COMPOSITION:
Each tablet contains:
Didanosine 25/50/100/250/400 mg
(Chewable and Buffered Tablets)
Pharmacodynamics / Pharmacokinetics

PHARMACODYNAMICS:
Nucleoside reverse transcriptase inhibitor: ATC Code: J05AF02
Didanosine is an inhibitor of the in vitro replication of the Human Immunodeficiency Virus (HIV) [(also known as HTLV III, LAV)] in human primary cell cultures and in established cell lines. After Didanosine enters the cell, it is enzymatically converted to dideoxyadenosine triphosphate (ddATP), its active metabolite. In viral nucleic acid replication, incorporation of this 2',3'-dideoxynucleoside prevents chain extension and thereby inhibits viral replication. In addition, ddATP inhibits HIV- reverse transcriptase by competing with dATP for binding to the enzyme's active site, preventing proviral DNA synthesis. The relationship between in vitro susceptibility of HIV to didanosine and clinical response to therapy has not been established. Likewise, in vitro sensitivity results vary greatly and methods to establish virologic responses have not been pro

PHARMACOKINETIC:Adults
Absorption: Didanosine is rapidly degraded at an acidic pH. Therefore, the tablets contain buffering agents designed to increase gastric pH. The administration of didanosine with a meal results in a significant decrease (about 50%) in bioavailability. Didanosine tablets should be administered at least 30 minutes before a meal. A study in 10 asymptomatic HIV seropositive patients demonstrated that administration of Didanosine tablets 30 min to 1 hour before a meal did not result in any significant changes in the bioavailability of didanosine compared to administration under fasting conditions.
Administration of the tablets 1 to 2 hours after a meal was associated with a 55% decrease in Cmax and AUC values, which was comparable to the decrease observed when the formulation was given immediately after a meal. In 30 patients receiving didanosine 400 mg once daily in the fasted state as Didanosine buffered tablets, single dose AUC was 2516 ± 847 ng·h/ml (34%) (mean ± SD [%CV]) and Cmax was 1475 ± 673 ng/ml (46%).

Contraindications
Didanosine is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulation.

Pregnancy and Lactation
Pregnancy: There are no adequate and well-controlled studies in pregnant women and it is not known whether didanosine can cause foetal harm or affect reproductive capacity when administered during pregnancy. Lactic acidosis, sometimes fatal, has been reported in pregnant women who received the combination of didanosine and stavudine with or without other antiretroviral treatment. Therefore, the use of didanosine during pregnancy should be considered only if clearly indicated, and only when the potential benefit outweighs the possible risk. Teratology studies in rats and rabbits did not produce evidence of embryotoxic, foetotoxic, or teratogenic effects. A study in rats showed that didanosine and/or its metabolites are transferred to the foetus through the placenta.

Lactation: It is not known whether didanosine is excreted in human milk. It is recommended that women taking didanosine do not breast-feed because of the potential for serious adverse reactions in nursing infants. At the 1000 mg/kg/day dose levels in rats, didanosine was slightly toxic to females and pups during mid and late lactation (reduced food intake and body weight gains), but the physical and functional development of the subsequent offsprings were not impaired. A further study showed that, following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats.

Side Effects
The major toxicity of didanosine is pancreatitis. Other important toxicities include lactic acidosis/ severe hepatomegaly with steatosis and retinal/visual changes.

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 most frequently reported serious laboratory abnormalities with didanosine monotherapy are leukopenia, granulocytopenia and elevations of amylase, SGOT and SGPT values.

Children: Almost all 98 children treated in the clinical trials presented with various signs and symptoms at the time of enrollment. During the studies, the most frequently reported adverse signs and symptoms were generally those also seen in adults.
Other serious paediatric clinical adverse events reported include retinal depigmentation, seizure, neurologic effects, pneumonia, diabetes mellitus and diabetes insipidus.

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:

Patient Weight Didanosine Tablets
> 60 kg 200 mg b.d.
< 60 kg 125 mg b.d.

Method of administration
Adults: Patients should take minimally two tablets of 25mg in each dose, to provide sufficient antacid against acid degradation of didanosine. The tablets should be thoroughly chewed or dispersed in at least 30 ml of water prior to consumption. To disperse tablets, stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with 30 ml of clear apple juice. Stir the further dispersion just prior to consumption.

Children: Children older than 1 year of age should receive a 2-tablet of 25mg dose, children under year should receive a 1- tablet of 25mg dose. Tablets should be chewed or dispersed in water prior to consumption, as described above. When a one tablet of 25mg dose is required, the volume of water for dispersion should be 15 ml. Fifteen ml of clear apple juice may be added to the dispersion as a flavouring. Stir the further dispersion just prior to con

Shelf life
24 months

Storage Condition
Store in cool, dark and dry place.

PACKING:
HDPE Bottle pack of 30’s& 60’s tablets and packed in a unit carton along with package insert.