirin should be avoided unless the potential benefit of use outweighs the risk of side effects.

Less than 5% of didanosine is bound to plasma proteins, indicating a low likelihood of drug interactions involving a displacement mechanism from binding sites.

Storage Conditions

Chewable tablets or tablets for preparation of oral suspension, powder for preparation of oral solution for children should be stored at a temperature from 15°C (59°F) to 30°C (86°F).

Capsules should be stored at a temperature not exceeding 25°C (77°F).

The drug should be stored out of the reach of children.

Shelf Life

The shelf life of chewable tablets or tablets for preparation of oral suspension and capsules is 2 years, powder for preparation of oral solution for children is 3 years.

Do not take the drug after the expiration date indicated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.