WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS Fatal and nonfatal pancreatitis has 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 suspected pancreatitis and discontinued in patients with confirmed pancreatitis [see Warnings and Precautions (5.1) ] . 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 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 Warnings and Precautions (5.2) ] . WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS See full prescribing information for complete boxed warning. Fatal and nonfatal pancreatitis. Didanosine should be suspended in patients with suspected pancreatitis and discontinued in patients with confirmed pancreatitis. (5.1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine. (5.2)
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Pancreatitis: Suspension or discontinuation of didanosine may be necessary. (5.1) Lactic acidosis and severe hepatomegaly with steatosis: Suspend didanosine in patients who develop clinical symptoms or signs with or without laboratory findings. (5.2) Hepatic toxicity: Interruption or discontinuation of didanosine must be considered upon worsening of liver disease. (5.3) Non-cirrhotic portal hypertension: Discontinue didanosine in patients with evidence of non-cirrhotic portal hypertension. (5.4) Patients may develop peripheral neuropathy (5.5), retinal changes and optic neuritis (5.6), immune reconstitution syndrome (5.7) , and redistribution/accumulation of body fat. (5.8) 5.1 Pancreatitis Fatal and nonfatal pancreatitis has 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 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-1 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. [See Adverse Reactions (6) .] 5.2 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 Use in Specific Populations (8.1) ] . 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 signs or symptoms with or without laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.3 Hepatic Toxicity The safety and efficacy of didanosine have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. [See Adverse Reactions (6) .] 5.4 Non-cirrhotic Portal Hypertension Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Patients receiving didanosine should be monitored for early signs of portal hypertension (e.g., thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Didanosine should be discontinued in patients with evidence of non-cirrhotic portal hypertension. 5.5 Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of didanosine should be considered in patients who develop peripheral neuropathy. [See Adverse Reactions (6) .] 5.6 Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving didanosine [see Adverse Reactions (6) ] . 5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including didanosine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.8 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.9 Patients with Phenylketonuria Didanosine tablets for oral suspension contain the following quantities of phenylalanine: Table 3 All Strengths Phenylalanine per 2 tablet dose 73 mg Phenylalanine per tablet 36.5 mg
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections: Pancreatitis [see Boxed Warning , Warnings and Precautions (5.1) ] Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.2) ] Hepatic toxicity [see Warnings and Precautions (5.3) ] Non-cirrhotic portal hypertension [see Warnings and Precautions (5.4) ] Peripheral neuropathy [see Warnings and Precautions (5.5) ] Retinal changes and optic neuritis [see Warnings and Precautions (5.6) ] In adults, the most common adverse reactions (greater than 10%, all grades) are diarrhea, peripheral neurologic symptoms/neuropathy, abdominal pain, nausea, headache, rash, and vomiting. (6.1) Adverse reactions in pediatric patients were consistent with those in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Selected clinical adverse reactions that occurred in adult patients in clinical studies with didanosine are provided in Tables 4 and 5. Table 4: Selected Clinical Adverse Reactions from Monotherapy Studies Adverse Reactions Percent of Patients* ACTG 116A ACTG 116B/117 didanosine n=197 zidovudine n=212 didanosine n=298 zidovudine n=304 * The incidences reported included all severity grades and all reactions regardless of causality. Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropathy 17 14 20 12 Abdominal Pain 13 8 7 8 Rash/Pruritus 7 8 9 5 Pancreatitis 7 3 6 2 Table 5: Selected Clinical Adverse Reactions from Combination Studies Percent of Patients a,c AI454-148 b START 2 b didanosine + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 didanosine + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 a Percentages based on treated subjects. b Median duration of treatment 48 weeks. c The incidences reported included all severity grades and all reactions regardless of causality. * This event was not observed in this study arm. Diarrhea 70 60 45 39 Nausea 28 40 53 67 Peripheral Neurologic Symptoms/Neuropathy 26 6 21 10 Headache 21 30 46 37 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * less than 1 * Pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir in Study AI454-148 and in one patient who received didanosine plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial [see Warnings and Precautions (5) ] . The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with didanosine are shown in Tables 6 to 8. Table 6: Selected Laboratory Abnormalities from Monotherapy Studies Parameter Percent of Patients ACTG 116A ACTG 116B/117 didanosine n=197 zidovudine n=212 didanosine n=298 zidovudine n=304 ULN = upper limit of normal. SGOT (AST) (greater than 5 x ULN) 9 4 7 6 SGPT (ALT) (greater than 5 x ULN) 9 6 6 6 Alkaline phosphatase (greater than 5 x ULN) 4 1 1 1 Amylase (at least 1.4 x ULN) 17 12 15 5 Uric acid (greater than 12 mg/dL) 3 1 2 1 Table 7: Selected Laboratory Abnormalities from Combination Studies (Grades 3 to 4) Parameter Percent of Patients a AI454-148 b START 2 b didanosine + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 didanosine + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 ULN = upper limit of normal. NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Bilirubin (greater than 2.6 x ULN) less than 1 less than 1 16 8 SGOT (AST) (greater than 5 x ULN) 3 2 7 7 SGPT (ALT) (greater than 5 x ULN) 3 3 8 5 GGT (greater than 5 x ULN) NC NC 5 2 Lipase (greater than 2 x ULN) 7 2 5 5 Amylase (greater than 2 x ULN) NC NC 8 2 Table 8: Selected Laboratory Abnormalities from Combination Studies (All Grades) Parameter Percent of Patients a AI454-148 b START 2 b didanosine + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 didanosine + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 Pediatric Patients In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m 2 /day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m 2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m 2 every 12 hours in combination with zidovudine [see Clinical Studies (14) ] . Retinal changes and optic neuritis have been reported in pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of didanosine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors. Blood and Lymphatic System Disorders anemia, leukopenia, and thrombocytopenia. Body as a Whole alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat [see Warnings and Precautions (5.8) ] . Digestive Disorders anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders pancreatitis (including fatal cases) [see Boxed Warning , Warnings and Precautions (5.1) ] , sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hepatobiliary Disorders symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Boxed Warning , Warnings and Precautions (5.2) ] ; non-cirrhotic portal hypertension [see Warnings and Precautions (5.4) ] ; hepatitis and liver failure. Metabolic Disorders diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders retinal depigmentation and optic neuritis [see Warnings and Precautions (5.6) ] . Use with Stavudine- and Hydroxyurea-Based Regimens 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 pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5) ] . The combination of didanosine and hydroxyurea, with or without stavudine, should be avoided.