Videx (Didanosine)

VIDEX™

Bristol

Didanosine

Antiretroviral Agent

Action And Clinical Pharmacology: Didanosine is a synthetic, purine nucleoside analogue of deoxyadenosine, active against the Human Immunodeficiency Virus (HIV).

Didanosine inhibits the in vitro replication of HIV in human primary cells cultures and in established cell lines. The active antiviral metabolite, dideoxyadenosine-triphosphate (ddATP), is formed in several steps by phosphorylation of didanosine by cellular enzymes. Inhibition of HIV reverse transcriptase by ddATP is through competition with endogenous deoxyadenosine triphosphate (dATP) for binding to the active site of the enzyme. In addition, ddATP is a substrate for reverse transcriptase and is incorporated into the growing DNA chain. The resulting nucleoside, dideoxyadenosine (ddA) lacks a 3-hydroxyl group, which normally is the acceptor for covalent attachment of subsequent nucleoside 5-monophosphates in DNA chain extension. Thus, ddA incorporated in the DNA prevents further chain extension and aborts proviral DNA synthesis.

Indications And Clinical Uses: For the treatment of HIV infection when antiretroviral therapy is warranted.

Clinical benefit of didanosine was demonstrated in several important clinical trials.

The duration of clinical benefit from antiretroviral therapy may be limited. Alteration in antiretroviral therapy should be considered if disease progression occurs while receiving didanosine.

Contra-Indications: In patients with previously demonstrated hypersensitivity to any of the components of the formulations.

Manufacturers’ Warnings In Clinical States: The major clinical toxicity of didanosine is pancreatitis (see Adverse Effects).

Patients receiving didanosine or any antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV-associated diseases.

Pancreatitis: Pancreatitis, which has been fatal in some cases, is the major clinical toxicity of didanosine (see Adverse Effects). Pancreatitis must be considered whenever a patient receiving didanosine develops abdominal pain and nausea, vomiting or elevated biochemical markers for pancreatitis. Under these circumstances, didanosine use should be suspended until the diagnosis of pancreatitis is excluded. Similarly, when treatment with other drugs known to cause pancreatic toxicity is required (for example, i.v. pentamidine), suspension of didanosine therapy should be considered. Didanosine should be used only with extreme caution in patients with a history of pancreatitis. Positive relationships have been found between the risk of pancreatitis and daily dose. Patients with a heightened risk of pancreatitis such as those with a history of pancreatitis, alcohol consumption, elevated triglycerides or evidence of advanced HIV infection should be followed closely for signs and symptoms of pancreatitis. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment.

Peripheral Neuropathy: Peripheral neuropathy occurs in patients treated with didanosine and the frequency appears to be dose related. Patients should be monitored for the development of a neuropathy that is usually characterized by symmetrical distal numbness, tingling, or pain in the feet or hands. In the U.S. Expanded Access Program, neuropathy occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy. These patients may be at increased risk of neuropathy during didanosine therapy.

Neuropathy has been reported rarely in children treated with didanosine. However, because signs and symptoms of neuropathy are difficult to assess in children, physicians should be alerted to the possibility of this event.

Liver Failure: In the ACTG 116B/117 trial, which compared 2 doses of didanosine with zidovudine, there was no difference in the 1-year rates of grade 3 or 4 liver function test (LFT) abnormalities between didanosine buffered powder at the recommended dose (250 mg b.i.d.) and zidovudine (600 mg/day). However, the difference in LFT abnormalities were statistically significant at the high dose (375 mg b.i.d.) of didanosine. In the ACTG 116A trial, the difference in the 1-year rate of LFT abnormalities was statistically significant for didanosine buffered powder at the recommended dose compared with zidovudine, but not at the high dose. Fatal liver failure of unknown etiology occurred during didanosine therapy in 0.6% patients in the Phase I trials and 0.2% in the U.S. Expanded Access Program. There were 3 reports of patients who died of unexplained liver failure in the ACTG 116B/117 trial: no such events were reported in the ACTG 116A trial.

Retinal Depigmentation and Vision: Pediatric patients have demonstrated retinal depigmentation or optic neuritis on rare.
Precautions: General: Patients receiving didanosine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, these patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV disease.

Ingestion of didanosine with food or as long as 2 hours after a meal reduces the absorption of didanosine by as much as 55%. Didanosine should be administered at least 30 minutes before a meal.

Lactic Acidosis: Occurrences of lactic acidosis (in the absence of hypoxemia), usually associated with severe hepatomegaly and hepatic steatosis have been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown etiology. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

Children: Efficacy and safety have been demonstrated in a comparative clinical trial, ACTG 152, involving over 800 pediatric patients which compared didanosine, zidovudine and the combination of the 2 drugs. Additionally, the pharmacokinetics of didanosine have been evaluated in pediatric studies. Insufficient clinical experience exists to recommend a dosing regimen in infants under 3 months of age.

Pregnancy: There are no adequate and well-controlled studies in pregnant women and it is not known whether didanosine can cause fetal harm or affect reproductive capacity when administered to a pregnant woman.

Reproduction studies have been performed in rats and rabbits at doses up to 12 to 14.2 times the estimated human exposure (based upon plasma levels) respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: It is not known whether didanosine is excreted in human milk. A study in rats showed that, following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. Because of uncertainties related to transmission of virus and to excretion of didanosine in breast milk, it is advisable to caution mothers against breast-feeding.

Patients with Special Diseases and Conditions: Patients with Phenylketonuria: The chewable/dispersible buffered tablets contain the following quantities of phenylalanine: per 2-tablet dose: 73 mg (100 and 150 mg strengths), 45 mg (25 and 50 mg strengths); per tablet: 36.5 mg (100 and 150 mg strengths), 22.5 mg (25 and 50 mg strengths).

Patients with Renal Impairment: Patients with renal impairment (serum creatinine >1.5 mg/dL or creatinine clearance
Patients with Hepatic Impairment: Patients with hepatic impairment may be at greater risk for toxicity related to didanosine treatment due to altered metabolism; a dose reduction may be necessary.

Hyperuricemia: Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail.

Drug Interactions: Coadministration of didanosine with drugs that are known to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities (see Warnings) and should be done only with extreme caution. Drug interaction studies have demonstrated that there are no clinically significant interactions with didanosine and the following: stavudine, foscarnet, trimethoprim, sulfamethoxazole, dapsone, ranitidine, loperamide, metoclopramide and rifabutin.

Drugs whose absorption can be affected by the level of acidity in the stomach (e.g., ketoconazole, itraconazole, dapsone), should be administered at least 2 hours prior to dosing with didanosine.

Combination studies of didanosine buffered powder (up to 500 mg/day) and zidovudine (up to 600 mg/day) have not revealed any unexpected toxicities or alteration of pharmacokinetics of either drug.

A study in 4 patients revealed that concomitant administration of ganciclovir does not significantly affect the pharmacokinetics of didanosine. There is no evidence that didanosine potentiates the myelosuppressive effects of ganciclovir or zidovudine.

As with other products containing magnesium and/or aluminum antacid components, the didanosine tablets should not be administered with a prescription antibiotic containing any form of tetracycline.

Plasma concentrations of some quinolone antibiotics are decreased when administered with antacids containing magnesium and/or aluminum. Therefore, doses of quinolone antibiotics should not be administered within 2 hours of taking didanosine tablets. Concomitant administration of antacids containing magnesium or aluminum with the didanosine tablets may potentiate adverse effects associated with the antacid component.

Information for Patients: Didanosine is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses including opportunistic infections. Therefore, patients should remain under the care of a physician when using didanosine.

The major toxicity of didanosine is pancreatitis, which has been fatal in some patients. Symptoms of pancreatitis include abdominal pain, and nausea and vomiting. Peripheral neuropathy occurs in patients treated with didanosine. Symptoms of peripheral neuropathy include tingling, burning, pain or numbness in the hands or feet. These symptoms should be reported to your physician. The above toxicities of didanosine occur with the greatest frequency in patients with a history of these events and dose modification and/or discontinuation of didanosine may be required if toxicity develops. There are other medications including alcohol which may exacerbate didanosine toxicity. You should consult your physician about such medications.

The long-term effects of didanosine are unknown at this time. Didanosine therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

Adverse Reactions: The major clinical toxicity of didanosine is pancreatitis (see Warnings).

Adults: Table I lists all adverse events which occurred in at least 5% of adult patients participating in 2 controlled clinical trials (ACTG 116B /117 and 116A) comparing 2 doses of didanosine (buffered powder for oral solution) to zidovudine.

Other clinical adverse events which occurred with a cumulative incidence of
Cardiovascular: Recommended dose: angina pectoris, migraine, palpitation, peripheral vascular disorder, shock and syncope. High dose: aortic stenosis, arrhythmia, cardiovascular disorder, chest pain substernal, heart arrest, heart failure right, hypotension, intracranial aneurysm, migraine, myocardial infarct, palpitation and tachycardia.

Digestive: Recommended dose: aphthous stomatitis, colitis, dyspepsia, eructation, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gum hemorrhage, rectal hemorrhage, sialadenitis and stomach ulcer hemorrhage. High dose: abnormal stools, cholecystitis, cholelithiasis, colitis, duodenitis, dyspepsia, esophagitis, flatulence, gastritis, gastrointestinal carcinoma, gingivitis, hemorrhagic pancreatitis, hepatomegaly, leukoplakia, oral moniliasis, parotid gland enlargement, pseudomembranous enterocolitis, rectal hemorrhage and tongue disorder.

Endocrine: High dose: inappropriate ADH.

Hemic/Lymphatic: Recommended dose: lymphoma-like reaction. High dose: lymphoma-like reaction.

Metabolic/Nutritional: Recommended dose: edema peripheral. High dose: acidosis, dehydration, generalized edema and thirst.

Musculoskeletal: Recommended dose: arthralgia, arthritis, hemiparesis, joint disorder, leg cramps and tenosynovitis. High dose: arthritis, bone disorder, joint disorder, myositis and pyogenic arthritis.

Nervous: Recommended dose: acute brain syndrome, ataxia, dementia, drug dependence, encephalitis, encephalopathy, grand mal convulsion, hyperesthesia, hypertonia, ileus, incoordination, insomnia, intracranial hemorrhage, libido decreased, paralysis, paranoid reaction, psychosis, sleep disorder, speech disorder, tremor and withdrawal syndrome. High dose: abnormal gait, agitation, amnesia, aphasia, CNS depression, dementia, drug dependence, emotional lability, encephalitis, encephalopathy, foot drop, grand mal convulsion, hyperesthesia, hypertonia, insomnia, manic reaction, neuralgia, psychosis, reflexes decreased, reflexes increased, speech disorder, tremor and withdrawal syndrome.

Respiratory: Recommended dose: apnea, asthma, bronchiectasis, espistaxis, hemoptysis, hypoxia, laryngitis, lung function decreased, pharyngitis, pneumonia interstitial, pneumothorax and respiratory disorder. High dose: asthma, bronchitis, epistaxis, hemoptysis, hypoventilation and pharyngitis.

Skin and Appendages: Recommended dose: acne, exfoliative dermatitis, Herpes simplex, skin disorder and skin ulcer. High dose: acne, angioedema, fungal dermatitis, Herpes zoster, pruritus, skin discoloration, skin hypertrophy, sweating, urticaria and vesiculobullous rash.

Special Senses: Recommended dose: conjunctivitis, deafness, diplopia, dry eye, ear disorder, glaucoma, otitis externa and tinnitus. High dose: abnormal vision, blurred vision, conjunctivitis, ear pain, eye disorder, eye pain, iritis, photophobia, retinal detachment, retinitis, taste perversion and visual field defect.

Urogenital: Recommended dose: bladder carcinoma, breast abscess, impotence, kidney calculus, kidney failure, kidney function abnormal, nocturia, urinary frequency and vaginal hemorrhage. High dose: acute kidney failure, bladder carcinoma, hematuria, kidney function abnormal, kidney pain, penis disorder, polyuria, prostatic disorder, urinary frequency and vaginal hemorrhage.

There have been rare
Reports of rhabdomyolysis, hepatitis, impaired glucose tolerance, diabetes mellitus and alopecia have been received as part of ongoing surveillance. A few cases of rhabdomyolysis were complicated by acute renal failure, which required hemodialysis.

Cases of lactic acidosis (in the absence of hypoxemia), usually associated with severe hepatomegaly and hepatic steatosis have been reported with the use of nucleoside analogues.

Children: Adverse events reported in more than 4% of 98 patients in pediatric phase I trials (which includes all signs and symptoms while on study) are listed by organ system in Table III. There are no controlled comparative data to assess the incidence of adverse effects from didanosine at this time. Therefore, the adverse events reported in these pediatric studies should be considered as potential hazards of didanosine treatment.

In pediatric studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/mday and in 5 of 38 (13%) patients treated at higher doses.

Serious adverse events reported in the pediatric phase I trials were: neurologic (2%), seizure (1%), pneumonia (1%), diabetes mellitus (1%), diabetes insipidus (1%).

Laboratory Test Abnormalities: Adults: The cumulative incidences of serious laboratory abnormalities in the 2 controlled clinical trials comparing 2 doses of Videx to zidovudine, are listed in Table IV.

Children: Serious laboratory abnormalities experienced by 60 pediatric patients who received didanosine at doses £300 mg/mday are listed in Table V. These laboratory abnormalities were observed more frequently among patients who began didanosine therapy with abnormal values.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no known antidote for didanosine overdosage. Experience in the Phase I studies in which didanosine was initially administered at doses 10 times the currently recommended doses indicates that the complications of chronic overdosage would include pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis.

Dosage And Administration: Adults: The dosing interval should be 12 hours. All formulations should be administered at least 30 minutes before a meal. Adult patients should take 2 tablets at each dose so that adequate buffering is provided to prevent gastric degradation of didanosine.

Dose Adjustment: Clinical signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. Only after pancreatitis has been ruled out should dosing be resumed.

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.

For patients undergoing dialysis, the daily dose of didanosine should be administered after dialysis. It is not necessary to administer a supplemental dose of didanosine following hemodialysis.

Since urinary excretion is also a major route of elimination of didanosine in pediatric patients, the clearance of didanosine may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend a specific dosage adjustment of didanosine in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.

There are insufficient data to recommend a specific dose adjustment of didanosine in patients with hepatic impairment, but an adjustment in the dose in these patients should also be considered.

Method of Preparation: Adult Dosing: 2 tablets should be thoroughly chewed, manually crushed, or dispersed in at least 30 mL of water prior to consumption. To disperse tablets, add 2 tablets to at least 30 mL of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the aqueous dispersion may be further diluted with 30 mL of clear apple juice. Stir and drink the entire dispersion immediately.

Storage and Stability of Reconstituted Preparations: Chewable/dispersible buffered tablets dispersed in water may be held for up to 1 hour at ambient temperature. The aqueous dispersion further diluted with apple juice is also stable for up to 1 hour at ambient temperature.

Availability And Storage: 25 mg: Each round, off-white to light orange/yellow with a mottled appearance, orange-flavored, chewable, dispersible buffered tablet, embossed with “VIDEX” on one side and 25 on the other, contains: didanosine 25 mg. Nonmedicinal ingredients: aspartame, calcium carbonate, magnesium hydroxide, magnesium stearate, mandarin-orange flavor, microcrystalline cellulose, polyplasdone and sorbitol. Bottles of 60.

50 mg: Each round, off-white to light orange/yellow with a mottled appearance, orange-flavored, chewable, dispersible buffered tablet, embossed with “VIDEX” on one side and 50 on the other, contains: didanosine 50 mg. Nonmedicinal ingredients: aspartame, calcium carbonate, magnesium hydroxide, magnesium stearate, mandarin-orange flavor, microcrystalline cellulose, polyplasdone and sorbitol. Bottles of 60.

100 mg: Each round, off-white to light orange/yellow with a mottled appearance, orange-flavored, chewable, dispersible buffered tablet, embossed with “VIDEX” on one side and 100 on the other, contains: didanosine 100 mg. Nonmedicinal ingredients: aspartame, calcium carbonate, magnesium hydroxide, magnesium stearate, mandarin-orange flavor, microcrystalline cellulose, polyplasdone and sorbitol. Bottles of 60.

150 mg: Each round, off-white to light orange/yellow with a mottled appearance, orange-flavored, chewable, dispersible buffered tablet, embossed with “VIDEX” on one side and 150 on the other, contains: didanosine 150 mg. Nonmedicinal ingredients: aspartame, calcium carbonate, magnesium hydroxide, magnesium stearate, mandarin-orange flavor, microcrystalline cellulose, polyplasdone and sorbitol. Bottles of 60.

Store at room temperature (15 to 30°C).

VIDEX™ Bristol Didanosine Antiretroviral Agent

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