WARNING: FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALSONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION, DIDANOSINE SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (see WARNINGS ). 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. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANSOINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS , Pregnancy, Reproduction and Fertility ),
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warnings
WARNINGS 1. Pancreatitis: FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. DIDANOSINE SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH DIDANOSINE IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining 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, especially the elderly, 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 with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis: 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. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS , Pregnancy, Reproduction and Fertility ). Particular caution should be exercised when administering didanosine to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with didanosine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving didanosine (see ADVERSE REACTIONS .)
ADVERSE REACTIONS A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS ). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS. RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS ). When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with didanosine in combination with stavudine, with or without hydroxyurea, may be at increased risk for peripheral neuropathy (see PRECAUTIONS ). Selected clinical adverse events that occurred in a study of didanosine in combination with other antiretroviral agents are provided in Table 10 . Table 10: Selected Clinical Adverse Events, Study AI454-152 a Percent of Patients b Adverse Events didanosine+ stavudine+ nelfinavir n=258 zidovudine/ lamivudine c + nelfinavir n=253 Diarrhea 57 58 Peripheral Neurologic Symptoms/Neuropathy 25 11 Nausea 24 36 Headache 22 17 Rash 14 12 Vomiting 14 19 Pancreatitis (see below ) <1 * a Median duration of treatment was 62 weeks in the didansoine+stavudine+nelfinavir group and 61 weeks in the zidovudine/lamivudine+nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. *This event was not observed in this study arm. In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patietns who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. Selected laboratory abnormalities that occurred in a study of didanosine in combination with other antiretroviral agents are shown in Table 11 . Table 11: Selected Laboratory Abnormalities, Study AI454-152 a Percent of Patients b didanosine+ stavudine+ nelfinavir n=258 zidovudine/lamivudine c + nelfinavir n=253 Parameter Grades 3 to 4 d All Grades Grades 3 to 4 d All Grades SGOT (AST) 5 46 5 19 SGPT (ALT) 6 44 5 22 Lipase 5 23 2 13 Bilirubin <1 9 <1 3 a Median duration of treatment was 62 weeks in the didanosine+stavudine+nelfinavir group and 61 weeks in the zidovudine/lamivudine+nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN = upper limit of normal). Observed During Clinical Practice: The following events have been identified during postapproval use of didanosine beffered formulations. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors. Body as a Whole: abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS , Fat Redistribution ). Digestive Disorders: anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders: pancreatitis (including fatal cases) (see WARNINGS ), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders: anemia, leukopenia, and thrombocytopenia. Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS ); hepatitis and liver failure. Metabolic Disorders: diabete melitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders: myalgia (with or without increases in creatinine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders: retinal depigmentation and optic neuritis (see WARNINGS ).