SPL MEDGUIDE SECTION.

MEDICATION Guide DidanosineDelayed-Release Capsules (enteric-coated pellets) Read this Medication Guide before you start taking didanosine delayed-release capsules and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. You and your healthcare provider should talk about your treatment with didanosine delayed-release capsules before you start taking it and at regular check-ups. You should stay under your healthcare providers care when taking didanosine delayed-release capsules. What is the most important information should know about Didanosine Delayed-Release Capsules Didanosine Delayed-Release Capsules may cause serious side effects, including: Swelling of your pancreas (pancreatitis) that may cause death. Pancreatitis can happen at any time during your treatment with Didanosine Delayed-Release Capsules. Before you start taking didanosine delayed-release capsules, tell your healthcare provider if you:have had pancreatitishave advanced HIV (human immunodeficiency virus) infectionhave kidney problemsdrink alcoholic beveragestake medicine called ZERIT(R) (stavudine)It is important to call your healthcare provider right away if you have: stomach pain swelling of your stomach nausea and vomiting fever Build-up of acid in your blood (lactic acidosis). Lactic acidosis must be treated in the hospital as it may cause death. Before you start taking didanosine delayed-release capsules, tell your healthcare provider if you:have liver problems are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking didanosine delayed-release capsules and ZERIT (stavudine). are overweight have been treated for long time with other medicines to treat HIV It is important to call your healthcare provider right away if you: feel weak or tired have unusual (not normal) muscle pain have trouble breathing have stomach pain with nausea and vomiting feel cold, especially in your arms and legs feel dizzy or light-headed have fast or irregular heartbeat Liver problems. Serious liver problems have happened in some people (including pregnant women) who take didanosine delayed-release capsules. These problems include liver enlargement (hepatomegaly), fat in the liver (steatosis), liver failure, and high blood pressure in the large vein of the liver (portal hypertension). Severe liver problems can lead to liver transplantation or death in some people taking didanosine delayed-release capsules. Your healthcare provider should check your liver function while you are taking didanosine delayed-release capsules. You should be especially careful if you have history of heavy alcohol use or liver problems.It is important to call your healthcare provider right away if you have: yellowing of your skin or the white of your eyes (jaundice) dark urine pain on the right side of your stomach swelling of your stomach easy bruising or bleeding loss of appetite nausea or vomiting vomiting blood or dark colored stools (bowel movements) What is Didanosine Delayed-Release Capsules Didanosine delayed-release capsules are prescription medicine used with other antiretroviral medicines to treat human immunodeficiency virus (HIV) infection in children and adults. Didanosine delayed-release capsule belongs to class of drugs called nucleoside analogues. Didanosine delayed-release capsules will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking didanosine delayed-release capsules, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your healthcare provider regularly and report any medical problems that occur. Who should not take Didanosine Delayed-Release Capsules Do not take Didanosine Delayed-Release Capsules if you take: ZYLOPRIM(R), LOPURIN(R), ALOPRIM(R) (allopurinol) COPEGUS(R), REBETOL(R), RIBASPHERE(R), RIBAVIRIN(R), VIRAZOLE(R) (ribavirin) What should tell my healthcare provider before takingDidanosine Delayed-Release Capsules Before you take didanosine delayed-release capsules, tell your healthcare provider if you: have or had kidney problems have or had liver problems (such as hepatitis) have or had persistent numbness, tingling, or pain in the hands or feet (neuropathy) have any other medical conditions are pregnant or plan to become pregnant. It is not known if didanosine delayed-release capsules will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking didanosine delayed-release capsules. You and your healthcare provider will decide if you should take didanosine delayed-release capsules while you are pregnant. Pregnancy Registry: There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.arebreastfeeding or plan to breastfeed. Do not breastfeed. It is not known if didanosine delayed-release capsules can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Didanosine delayed-release capsules may affect the way other medicines work, and other medicines may affect how didanosine delayed-release capsules works. Especially tell your healthcare provider if you take: CYTOVENE(R), VALCYTE(R) (ganciclovir) DOLOPHINE(R) HYDROCHLORIDE, METHADOSE(R) (methadone) VIRACEPT(R) (nelfinavir) VIREAD(R) (tenofovir disoproxil fumarate) alcoholic beverages Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. Ask your healthcare provider if you are not sure if you take one of the medicines listed above. How should take Didanosine Delayed-Release Capsules Take didanosine delayed-release capsules exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much didanosine delayed-release capsules to take and when to take it. Your healthcare provider may change your dose. Do not change your dose of didanosine delayed-release capsules without talking to your healthcare provider. Do not take Didanosine Delayed-Release Capsuleswith food. Take didanosine delayed-release capsules on an empty stomach. Take didanosine delayed-release capsules whole. Do not break, crush, dissolve, or chew didanosine delayed-release capsules before swallowing. If you cannot swallow didanosine delayed-release capsules whole, tell your healthcare provider. You may need different medicine. Try not to miss dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Some medicines should not be taken at the same time of day that you take Didanosine Delayed-Release Capsules. Check with your healthcare provider. If your kidneys are not working well, your healthcare provider will need to do regular blood and urine tests to check how they are working while you take didanosine delayed-release capsule. Your healthcare provider may also lower your dosage of didanosine delayed-release capsule if your kidneys are not working well. If you take too much Didanosine Delayed-Release Capsules, contact poison control center or emergency room right away.What should avoid while taking Didanosine Delayed-Release Capsules Alcohol. Do not drink alcohol while taking didanosine delayed-release capsules. Alcohol may increase your risk of getting pain and swelling of your pancreas (pancreatitis) or may damage your liver. What are the possible side effects of Didanosine Delayed-Release Capsules Didanosine delayed-release capsules can cause pancreatitis, lactic acidosis, and liver problems. See What is the most important information should know about didanosine delayed-release capsules at the beginning of this Medication Guide. Vision changes. You should have regular eye exams while taking didanosine delayed-release capsules. Peripheral neuropathy. Symptoms include: numbness, tingling, or pain in your hands or feet. This condition is more likely to happen in people who have had it before, in patients taking medicines that affect the nerves, and in people with advanced HIV disease. child may not notice these symptoms. Ask the childs healthcare provider for the signs and symptoms of peripheral neuropathy in children. Changes in your immune system (immune reconstitution syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking HIV medicine. Changes in body fat (fat redistribution). Changes in body fat have been seen in people who take antiretroviral medicines. These changes may include: more fat in or around your upper back and neck (buffalo hump) breasts or chest trunk less fat in your legs arms face Tell your healthcare provider if you have any of the symptoms listed above. The most common side effects of didanosine delayed-release capsules include: diarrhea stomach pain nausea vomiting headache rash Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of didanosine delayed-release capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store Didanosine Delayed Release Capsules Store didanosine delayed-release capsules at 20o to 25o (68o to 77o F) Safely throw away any unused didanosine delayed-release capsulesKeep Didanosine Delayed-Release Capsulesand all medicines out of the reach of children and pets. General Information about the safe and effective use of Didanosine Delayed-Release Capsules. Avoid doing things that can spread HIV-1 infection to others. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safe sex by using latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use didanosine delayed-release capsules for condition for which it was not prescribed. Do not give didanosine delayed-release capsules to other people, even if they have the same symptoms as you have. It may harm them. Do not keep medicine that is out of date or that you no longer need. Dispose of unused medicines through community take-back disposal programs when available or place didanosine delayed-release capsules in an unrecognizable closed container in the household trash. This Medication Guide summarizes the most important information about didanosine delayed-release capsules. If you would like more information about didanosine delayed-release capsules, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about didanosine delayed-release capsules that is written for health professionals. For more information call 1-888-838-2872, Medical Affairs.What are the ingredients in Didanosine Delayed-Release Capsules Active Ingredients: didanosine Inactive Ingredients: Black iron oxide, croscarmellose sodium, D&C yellow no. 10 aluminum lake, FD&C blue no. 1, FD&C blue no. aluminum lake, FD&C blue no. aluminum lake, FD&C red no. 40 aluminum lake, gelatin, hydroxypropyl cellulose, hypromellose, methacrylic acid copolymer dispersion, microcrystalline cellulose, polydextrose, polyethylene glycol, propylene glycol, shellac glaze, silicon dioxide, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate. The 200 mg and 400 mg capsule also contains D&C red no. 33 and FD&C yellow no. 6, and the 250 mg also contains D&C red no. 28.ZERIT(R) is registered trademark of Bristol-Myers Squibb Company.LOPURIN(R) is registered trademark of Dr. Reddys Labs.ALOPRIM(R) is registered trademark of Bioniche Pharma.COPEGUS(R), CYTOVENE(R), and VALCYTE(R) are registered trademarks of Hoffman-La Roche.REBETOL(R) is registered trademark of Schering Corporation.RIBASPHERE(R) is registered trademark of Three Rivers Pharms.VIRAZOLE(R) is registered trademark of Valeant Pharm.DOLOPHINE(R) is registered trademark of Roxane Labs.METHADOSE(R) is registered trademark of Mallinckrodt, Inc.VIRACEPT(R) is registered trademark of Aguoron Pharmaceuticals, Inc.VIREAD(R) is registered trademark of Gilead Sciences, Inc.TEVA PHARMACEUTICALS USASellersville, PA 18960Rev. 12/2011This Medication Guide has been approved by the U.S. Food and Drug Administration. Swelling of your pancreas (pancreatitis) that may cause death. Pancreatitis can happen at any time during your treatment with Didanosine Delayed-Release Capsules. Before you start taking didanosine delayed-release capsules, tell your healthcare provider if you:. have had pancreatitis. have advanced HIV (human immunodeficiency virus) infection. have kidney problems. drink alcoholic beverages. take medicine called ZERIT(R) (stavudine). stomach pain swelling of your stomach nausea and vomiting fever Build-up of acid in your blood (lactic acidosis). Lactic acidosis must be treated in the hospital as it may cause death. Before you start taking didanosine delayed-release capsules, tell your healthcare provider if you:. have liver problems are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking didanosine delayed-release capsules and ZERIT (stavudine). are overweight have been treated for long time with other medicines to treat HIV feel weak or tired have unusual (not normal) muscle pain have trouble breathing have stomach pain with nausea and vomiting feel cold, especially in your arms and legs feel dizzy or light-headed have fast or irregular heartbeat Liver problems. Serious liver problems have happened in some people (including pregnant women) who take didanosine delayed-release capsules. These problems include liver enlargement (hepatomegaly), fat in the liver (steatosis), liver failure, and high blood pressure in the large vein of the liver (portal hypertension). Severe liver problems can lead to liver transplantation or death in some people taking didanosine delayed-release capsules. Your healthcare provider should check your liver function while you are taking didanosine delayed-release capsules. You should be especially careful if you have history of heavy alcohol use or liver problems.. yellowing of your skin or the white of your eyes (jaundice) dark urine pain on the right side of your stomach swelling of your stomach easy bruising or bleeding loss of appetite nausea or vomiting vomiting blood or dark colored stools (bowel movements) yellowing of your skin or the white of your eyes (jaundice) dark urine pain on the right side of your stomach swelling of your stomach easy bruising or bleeding loss of appetite nausea or vomiting vomiting blood or dark colored stools (bowel movements) yellowing of your skin or the white of your eyes (jaundice) dark urine pain on the right side of your stomach swelling of your stomach easy bruising or bleeding loss of appetite nausea or vomiting vomiting blood or dark colored stools (bowel movements) have or had kidney problems have or had liver problems (such as hepatitis) have or had persistent numbness, tingling, or pain in the hands or feet (neuropathy) have any other medical conditions are pregnant or plan to become pregnant. It is not known if didanosine delayed-release capsules will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking didanosine delayed-release capsules. You and your healthcare provider will decide if you should take didanosine delayed-release capsules while you are pregnant. arebreastfeeding or plan to breastfeed. Do not breastfeed. It is not known if didanosine delayed-release capsules can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. CYTOVENE(R), VALCYTE(R) (ganciclovir) DOLOPHINE(R) HYDROCHLORIDE, METHADOSE(R) (methadone) VIRACEPT(R) (nelfinavir) VIREAD(R) (tenofovir disoproxil fumarate) alcoholic beverages Take didanosine delayed-release capsules exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much didanosine delayed-release capsules to take and when to take it. Your healthcare provider may change your dose. Do not change your dose of didanosine delayed-release capsules without talking to your healthcare provider. Do not take Didanosine Delayed-Release Capsuleswith food. Take didanosine delayed-release capsules on an empty stomach. Take didanosine delayed-release capsules whole. Do not break, crush, dissolve, or chew didanosine delayed-release capsules before swallowing. If you cannot swallow didanosine delayed-release capsules whole, tell your healthcare provider. You may need different medicine. Try not to miss dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Some medicines should not be taken at the same time of day that you take Didanosine Delayed-Release Capsules. Check with your healthcare provider. If your kidneys are not working well, your healthcare provider will need to do regular blood and urine tests to check how they are working while you take didanosine delayed-release capsule. Your healthcare provider may also lower your dosage of didanosine delayed-release capsule if your kidneys are not working well. If you take too much Didanosine Delayed-Release Capsules, contact poison control center or emergency room right away.. Alcohol. Do not drink alcohol while taking didanosine delayed-release capsules. Alcohol may increase your risk of getting pain and swelling of your pancreas (pancreatitis) or may damage your liver. Vision changes. You should have regular eye exams while taking didanosine delayed-release capsules. Peripheral neuropathy. Symptoms include: numbness, tingling, or pain in your hands or feet. This condition is more likely to happen in people who have had it before, in patients taking medicines that affect the nerves, and in people with advanced HIV disease. child may not notice these symptoms. Ask the childs healthcare provider for the signs and symptoms of peripheral neuropathy in children. Changes in your immune system (immune reconstitution syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking HIV medicine. Changes in body fat (fat redistribution). Changes in body fat have been seen in people who take antiretroviral medicines. These changes may include: more fat in or around your less fat in your diarrhea stomach pain nausea vomiting headache rash Store didanosine delayed-release capsules at 20o to 25o (68o to 77o F) Safely throw away any unused didanosine delayed-release capsules. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safe sex by using latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.

WARNINGS AND PRECAUTIONS SECTION.

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). 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 delayed-release capsules should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with didanosine delayed-release capsules 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 delayed-release capsules therapy is recommended. In patients with risk factors for pancreatitis, didanosine delayed-release capsules 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. 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules should be monitored for early signs of portal hypertension (eg, 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 delayed-release capsules 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 history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of didanosine delayed-release capsules 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 patients taking didanosine. Periodic retinal examinations should be considered for patients receiving didanosine delayed-release capsules [see Adverse Reactions (6)].. 5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including didanosine delayed-release capsules. 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-Barre 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. causal relationship has not been established.

ADVERSE REACTIONS SECTION.

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)] 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, 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 TEVA USA, PHARMACOVIGILANCE at tel: 1-888-838-2872, X6351 or drug.safetytevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch In adults, the most common adverse reactions (greater than 10%, all grades) are diarrhea, peripheral neurologic symptoms/neuropathy, nausea, headache, rash and vomiting. (6.1). Adverse reactions in pediatric patients were consistent with those in adults. (6.1). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Study AI454-152 was 48-week, randomized, open-label study comparing didanosine delayed-release capsules (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients. Selected clinical adverse reactions that occurred in combination with other antiretroviral agents are provided in Table 3. Table 3: Selected Clinical Adverse Reactions, Study AI454-152 Percent of Patients, Adverse Reactionsdidanosine delayed-release capsules +stavudine +nelfinavirn 258zidovudine/lamivudine+nelfinavirn 253Diarrhea5758Peripheral Neurologic Symptoms/Neuropathy 2511Nausea2436Headache2217Rash1412Vomiting1419Pancreatitis (see below)less than 1In clinical trials using 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 of 68 patients who received didanosine delayed-release capsules 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 and Precautions (5)]. The frequency of pancreatitis is dose related. In phase 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 study of didanosine delayed-release capsules in combination with other antiretroviral agents are shown in Table 4. Table 4: Selected Laboratory Abnormalities, Study AI454-152 Percent of Patients didanosine delayed-release capsules stavudine nelfinavirn 258zidovudine/lamivudine nelfinavirn 253ParameterGrades to 4Greater than x ULN for SGOT and SGPT, at least 2.1 ULN for lipase, and at least 2.6 ULN for bilirubin (ULN upper limit of normal). All GradesGrades to All GradesSGOT (AST)546519SGPT (ALT)644522Lipase523213Bilirubinless than 19less than 13Pediatric PatientsIn clinical trials, 743 pediatric patients between 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 studies, pancreatitis occurred in of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 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/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m2 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 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 combination of these factors. Blood and Lymphatic System Disorders anemia, leukopenia, and thrombocytopenia.Body as Whole abdominal pain, 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 Warnings and Precautions (5.1)], sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.Hepatobiliary Disorders symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)]; non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]; hepatitis and liver failure. Metabolic Disorders diabetes mellitus, 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 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 delayed-release capsules 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 delayed-release capsules and hydroxyurea, with or without stavudine, should be avoided.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Didanosine is an antiviral agent [see Clinical Pharmacology (12.4)]. 12.3 Pharmacokinetics. The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the mean (+- standard deviation) oral bioavailability following single oral dosing with buffered formulation is 42 (+-12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (+-8)% of the dose. The CSF-plasma ratio following IV administration is 21 (+-0.03)%. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.Table 7: Pharmacokinetic Parameters for Didanosine in HIV-infected PatientsPediatricsAdultsParameter 20 kg to less than 25 kg = 1025 kg to less than 60 kg = 17At least 60 kg = 7At least 60 kg = 44Apparent clearance (L/h)89.5 21.6116.2 38.6196 55.8174.5 69.7Apparent volume of distribution (L)98.1 30.2154.7 55363 137.7308.3 164.3Elimination half-life (h)0.75 0.130.92 0.091.26 0.191.19 0.21Steady-state (AUC)(mgoh/L) 2.38 0.662.36 0.702.25 0.892.65 1.07Comparison of Didanosine Formulations In didanosine delayed-release capsules, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the pellets in the capsule. The enteric coating dissolves when the pellets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid. In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for didanosine administered as the didanosine delayed-release capsules formulation relative to buffered tablet formulation. The peak plasma concentration (Cmax) of didanosine, administered as didanosine delayed-release capsules, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for didanosine buffered tablets to hours for didanosine delayed-release capsules.Effect of Food In the presence of food, the Cmax and AUC for didanosine delayed-release capsules were reduced by approximately 46% and 19%, respectively, compared to the fasting state [see Dosage and Administration (2)]. Didanosine delayed-release capsules should be taken on an empty stomach. Special Populations Renal Insufficiency: Data from two studies using buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 8). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n 6); recovery in hemodialysate (n 5) ranged from 0.6% to 7.4% of the dose over 3 to hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. [See Dosage and Administration (2.2).] Table 8: Mean +- SD Pharmacokinetic Parameters for Didanosine Following Single Oral Dose of Buffered Formulation ND not determined due to anuria. CLcr creatinine clearance.CL/F apparent oral clearance.CLR renal clearance. Creatinine Clearance (mL/min)Parameterat least 90 = 1260-90n 630-59n 610-29n 3Dialysis Patientsn 11CLcr (mL/min)112 2268 846 813 5NDCL/F (mL/min)2164 6381566 8331023 378628 104543 174CLR (mL/min)458 164247 153100 4420 8less than 10T1/2 (h)1.42 0.331.59 0.131.75 0.432 0.34.1 1.2Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV-infected subjects with moderate (n 8) to severe (n 4) hepatic impairment (Child-Pugh Class or C). Mean AUC and Cmax values following single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [See Dosage and Administration (2.3)]. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet, and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with weight-based dosing scheme [see Dosage and Administration (2)]. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age [see Use in Specific Populations (8.5)]. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions Tables and 10 summarize the effects on AUC and Cmax, with 90% confidence interval (CI) when available, following coadministration of didanosine delayed-release capsules with variety of drugs. For clinical recommendations based on drug interaction studies for drugs in bold font [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Table 9: Results of Drug Interaction Studies with Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values Indicates increase. Indicates decrease.<-> Indicates no change, or mean increase or decrease of less than 10%.% Change of DidanosinePharmacokinetic Parameters Drug Didanosine Dosage AUC of Didanosine(90% CI)Cmax of Didanosine(90% CI)tenofovir, All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min., Tenofovir disoproxil fumarate. 300 mg once daily with light meal373 kcalories, 8.2 grams fat. tenofovir, 300 mg once daily with light meal tenofovir, 300 mg once daily with light meal methadone, chronicmaintenance dose400 mg single dosefasting hours before tenofovir400 mg single dosewith tenofovir and light meal200 mg single dosewith tenofovir and light meal250 mg single dosewith tenofovir and light meal325 mg single dosewith tenofovir and light meal400 mg single dose262533333315, 16 48%(31, 67%) 60%(44, 79%) 16%(6, 27%) Compared with didanosine delayed-release capsules 250 mg administered alone under fasting conditions. <->(-13, 5%)Compared with didanosine delayed-release capsules 400 mg administered alone under fasting conditions. 13%(3, 24%) 17%(-29, -2%) 48%(25, 76%) 64%(41, 89%) 12%(-25, 3%) 20%(-32, -7%) 11%(-24, 4%) 16%(-33, 4%) Table 10: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsule: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values<-> Indicates no change, or mean increase or decrease of less than 10%. Change of Coadministered Drug Pharmacokinetic Parameters, Drug Didanosine Dosage AUC of Coadministered Drug(90% CI)Cmax of Coadministered Drug(90% CI)ciprofloxacin, 750 mg single doseindinavir, 800 mg single doseketoconazole, 200 mg single dosetenofovir,Tenofovir disoproxil fumarate. 300 mg once daily with light meal373 kcalories, 8.2 grams fat. tenofovir, 300 mg once daily with light meal 400 mg single dose400 mg single dose400 mg single dose400 mg single dosefasting hours beforetenofovir400 mg single dosewith tenofovir anda light meal1623212525<-><-><-><-><-><-><-><-><-><->Didanosine Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and Cmax, with 90% or 95% CI when available, following coadministration of buffered formulations of didanosine delayed-release capsules with variety of drugs. The results of these studies may be expected to apply to didanosine. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. For clinical recommendations based on drug interaction studies for drugs in bold font [see Dosage and Administration (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4.1) and Drug Interactions (7.1)]. Table 11: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug of Didanosine Plasma AUC and Cmax Values% Change of DidanosinePharmacokinetic Parameters Drug Didanosine Dosage AUC of Didanosine(95% CI)Cmax of Didanosine(95% CI)allopurinol,renally impaired, 300 mg/dayhealthy volunteer, 300 mg/day for daysganciclovir, 1000 mg every hours, hours after didanosineciprofloxacin, 750 mg every 12 hours for days, hours before didanosine indinavir, 800 mg single dose simultaneous hour before didanosineketoconazole, 200 mg/day for days, hours before didanosineloperamide, mg every hours for daymetoclopramide, 10 mg single doseranitidine, 150 mg single dose, hours before didanosinerifabutin, 300 mg or 600 mg/day for 12 daysritonavir, 600 mg every 12 hours for daysstavudine, 40 mg every 12 hours for dayssulfamethoxazole, 1000 mg single dosetrimethoprim, 200 mg single dosezidovudine, 200 mg every hours for days200 mg single dose400 mg single dose200 mg every12 hours200 mg every12 hours for days200 mg single dose200 mg single dose375 mg every 12 hours for days300 mg single dose300 mg single dose375 mg single dose167 mg or 250 mg every 12 hours for 12 days200 mg every 12 hours for days100 mg every 12 hours for days200 mg single dose200 mg single dose200 mg every12 hours for days214128HIV-infected patients. 161612 12 12 12 1112108 6 312% 113% 111% 16%<-> 17% (-27, -7%)90% CI. <-> <-> <-> 14% 13% (-1, 27%) 13% (0, 23%) <-> <-> <-> <-> 232% 69%NA 28%<-> 13% (-28, 5%) 12% 23% 13% 13% 17% (-4, 38%) 16% (5, 26%)<-><-> 17%(-23, 77%)<-> Indicates increase. Indicates decrease.<-> Indicates no change, or mean increase or decrease of less than 10%.NA Not available. Table 12: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values Indicates increase. Indicates decrease.<-> Indicates no change, or mean increase or decrease of less than 10%.NA Not available.% Change of Coadministered Drug Pharmacokinetic Parameters Drug Didanosine Dosage AUC of Coadministered Drug(95% CI)Cmax of Coadministered Drug(95% CI)dapsone, 100 mg single doseganciclovir, 1000 mg every hours, hours after didanosinenelfinavir, 750 mg single dose, hour after didanosineranitidine, 150 mg single dose, hours before didanosineritonavir, 600 mg every 12 hours for daysstavudine, 40 mg every 12 hours for dayssulfamethoxazole, 1000 mg single dosetrimethoprim, 200 mg single dosezidovudine, 200 mg every hours for days200 mg every 12 hoursfor 14 days200 mg every 12 hours200 mg single dose375 mg single dose200 mg every 12 hoursfor days100 mg every 12 hoursfor days200 mg single dose200 mg single dose200 mg every 12 hoursfor days6HIV-infected patients. 12 10 12 1210 8 6<-> 21% 12% 16%<-><-> 11%(-17, -4%) 10%(-9, 34%) 10%(-27, 11%)<->NA<-><-><-> 17% 12%(-28, 8%) 22%(-59, 49%) 16.5%(-53, 47%)NA Not available.. 12.4 Microbiology Mechanism of Action Didanosine is synthetic 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. Dideoxyadenosine 5-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.Antiviral Activity in Cell Culture The anti-HIV-1 activity of didanosine was evaluated in variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 uM (1 uM 0.24 mcg/mL) in lymphoblastic cell lines and 0.01 to 0.1 uM in monocyte/macrophage cell cultures. Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of 10-fold decrease in susceptibility to didanosine in cell culture compared to baseline isolates. Clinical isolates that exhibited decrease in didanosine susceptibility harbored one or more didanosine resistance-associated substitutions. Cross-resistance HIV-1 isolates from of 39 patients receiving combination therapy for up to years with didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Didanosine delayed-release capsules should be administered on an empty stomach. Didanosine delayed-release capsules should be swallowed intact.. Adult patients: Administered on an empty stomach. Dosing is based on body weight. (2.1) Pediatric patients: Ages to 18 years, can safely swallow capsules and body weight at least 20 kg. Administered on an empty stomach, dosing is based on body weight. (2.1) Body WeightDose20 kg to less than 25 kg200 mg once daily25 kg to less than 60 kg250 mg once dailyat least 60 kg400 mg once dailyRenal impairment: Dose reduction is recommended. (2.2)Coadministration with tenofovir: Dose reduction is recommended. Patients should be monitored closely for didanosine-associated adverse reactions. (2.3, 7.1). Adult patients: Administered on an empty stomach. Dosing is based on body weight. (2.1) Pediatric patients: Ages to 18 years, can safely swallow capsules and body weight at least 20 kg. Administered on an empty stomach, dosing is based on body weight. (2.1) Renal impairment: Dose reduction is recommended. (2.2). Coadministration with tenofovir: Dose reduction is recommended. Patients should be monitored closely for didanosine-associated adverse reactions. (2.3, 7.1). 2.1 Recommended Dosage (Adult and Pediatric Patients). The recommended total daily dose is based on body weight and is administered as one capsule given on once-daily schedule as outlined in Table 1.The recommended total daily dose to be administered once daily to pediatric patients weighing at least 20 kg who can swallow capsules is based on body weight (kg), consistent with the recommended adult dosing guidelines (see Table 1). Please consult the complete prescribing information for Didanosine Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients weighing less than 20 kg or who can not swallow capsules. Table 1: Recommended Dosage (Adult and Pediatric Patients)Body WeightDose20 kg to less than 25 kg200 mg once daily25 kg to less than 60 kg250 mg once dailyat least 60 kg400 mg once daily 2.2 Renal Impairment Dosing recommendations for didanosine delayed-release capsules are different for patients with renal impairment. Adult PatientsIn adult patients with impaired renal function, the dose of didanosine delayed-release capsules should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of didanosine delayed-release capsules in adult patients with renal insufficiency are presented in Table 2. Table 2: Recommended Dosage in Patients with Renal Impairment by Body Weight Creatinine Clearance(mL/min)Dosage (mg)at least 60 kgless than 60 kgat least 60400 once daily250 once daily30 to 59200 once daily125 once daily10 to 29125 once daily125 once dailyless than 10125 once daily Pediatric Patients Urinary excretion is also major route of elimination of didanosine in pediatric patients, therefore the clearance of didanosine may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend specific dose adjustment of didanosine delayed-release capsules in this patient population, reduction in the dose should be considered (see Table 2). Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance of less than 10 mL/min, shown in Table 2. It is not necessary to administer supplemental dose of didanosine following hemodialysis. 2.3 Dose Adjustment Concomitant Therapy with Tenofovir Disoproxil Fumarate In patients who are also taking tenofovir disoproxil fumarate, dose reduction of didanosine delayed-release capsules to 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) or 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) once daily taken together with tenofovir disoproxil fumarate and light meal (400 kcalories or less, 20% fat or less) or in the fasted state is recommended. The appropriate dose of didanosine delayed-release capsules coadministered with tenofovir disoproxil fumarate in patients with creatinine clearance of less than 60 mL/min has not been established [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Hepatic Impairment No dose adjustment is required in patients with hepatic impairment [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both didanosine and stavudine with other agents. This combination should be used with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk. (5.2, 8.1) Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263.. 8.1 Pregnancy. Pregnancy Category Reproduction studies have been performed in rats and rabbits at doses up to 12 and 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. study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk.Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see Warnings and Precautions (5.2)]. 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. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.. 8.3 Nursing Mothers. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving didanosine. 8.4 Pediatric Use. Use of didanosine in pediatric patients from weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of didanosine in adult and pediatric patients [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Additional pharmacokinetic studies in pediatric patients support use of didanosine delayed-release capsules in pediatric patients who weigh at least 20 kg.. 8.5 Geriatric Use. In an Expanded Access Program using buffered formulation of didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had higher frequency of pancreatitis (10%) than younger patients (5%) [see Warnings and Precautions (5.1)]. Clinical studies of didanosine, including those for didanosine delayed-release capsules, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.2)]. 8.6 Renal Impairment Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance [see Clinical Pharmacology (12.3)]. dose reduction is recommended for these patients [see Dosage and Administration (2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See Medication Guide 17.1 Pancreatitis Patients should be informed that serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal. 17.2 Peripheral Neuropathy Patients should be informed that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with didanosine delayed-release capsules. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or history of peripheral neuropathy, and discontinuation of didanosine delayed-release capsules may be required if toxicity develops. 17.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis Patients should be informed that 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.. 17.4 Hepatic Toxicity Patients should be informed that hepatotoxicity including fatal hepatic adverse events were reported in patients with preexisting liver dysfunction. The safety and efficacy of didanosine delayed-release capsules has not been established in HIV-infected patients with significant underlying liver disease. 17.5 Non-cirrhotic Portal Hypertension Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking didanosine delayed-release capsules, including cases leading to liver transplantation or death.. 17.6 Retinal Changes and Optic Neuritis Patients should be informed that retinal changes and optic neuritis have been reported in adult and pediatric patients.. 17.7 Fat Redistribution Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. 17.8 Concomitant Therapy Patients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, which may exacerbate didanosine delayed-release capsules toxicities. 17.9 General Information Didanosine is not cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Therefore, patients should remain under the care of physician when using didanosine. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safe sex by using latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. Do not breast-feed. It is not known if didanosine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk. Patients should be instructed to swallow the capsule as whole and to not open the capsule. Patients should be instructed to not miss dose but if they do, patients should take didanosine as soon as possible. Patients should be told that if it is almost time for the next dose, they should skip the missed dose and continue with the regular dosing schedule. Patients should be instructed to contact poison control center or emergency room right away in case of an overdose.TEVA PHARMACEUTICALS USA Sellersville, PA 18960Rev. 12/2011. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safe sex by using latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. Do not breast-feed. It is not known if didanosine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk. Additional barcode labeling by:Physicians Total Care, Inc.Tulsa, Oklahoma 74146.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the mean (+- standard deviation) oral bioavailability following single oral dosing with buffered formulation is 42 (+-12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (+-8)% of the dose. The CSF-plasma ratio following IV administration is 21 (+-0.03)%. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.Table 7: Pharmacokinetic Parameters for Didanosine in HIV-infected PatientsPediatricsAdultsParameter 20 kg to less than 25 kg = 1025 kg to less than 60 kg = 17At least 60 kg = 7At least 60 kg = 44Apparent clearance (L/h)89.5 21.6116.2 38.6196 55.8174.5 69.7Apparent volume of distribution (L)98.1 30.2154.7 55363 137.7308.3 164.3Elimination half-life (h)0.75 0.130.92 0.091.26 0.191.19 0.21Steady-state (AUC)(mgoh/L) 2.38 0.662.36 0.702.25 0.892.65 1.07Comparison of Didanosine Formulations In didanosine delayed-release capsules, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the pellets in the capsule. The enteric coating dissolves when the pellets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid. In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for didanosine administered as the didanosine delayed-release capsules formulation relative to buffered tablet formulation. The peak plasma concentration (Cmax) of didanosine, administered as didanosine delayed-release capsules, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for didanosine buffered tablets to hours for didanosine delayed-release capsules.Effect of Food In the presence of food, the Cmax and AUC for didanosine delayed-release capsules were reduced by approximately 46% and 19%, respectively, compared to the fasting state [see Dosage and Administration (2)]. Didanosine delayed-release capsules should be taken on an empty stomach. Special Populations Renal Insufficiency: Data from two studies using buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 8). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n 6); recovery in hemodialysate (n 5) ranged from 0.6% to 7.4% of the dose over 3 to hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. [See Dosage and Administration (2.2).] Table 8: Mean +- SD Pharmacokinetic Parameters for Didanosine Following Single Oral Dose of Buffered Formulation ND not determined due to anuria. CLcr creatinine clearance.CL/F apparent oral clearance.CLR renal clearance. Creatinine Clearance (mL/min)Parameterat least 90 = 1260-90n 630-59n 610-29n 3Dialysis Patientsn 11CLcr (mL/min)112 2268 846 813 5NDCL/F (mL/min)2164 6381566 8331023 378628 104543 174CLR (mL/min)458 164247 153100 4420 8less than 10T1/2 (h)1.42 0.331.59 0.131.75 0.432 0.34.1 1.2Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV-infected subjects with moderate (n 8) to severe (n 4) hepatic impairment (Child-Pugh Class or C). Mean AUC and Cmax values following single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [See Dosage and Administration (2.3)]. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet, and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with weight-based dosing scheme [see Dosage and Administration (2)]. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age [see Use in Specific Populations (8.5)]. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions Tables and 10 summarize the effects on AUC and Cmax, with 90% confidence interval (CI) when available, following coadministration of didanosine delayed-release capsules with variety of drugs. For clinical recommendations based on drug interaction studies for drugs in bold font [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Table 9: Results of Drug Interaction Studies with Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values Indicates increase. Indicates decrease.<-> Indicates no change, or mean increase or decrease of less than 10%.% Change of DidanosinePharmacokinetic Parameters Drug Didanosine Dosage AUC of Didanosine(90% CI)Cmax of Didanosine(90% CI)tenofovir, All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min., Tenofovir disoproxil fumarate. 300 mg once daily with light meal373 kcalories, 8.2 grams fat. tenofovir, 300 mg once daily with light meal tenofovir, 300 mg once daily with light meal methadone, chronicmaintenance dose400 mg single dosefasting hours before tenofovir400 mg single dosewith tenofovir and light meal200 mg single dosewith tenofovir and light meal250 mg single dosewith tenofovir and light meal325 mg single dosewith tenofovir and light meal400 mg single dose262533333315, 16 48%(31, 67%) 60%(44, 79%) 16%(6, 27%) Compared with didanosine delayed-release capsules 250 mg administered alone under fasting conditions. <->(-13, 5%)Compared with didanosine delayed-release capsules 400 mg administered alone under fasting conditions. 13%(3, 24%) 17%(-29, -2%) 48%(25, 76%) 64%(41, 89%) 12%(-25, 3%) 20%(-32, -7%) 11%(-24, 4%) 16%(-33, 4%) Table 10: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsule: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values<-> Indicates no change, or mean increase or decrease of less than 10%. Change of Coadministered Drug Pharmacokinetic Parameters, Drug Didanosine Dosage AUC of Coadministered Drug(90% CI)Cmax of Coadministered Drug(90% CI)ciprofloxacin, 750 mg single doseindinavir, 800 mg single doseketoconazole, 200 mg single dosetenofovir,Tenofovir disoproxil fumarate. 300 mg once daily with light meal373 kcalories, 8.2 grams fat. tenofovir, 300 mg once daily with light meal 400 mg single dose400 mg single dose400 mg single dose400 mg single dosefasting hours beforetenofovir400 mg single dosewith tenofovir anda light meal1623212525<-><-><-><-><-><-><-><-><-><->Didanosine Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and Cmax, with 90% or 95% CI when available, following coadministration of buffered formulations of didanosine delayed-release capsules with variety of drugs. The results of these studies may be expected to apply to didanosine. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. For clinical recommendations based on drug interaction studies for drugs in bold font [see Dosage and Administration (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4.1) and Drug Interactions (7.1)]. Table 11: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug of Didanosine Plasma AUC and Cmax Values% Change of DidanosinePharmacokinetic Parameters Drug Didanosine Dosage AUC of Didanosine(95% CI)Cmax of Didanosine(95% CI)allopurinol,renally impaired, 300 mg/dayhealthy volunteer, 300 mg/day for daysganciclovir, 1000 mg every hours, hours after didanosineciprofloxacin, 750 mg every 12 hours for days, hours before didanosine indinavir, 800 mg single dose simultaneous hour before didanosineketoconazole, 200 mg/day for days, hours before didanosineloperamide, mg every hours for daymetoclopramide, 10 mg single doseranitidine, 150 mg single dose, hours before didanosinerifabutin, 300 mg or 600 mg/day for 12 daysritonavir, 600 mg every 12 hours for daysstavudine, 40 mg every 12 hours for dayssulfamethoxazole, 1000 mg single dosetrimethoprim, 200 mg single dosezidovudine, 200 mg every hours for days200 mg single dose400 mg single dose200 mg every12 hours200 mg every12 hours for days200 mg single dose200 mg single dose375 mg every 12 hours for days300 mg single dose300 mg single dose375 mg single dose167 mg or 250 mg every 12 hours for 12 days200 mg every 12 hours for days100 mg every 12 hours for days200 mg single dose200 mg single dose200 mg every12 hours for days214128HIV-infected patients. 161612 12 12 12 1112108 6 312% 113% 111% 16%<-> 17% (-27, -7%)90% CI. <-> <-> <-> 14% 13% (-1, 27%) 13% (0, 23%) <-> <-> <-> <-> 232% 69%NA 28%<-> 13% (-28, 5%) 12% 23% 13% 13% 17% (-4, 38%) 16% (5, 26%)<-><-> 17%(-23, 77%)<-> Indicates increase. Indicates decrease.<-> Indicates no change, or mean increase or decrease of less than 10%.NA Not available. Table 12: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values Indicates increase. Indicates decrease.<-> Indicates no change, or mean increase or decrease of less than 10%.NA Not available.% Change of Coadministered Drug Pharmacokinetic Parameters Drug Didanosine Dosage AUC of Coadministered Drug(95% CI)Cmax of Coadministered Drug(95% CI)dapsone, 100 mg single doseganciclovir, 1000 mg every hours, hours after didanosinenelfinavir, 750 mg single dose, hour after didanosineranitidine, 150 mg single dose, hours before didanosineritonavir, 600 mg every 12 hours for daysstavudine, 40 mg every 12 hours for dayssulfamethoxazole, 1000 mg single dosetrimethoprim, 200 mg single dosezidovudine, 200 mg every hours for days200 mg every 12 hoursfor 14 days200 mg every 12 hours200 mg single dose375 mg single dose200 mg every 12 hoursfor days100 mg every 12 hoursfor days200 mg single dose200 mg single dose200 mg every 12 hoursfor days6HIV-infected patients. 12 10 12 1210 8 6<-> 21% 12% 16%<-><-> 11%(-17, -4%) 10%(-9, 34%) 10%(-27, 11%)<->NA<-><-><-> 17% 12%(-28, 8%) 22%(-59, 49%) 16.5%(-53, 47%)NA Not available.