INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ASPEN DIDANOSINE 150 mg Tablet
ASPEN DIDANOSINE 100 mg Tablet
ASPEN DIDANOSINE 50 mg Tablet
ASPEN DIDANOSINE 25 mg Tablet

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ASPEN DIDANOSINE 150 mg Tablet
ASPEN DIDANOSINE 100 mg Tablet
ASPEN DIDANOSINE 50 mg Tablet
ASPEN DIDANOSINE 25 mg Tablet

COMPOSITION:
Each ASPEN DIDANOSINE 150 mg TABLET contains Didanosine 150 mg.
Each ASPEN DIDANOSINE 100 mg TABLET contains Didanosine 100 mg.
Each ASPEN DIDANOSINE 50 mg TABLET contains Didanosine 50 mg.
Each ASPEN DIDANOSINE 25 mg TABLET contains Didanosine 25 mg.
PHENYLKETONURICS: CONTAINS ASPARTAME (a phenylalanine)

PHARMACOLOGICAL CLASSIFICATION:
A.20.2.8 Antiviral agents

PHARMACOLOGICAL ACTION:
Didanosine (2’, 3’-dideoxyinosine) is a purine nucleoside analog active against HIV-1 and HIV2 in vitro. Following intracellular diffusion, didanosine is metabolised initially by 5’-nucleotidase and further by other cellular enzymes to its active derivative, 2’, 3’-dideoxyadenosine triphosphate (ddATP).
DdATP functions as a competitive inhibitor of viral reverse transcriptase with respect to deoxyadenosine triphosphate and as a chain terminator of viral DNA synthesis.

PHARMACOKINETICS:
Adults:
Didanosine is rapidly degraded at an acidic pH. The bioavailability of didanosine is significantly reduced by the presence of food. Therefore Aspen Didanosine should be administered at least 30 minutes before a meal or in the fasting state. Although patients exhibit significant variability, Cmax and AUC values increase in proportion to the dose. The steady state volume of distribution after IV administration averages 54 L.
The concentration in the cerebrospinal fluid averages 21% of the simultaneous plasma concentration 1 hour after an intravenous dose.
In patients with normal renal function, renal clearance is approximately 400 mL/min representing 50% of the total body clearance indicating that renal clearance is by active tubular secretion and glomerular filtration. Urinary recovery is approximately 20% after a single oral dose in adults. No accumulation was evident in either adults or children. 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 has not been fully evaluated in humans. Based on animal studies, it is presumed that it follows the same pathways responsible for the elimination of endogenous purines.
Protein binding is less than 5%.
There is currently incomplete data on the effect of impaired renal and hepatic function on the pharmacokinetics of didanosine.
The AUC of both didanosine and delavirdine are decreased by 20% when administered together.
The AUC for Indinavir is also decreased with concomitant use of Didanosine. No clinical significant pharmacokinetic interactions were found between nevirapine, rifabutin, stavudine and zidovudine in specific interaction studies. The effect of rifampicin on the kinetics of didanosine is not known.
Children: The average absolute bioavailability, after ingestion, at steady state is 42% (24 – 60%). Although patients exhibit significant variability, Cmax and AUC values increase in proportion to the dose. Following IV administration the volume of distribution averages 35,6 L/m². The elimination half-life is approximately 0,8 hours.
After oral dosing the renal clearance is approximately 243 mL/min/m². This represents about 46% of the total body clearance.
Urinary recovery after an oral dose of didanosine is approximately 17%. No evidence of accumulation after oral administration for an average of 26 days was observed.
The concentration in the cerebrospinal fluid averages 46% (12 –85%) of the simultaneous plasma concentration.

INDICATIONS:
Didanosine is indicated for the palliative treatment of advanced HIV infection in adults and children over 6 months of age, in combination with other antiretroviral medicines. There is limited clinical experience of the safety and efficacy of Aspen Didanosine. Until further information becomes available, the use of Aspen Didanosine should be limited to a maximum of six months.

CONTRA-INDICATIONS:

•	Hypersensitivity to any of the ingredients.
•	Avoid in patients with hepatic or renal impairment.
•	Safety in children under 6 months of age has not been established.

PREGNANCY AND LACTATION:

•	Safety in pregnancy and lactation has not been established.
•	It is recommended that women taking Aspen Didanosine do not breast-feed because of potential for serious adverse reactions from Aspen Didanosine in nursing infants.

WARNINGS:

•	The most serious adverse drug reactions of didanosine therapy are peripheral neuropathy and potentially fatal pancreatitis.
•	Patients with a history of pancreatitis and those with increased triglyceride concentrations should be observed carefully for signs of pancreatitis during treatment with didanosine.
	Treatment with didanosine should be interrupted in all patients who develop abdominal pain, nausea or vomiting or with raised serum amylase or lipase until pancreatitis has been excluded. Once patients have recovered, treatment with didanosine can be resumed using a low dose increased gradually if appropriate. Didanosine therapy should also be suspended when drugs known to cause pancreatic toxicity (eg. Pentamide) is required. Concomitant treatment with other medicines likely to cause pancreatitis or peripheral neuropathy should be avoided if possible. Dose suspension is necessary when biochemical markers of pancreatitis increase to a clinically significant degree above the upper limit of normal, even in the absence of symptoms. If concomitant therapy is unavoidable, there should be close observation. Patients with renal impairment may be at a greater risk for pancreatitis if treated without dose adjustments.
•	Patients may develop toxic peripheral neuropathy (characterized by bilateral symmetrical distal numbness, tingling and pain in feet and hands). Therapy with didanosine should be suspended until resolution of symptoms. Once patients have recovered, treatment with didanosine can be resumed using a low dose increased gradually if appropriate.
•	Liver failure has occurred. Therapy with didanosine should be suspended if enzymes rise to a clinically significant level above the upper limit of normal. All nucleoside analogue therapy should be discontinued if aminotransferase levels continue rising.
•	Insufficient clinical experience exists to recommend a dosage regimen in infants under 6 months of age.
•	Retinal or optic nerve changes (when used above the recommended dose) have been observed in paediatrics. Retinal depigmentation in adults and children at doses above 300 mg/m²/day. Patients should undergo retinal examination every 6 months or if a change in vision occurs. Long-term effects of didanosine are unknown.
•	Aspen Didanosine has been associated with hyperuricaemia. Treatment should be suspended should uric acid levels rise significantly during treatment.
•	Patients receiving didanosine may continue to develop opportunistic infections and other complications of HIV infection.

DOSAGE AND DIRECTIONS FOR USE:
Dissolve the tablet in a glass of water. Stir the mixture until the powder has completely dissolved.
•        Adults:
Over 60 kg: 200 mg every 12 hours.
Under 60 kg: 125 mg every 12 hours.
•        Children:
Recommended starting dose is based on body surface area and on a 200 mg/m²/day average recommended dose. The recommended dosing interval should be approximately 12 hours. The recommended average starting dose is recommended below:
Paediatric Dosing Guidelines:

Body Surface area (m²)	Aspen Didanosine Tablets (*)
1,1 –1,4	100 mg 12 hourly
0,8 –1,0	75 mg 12 hourly
0,5 –0,7	50 mg 12 hourly
= 0,4	25 mg 12 hourly

* To ensure that patients taking Aspen Didanosine tablets receive a sufficient amount of antacid, each dose must be given as 2 tablets for adults and children older than 1 year, i.e. 4 tablets/day on the 12 hourly schedule.
Children 6 months to 1 year should receive a 1 tablet dose, i.e. 2 tablets/day on the 12 hourly schedule. Safety and efficacy in children under 6 months of age have not been established.
Dose adjustments:

-	Clinical signs suggestive of pancreatitis should prompt dose suspension. Only after pancreatitis has been ruled out should dosing be resumed.
-	Patients who have presented with neuropathy may tolerate a reduced dose of Aspen Didanosine after resolution of the symptoms upon drug discontinuation.
-	A reduction in dose is recommended in patients with mild to moderate renal impairment.
-	In anuric patients requiring dialysis, one fourth of the recommended total daily dose of didanosine should be administered once a day after dialysis.
-	Patients should be observed for liver enzyme elevations and Aspen Didanosine should be suspended if enzymes rise to a clinically significant level (see Warnings). Rapidly elevating aminotransferase levels, indicate that consideration should be given to discontinue all nucleoside analogue therapy (see Precautions).
-	When Aspen Didanosine is used with other antiretroviral agents, the respective package inserts should be referred to.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS: SIDE-EFFECTS:
ADULTS:
Serious Side-effects:

•	Peripheral neuropathy - tingling, burning, numbness and pain in hands or feet. Commonly seen in patients with advanced HIV or patients with a history of neuropathy or patients on neurotoxic drug therapy. Temporary withdrawal of Aspen Didanosine or permanent discontinuation in some patients may be required.
•	Pancreatitis - abdominal pain, nausea and vomiting. Pancreatitis may be fatal and is common in patients with advanced HIV. May be related to the daily dose of didanosine and steady state plasma concentration.

Frequent Side-effects:

•	Gastro-intestinal –diarrhoea

Rare Side-effects:

•	Lactic acidosis –Fatal in some cases and sometimes associated with severe hepatic stenosis (see Precautions)

Other Side-effects:

•	Blood –granulocytopaenia, haemorrhage
•	Cardiovascular –Hypertension/hypotension, chest pain.
•	CNS –headache, insomnia, dizziness, fainting, confusion, thinking abnormalities, amnesia, anxiety, CNS depression, convulsions, seizure.
•	Eye –blurred vision, retinal and optic nerve changes have been reported rarely.
•	Ear –otitis media.
•	Gastro-intestinal – nausea, vomiting, diarrhoea, abdominal pain, anorexia, flatulence, constipation.
•	Hair –alopecia.
•	Hypersensitivity reactions –fever, chills, rash, pruritis, allergic reaction.
•	Liver –hepatitis.
•	Lymphatics –lymphoma-like reaction, dehydration, oedema.
•	Mouth –oral candidiasis, stomatitis, taste disturbances, dry mouth.
•	Musculoskeletal - arthralgia, arthritis, asthenia, myopathy, myalgia, rhabdomyolysis.
•	Pancreas –impaired glucose tolerance, diabetes mellitus.
•	Pulmonary –pneumonia, asthma, dyspnoea, bronchitis, cough.
•	Skin – Herpes simplex, herpes zoster, sweating
•	Salivary gland –sialadenitis.

Other gastro-intestinal, metabolic, nutritional, nervous, musculoskeletal, respiratory, cardiovascular and urogenital system effects have been reported as have cutaneous and special organ effects.
Laboratory abnormalities reported as serious include: Leukopaenia, thrombocytopaenia, anaemia and changes in bilirubin, alkaline phosphatase, SGOT, SGPT, uric acid and amylase.
The relationship to therapy of these observations has not been established.

CHILDREN:
Eye –Retinal depigmentation at doses above 300 mg/m²/day has been observed.
Other serious adverse events include –seizure, neurologic effects, pneumonia, diabetes mellitus, and diabetes insipidus.
Frequently reported adverse signs and symptoms were generally those also seen in adults.

SPECIAL PRECAUTIONS:

•	Patients with a history of pancreatitis and those with increased triglyceride concentrations should be observed carefully for signs of pancreatitis during treatment with didanosine.
•	Concomitant treatment with other medicines likely to cause pancreatitis or peripheral neuropathy should be avoided if possible.
•	It may be necessary to interrupt treatment in patients who develop peripheral neuropathy; on recovery from peripheral neuropathy a reduced dose may be tolerated. Treatment should also be interrupted if uric acid concentrations are elevated.
•	Didanosine should be used with caution in patients with impaired renal function, and dosage reduction may be necessary.
•	Children should be monitored for retinal lesions and didanosine withdrawn if they occur.

Monitoring should also be considered in adults.

•	This formulation of didanosine contains aspartame, a source of phenylalanine. Care should be exercised when treating patients with phenylketonuria.
•	Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. Treatment with Aspen Didanosine should be stopped should the following levels continue to rise: aminotransferase, bilirubin, progressive hepatomegaly, or metabolic or lactic acidosis of unknown aetiology. Exercise caution when administering Aspen Didanosine to any patient particularly obese women with hepatomegaly, hepatitis, or other known risk factors for liver disease. These patients should be carefully monitored. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. Didanosine and stavudine are contra-indicated in pregnancy (see Contra-indications).
•	Patients with hepatic impairment may be at a greater risk for toxicity related to Aspen Didanosine treatment related to altered metabolism. Until further information becomes available, Aspen Didanosine should not be used in these patients. Liver failure has been reported.

INTERACTIONS:

•	Co-administration of didanosine with other medicines known to cause pancreatitis (such as intravenous Pentamide, Alcohol, Asparginase, Azathioprine, Oestrogens, Furosemide, Methyldopa, Nitrofurantoin, Sulfonamides, Sulindac, Tetracyclines, Thiazide diuretics or Valproic acid).
•	Atovaquone – concurrent administration with didanosine results in a decrease in the area under time-concentration curve.
•	HIV-protease inhibitors, Ketoconazole, Fluoroquinolone antibacterials and Dapsone –should be given at least one hour before or after didanosine as these medicines increase gastric pH and thus affect the absorption of didanosine.
•	Co-administration of didanosine with other medicines known to cause peripheral neuropathy (such as Chloramphenicol, Cisplatin, Dapsone, Ethambutol, Ethionamide, Hydralazine, Isoniazid, Lithium, Metronidazole, Nitrofurantoin, Nitrous oxide, Phenytoin, Stavudine, Vincristine and Zalcitabine).
•	Ganciclovir –concomitant use with didanosine was reported to increase plasma concentrations of didanosine.
•	Zidovudine – concomitant administration of didanosine and zidovudine has been reported to cause changes in pharmacokinetics, but studies have not been consistent.
•	Delaviridine -concomitant administration of didanosine and Delaviridine resulted in reductions in the area under the time-concentration curve for both medicines in a single-dose study.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
There is no known antidote for didanosine overdosage. Early studies, in which didanosine was initially administered at doses ten times the recommended doses indicate that the anticipated complications of chronic overdosage would be hyperuricaemia, pancreatitis, peripheral neuropathy and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by haemodialysis. The fractional removal of didanosine during an average haemodialysis session of 3 to 4 hours is approximately 20 –35% of the amount present in the body at start of dialysis.

IDENTIFICATION:
ASPEN DIDANOSINE 150 mg: A round, flat, white to off-white tablet with bevelled edges. Embossed with “150”
ASPEN DIDANOSINE 100 mg: A round, flat, white to off-white tablet with bevelled edges. Embossed with “100”
ASPEN DIDANOSINE 50 mg: A round, flat, white to off-white tablet with bevelled edges. Embossed with “50”
ASPEN DIDANOSINE 25 mg: A round, flat, white to off-white tablet with bevelled edges. Embossed with “25”

PRESENTATION:
White HDPE container with 60 tablets heat sealed with an aluminium foil layer and sealed with a white “child-proof”screw-on HDPE cap.

STORAGE INSTRUCTIONS:
Store below 25°C in tightly closed containers. Protect from moisture and light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:

ASPEN DIDANOSINE 150 mg:	37/20.2.8/0445
ASPEN DIDANOSINE 100 mg:	37/20.2.8/0444
ASPEN DIDANOSINE 50 mg:	37/20.2.8/0443
ASPEN DIDANOSINE 25 mg:	37/20.2.8/0442

NAME AND BUSINESS ADDRESS OF APPLICANT:
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148
South Africa

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
19 September 2003

A218
A&S PRINTERS

New addition to this site: January 2006
Source: Pharmaceutical Industry
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