D-SINE 100 TABLETS/ D-SINE 200 TABLETS

(Didanosine Tablets 100mg/200mg)

Composition:
I) Each Tablet contains:
Didanosine 100mg

II) Each Tablet contains:
Didanosine 200mg

Presentation:
10x10's

Pharmacology:
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.

Pharmacokinetics:

Adults:
Didanosine is rapidly degraded at an acidic pH. Therefore, all oral formulations must contain or be administered with buffering agents designed to increase gastric pH. The presence of food significantly reduces the bioavailability of didanosine. Therefore, Didanosine should be administered at least 30 minutes before a meal or 2 hours after eating.
Although there is significant variability between patients, Cmax and AUC values increase in proportion to dose. The steady state volume of distribution after IV administration averages 54 litres. The concentration of didanosine in the cerebrospinal fluid (CSF), one hour after infusion, averages 21% of that of the simultaneous plasma concentration. Renal clearance in patients with normal renal function which is equivalent to approximately 400 mL/min represents an average of 50% of total body clearance, indicating that active tubular secretion, in addition to glomerular filtration is responsible for the renal elimination of didanosine. Urinary recovery of didanosine is approximately 20% of the dose after oral treatment. There is no evidence of didanosine accumulation after the administration of oral doses for 4 weeks.
The average elimination half-life is 1,6 hours.
The metabolism of didanosine in man has not been evaluated. However, based on animal studies, it is presumed that it follows the same pathways responsible for the elimination of endogenous purines. In vitro human plasma protein binding is less than 5% with didanosine, indicating that drug interactions involving binding site displacement are not anticipated.

Renal impairment: The apparent drug clearance decreased as creatinine clearance decreased. Dose adjustment is recommended in patients with impaired renal function (<60 mL/min/1.73m2).

Hepatic impairment: The metabolism of didanosine may be altered in patients with more severe or other types of hepatic impairment

The AUC of both didanosine and delaviradine are decreased (20%) when administered together. Didanosine also decreases the AUC of indinavir. No clinically significant pharmacokinetic interactions were found between nevirapine, rifabutin, stavudine and zidovudine in specific interaction studies. The effect of rifampicin on the kinetics is not known.

Children:
The average absolute bioavailability at steady state in children is 42%(+18%). Although there is significant variability between patients, Cmax and AUC values increase in proportion to dose in paediatric and adolescent patients. The volume of distribution after IV administration averages 35,6 L/m2. The average elimination half-life after oral didanosine administration is 0.8 hours. Renal clearance is approximately 243 mL/min/m2 after oral dosing and represents about 46% of the total body clearance. Urinary recovery of didanosine is approximately 17% of dose after oral treatment. There is no evidence of didanosine accumulation after oral administration for an average of 26 days. The cerebrospinal fluid didanosine concentration averages 46% (12 to 85%) of the concentration in a simultaneous plasma sample.

Indications:
Didanosine is indicated for the treatment of HIV infection when antiretroviral therapy is warranted.

Contra-indications:
Didanosine is contraindicated in patients with clinically significant hypersensitivity to any of the components.

Dosage and directions for use:

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: