ANTIRETROVIRAL DRUGS BACK Dinex-100 Tablets Warning PANCREATITIS, WHICH HAS BEEN FATAL IN SOME CASES, HAS OCCURRED DURING THERAPY WITH DIDANOSINE. DIDANOSINE USE SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (See Warnings and Precautions). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS INCLUDING FATAL CASES HAVE BEEN REPORTED WITH THE USE OF ANTIRETROVIRAL NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE (See Warnings and Precautions). Composition Each chewable tablet contains: Didanosine ......................... 100 mg Description Didanosine (formerly called dideoxyinosine-ddI) is a synthetic purine nucleoside analogue of the naturally occurring nucleoside deoxyadenosine, in which the 3' hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. This metabolite inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, and by its incorporation into viral DNA. The lack of a 3'-hydroxyl group in the incorporated nucleoside analogue prevents DNA chain elongation and therefore, the viral DNA growth is terminated. Indications Dinex-100 is indicated for the treatment of HIV infection when antiretroviral therapy is warranted. Dosage and Administration Adults: Dosage: The dosing interval should be 12 hours. Didanosine should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. Adult patients should take 2 tablets at each dose so that adequate buffering is provided to prevent gastric acid degradation of didanosine. No more than 4 tablets should be taken at each dose to reduce the risk of gastrointestinal side effects. The recommended starting dose in adults is dependent on weight, as outlined in the table below: Table 1: Adult Dosing Patient Weight Didanosine Tablets > 60 kg 200 mg b.d. < 60 kg 125 mg b.d. Administration: For full therapeutic effect, 2 tablets must be thoroughly chewed, crushed or dispersed in water before swallowing. The tablets should not be swallowed whole. To disperse the tablets, 2 tablets should be added to 2 tablespoons (30 ml) of water. The water should then be stirred until a uniform dispersion forms. The entire dispersion should be swallowed immediately. Dose Adjustment: Clinical signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. Didanosine use should be discontinued in patients with confirmed pancreatitis. Patients who have presented with symptoms of neuropathy may tolerate a reduced dose of didanosine after resolution of these symptoms upon drug discontinuation. In adult patients with impaired renal function, the dose of didanosine should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of didanosine in adult patients with renal insufficiency are given in the table below: Table 2: Recommended dose (mg) of didanosine by body weight Creatinine Clearance (mL/min) > 60 kg < 60 kg Interval (hr) > 60 kg 200 125 12 30-59 100 75 12 10-29 150 100 24 < 10 100 75 24 Patients requiring continuous ambulatory peritoneal dialysis (CAPD) or hemodialysis: It is recommended that one-fourth of the total daily dose of didanosine be administered once a day (See Table 2, recommended dosage for patients with CLCR < 10 mL/min). It is not necessary to administer a supplemental dose of didanosine following hemodialysis. Hepatic Impairment: See Warnings and Precautions. PAEDIATRICS Dosage: The recommended dose is 120 mg/m2 twice daily. Didanosine should be administered on an empty stomach, 30 minutes before or 2 hours after food. Tablets should be crushed, chewed or dispersed in water, as described for adults. Use at least 2 tablets per dose to provide adequate buffering. Maximum 4 tablets per dose. Contraindications Dinex-100 is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulation. Warnings and Precautions Pancreatitis Pancreatitis, which has been fatal in some cases, has occurred during therapy with didanosine. Didanosine use should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. When treatment with other drugs known to cause pancreatic toxicity is required, suspension of didanosine therapy is recommended. In patients with risk factors for pancreatitis, didanosine should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose-related. In phase 3 studies, incidence ranged from 1 to 10% with high dose and 1 to 7% with recommended dose. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including didanosine. Caution should be exercised when administering didanosine to any patient, and particularly to those with known risk-factors for liver disease. Treatment with didanosine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatoxicity. Retinal and Visual Changes Retinal changes and optic neuritis have been reported. Periodic retinal examinations should be considered for patients receiving didanosine (See 'Side Effects'). Hyperuricemia Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Impaired Renal Function Patients with renal impairment (creatinine clearance < 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance. A dose reduction is recommended in these patients (See 'Dosage and Administration'). Impaired Hepatic Function It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. Drug Interactions Coadministration of didanosine with drugs that are known to cause pancreatitis may increase the risk of this toxicity (See 'Warnings and Precautions') and should be done with extreme caution and only if clearly indicated. Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy and these patients may be at increased risk of neuropathy during didanosine therapy (See 'Side Effects'). Allopurinol: The AUC of didanosine was increased about 4-fold when allopurinol at 300 mg/day was coadministered with a single 200 mg dose of didanosine to two patients with renal impairment. The effects of allopurinol on didanosine pharmacokinetics in subjects with normal renal function are not known. Antacids: Concomitant administration of antacids containing magnesium or aluminium with didanosine may potentiate adverse events associated with the antacid components. Drugs whose absorption can be affected by the level of acidity in the stomach: Drugs such as ketoconazole and itraconazole should be administered at least 2 hours prior to dosing with didanosine. Ganciclovir: Administration of didanosine 2 hours prior to or concurrent with oral ganciclovir was associated with a 111% increase in the steady state AUC of didanosine. A 21% decrease in the steady-state AUC of ganciclovir was observed when didanosine was administered 2 hours prior to ganciclovir, but not when the two drugs were administered simultaneously. Quinolone antibiotics: Plasma concentrations of quinolone antibiotics are decreased when administered with antacids containing magnesium, calcium or aluminium. The optimal dosing interval for coadministration with didanosine should be determined by consulting the appropriate quinolone package insert. In the case of ciprofloxacin, didanosine should be administered at least 2 hours after or 6 hours before dosing with ciprofloxacin. Protease inhibitors: Separate dosing of indinavir or delavirdine by 1 hour. PREGNANCY Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed. LACTATION Although it is not known if didanosine is excreted in human milk, there is the potential for adverse effects from didanosine in nursing infants. Mothers should be instructed to discontinue nursing if they are receiving didanosine. Also, it is recommended that HIV-infected mothers do not breast feed their infants to avoid risking post-natal transmission of HIV infection. Side Effects The major toxicity of didanosine is pancreatitis. Other important toxicities include lactic acidosis/ severe hepatomegaly with steatosis and retinal/visual changes (See Warnings and Precautions). Adults: Clinical adverse events that occurred in at least 5% of adult patients in clinical trials with didanosine monotherapy are diarrhoea, neuropathy, chills/fever, rash/pruritus, abdominal pain, asthenia, headache, pain, nausea and vomiting and pancreatitis. The incidence of adverse events has been reported to be generally lower in patients with less advanced HIV disease. The frequency of peripheral neuropathy is related to dose and stage of disease. Patients should be monitored for the development of a neuropathy that is usually characterized by numbness, tingling or pain in the feet or hands. Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy and these patients may be at increased risk of neuropathy during didanosine therapy. The most frequently reported serious laboratory abnormalities with didanosine monotherapy are leukopenia, granulocytopenia and elevations of amylase, SGOT and SGPT values. Overdosage There is no known antidote for didanosine overdosage. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis. Presentation Dinex-100 Container pack of 60 tablets

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