Retrodel-Kit

Didanosine:

• Warning: pancreatitis, lactic acidosis and hepatomegaly with steatosis
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Retrodel-Kit (Didanosine) reviews

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Fatal and nonfatal pancreatitis has occurred during therapy with Retrodel-Kit (Didanosine) used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Retrodel-Kit (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 Retrodel-Kit (Didanosine) and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of Retrodel-Kit (Didanosine) and stavudine with other antiretroviral agents. The combination of Retrodel-Kit (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. Retrodel-Kit (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 Retrodel-Kit (Didanosine) and stavudine. (5.2)

1 INDICATIONS AND USAGE

VIDEX^® EC (didanosine, USP), also known as ddI, in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14) ].

Retrodel-Kit (Didanosine) (didanosine, USP) is a nucleoside reverse transcriptase inhibitor for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1 infection. (1)

2 DOSAGE AND ADMINISTRATION

Retrodel-Kit should be administered on an empty stomach. Retrodel-Kit (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 6 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 a 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. Please consult the complete prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for dosage and administration of Retrodel-Kit (Didanosine) to pediatric patients weighing less than 20 kg or who can not swallow capsules.

2.2 Renal Impairment

Dosing recommendations for Retrodel-Kit and VIDEX Pediatric Powder for Oral Solution are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX (didanosine) Pediatric Powder for Oral Solution to patients with renal impairment.

Adult Patients

In adult patients with impaired renal function, the dose of Retrodel-Kit (Didanosine) should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of Retrodel-Kit (Didanosine) in adult patients with renal insufficiency are presented in Table 2.

Pediatric Patients

Urinary excretion is also a major route of elimination of Retrodel-Kit in pediatric patients, therefore the clearance of Retrodel-Kit (Didanosine) may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of Retrodel-Kit (Didanosine) in this patient population, a reduction in the dose should be considered.

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 a supplemental dose of Retrodel-Kit (Didanosine) following hemodialysis.

2.3 Dose Adjustment

Concomitant Therapy with Tenofovir Disoproxil Fumarate

In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of Retrodel-Kit 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 a light meal (400 kcalories or less, 20% fat or less) or in the fasted state is recommended. The appropriate dose of Retrodel-Kit (Didanosine) 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) ].

3 DOSAGE FORMS AND STRENGTHS

Retrodel-Kit (Didanosine) (didanosine, USP) Delayed-Release Capsules are white, opaque capsules as described below:

• 125 mg capsule imprinted with “BMS 125 mg 6671” in Tan
• 200 mg capsule imprinted with “BMS 200 mg 6672” in Green
• 250 mg capsule imprinted with “BMS 250 mg 6673” in Blue
• 400 mg capsule imprinted with “BMS 400 mg 6674” in Red

Capsules: 125 mg, 200 mg, 250 mg, 400 mg (3)

4 CONTRAINDICATIONS

These recommendations are based on either drug interaction studies or observed clinical toxicities.

Coadministration with allopurinol or ribavirin is contraindicated.

4.1 Allopurinol

Coadministration of Retrodel-Kit (Didanosine) and allopurinol is contraindicated because systemic exposures of Retrodel-Kit (Didanosine) are increased, which may increase didanosine-associated toxicity [see Clinical Pharmacology (12.3) ].

4.2 Ribavirin

Coadministration of Retrodel-Kit (Didanosine) and ribavirin is contraindicated because exposures of the active metabolite of Retrodel-Kit (Didanosine) (dideoxyadenosine 5′-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both Retrodel-Kit (Didanosine) and ribavirin.

5 WARNINGS AND PRECAUTIONS

• Pancreatitis: Suspension or discontinuation of Retrodel-Kit may be necessary. (5.1)
• Lactic acidosis and severe hepatomegaly with steatosis: Suspend Retrodel-Kit (Didanosine) in patients who develop clinical symptoms or signs with or without laboratory findings. (5.2)
• Hepatic toxicity: Interruption or discontinuation of Retrodel-Kit (Didanosine) must be considered upon worsening of liver disease. (5.3)
• Non-cirrhotic portal hypertension: Discontinue Retrodel-Kit (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 Retrodel-Kit (Didanosine) used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Retrodel-Kit (Didanosine) should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with Retrodel-Kit (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 Retrodel-Kit (Didanosine) (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, Retrodel-Kit (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 Retrodel-Kit 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 Retrodel-Kit (Didanosine) and stavudine with other antiretroviral agents. The combination of Retrodel-Kit (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 Retrodel-Kit (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 Retrodel-Kit (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 Retrodel-Kit (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, Retrodel-Kit (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 Retrodel-Kit therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.

Patients receiving Retrodel-Kit (Didanosine) 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. Retrodel-Kit (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 Retrodel-Kit (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 Retrodel-Kit (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 patients taking Retrodel-Kit. Periodic retinal examinations should be considered for patients receiving Retrodel-Kit (Didanosine) [see Adverse Reactions (6) ].

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Retrodel-Kit (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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections:

• Pancreatitis [see Boxed Warning, Warnings and Precautions ]
• 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 Bristol-Myers Squibb at 1-800-721-5072 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

Study AI454-152 was a 48-week, randomized, open-label study comparing Retrodel-Kit (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.

In clinical trials using a buffered formulation of Retrodel-Kit (Didanosine), pancreatitis resulting in death was observed in one patient who received Retrodel-Kit (Didanosine) plus stavudine plus nelfinavir, one patient who received Retrodel-Kit (Didanosine) plus stavudine plus indinavir, and 2 of 68 patients who received Retrodel-Kit (Didanosine) plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received Retrodel-Kit (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 3 studies with buffered formulations of Retrodel-Kit (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 Retrodel-Kit (Didanosine) in combination with other antiretroviral agents are shown in Table 4.

Pediatric Patients

In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with Retrodel-Kit (Didanosine). Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of Retrodel-Kit (Didanosine) in adults.

In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m²/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 Retrodel-Kit (Didanosine) 120 mg/m² every 12 hours and in less than 1% of the 274 pediatric patients who received Retrodel-Kit (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 Retrodel-Kit. 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 Retrodel-Kit (Didanosine), or a combination of these factors.

• Blood and Lymphatic System Disorders - anemia, leukopenia, and thrombocytopenia.
• Body as a 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 Retrodel-Kit (Didanosine) is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Retrodel-Kit (Didanosine) is used alone. Thus, patients treated with Retrodel-Kit (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 Retrodel-Kit (Didanosine) and hydroxyurea, with or without stavudine, should be avoided.

7 DRUG INTERACTIONS

Coadministration of Retrodel-Kit can alter the concentration of other drugs and other drugs may alter the concentration of Retrodel-Kit (Didanosine). The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3)

7.1 Established Drug Interactions

Clinical recommendations based on the results of drug interaction studies are listed in Table 5. Pharmacokinetic results of drug interaction studies are shown in Tables 9-12 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3) ].

Exposure to Retrodel-Kit (Didanosine) is increased when coadministered with tenofovir disoproxil fumarate [Table 5 and see Clinical Pharmacokinetics (12.3, Tables 9 and 10) ]. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with Retrodel-Kit (Didanosine) should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. Retrodel-Kit (Didanosine) should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop [see Dosage and Administration (2.3), Warnings and Precautions (5) ]. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with Retrodel-Kit (Didanosine) at a dose of 400 mg daily.

7.2 Predicted Drug Interactions

Predicted drug interactions with Retrodel-Kit (Didanosine) are listed in Table 6.

8 USE IN SPECIFIC POPULATIONS

Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both Retrodel-Kit 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 B

Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Retrodel-Kit (Didanosine). At approximately 12 times the estimated human exposure, Retrodel-Kit (Didanosine) was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that Retrodel-Kit (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 Retrodel-Kit (Didanosine) in pregnant women. Retrodel-Kit (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 Retrodel-Kit (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 Retrodel-Kit (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 Retrodel-Kit (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 Retrodel-Kit (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 breastfeed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, Retrodel-Kit and/or its metabolites were excreted into the milk of lactating rats. It is not known if Retrodel-Kit (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 breastfeed if they are receiving Retrodel-Kit (Didanosine).

8.4 Pediatric Use

Use of Retrodel-Kit (Didanosine) in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of Retrodel-Kit (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 Retrodel-Kit (Didanosine) in pediatric patients who weigh at least 20 kg.

8.5 Geriatric Use

In an Expanded Access Program using a buffered formulation of Retrodel-Kit for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) [see Warnings and Precautions (5.1) ]. Clinical studies of Retrodel-Kit (Didanosine), including those for Retrodel-Kit (Didanosine), did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Retrodel-Kit (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 Retrodel-Kit (Didanosine) due to decreased drug clearance [see Clinical Pharmacology (12.3) ]. A dose reduction is recommended for these patients [see Dosage and Administration (2) ].

10 OVERDOSAGE

There is no known antidote for Retrodel-Kit (Didanosine) overdosage. In phase 1 studies, in which buffered formulations of Retrodel-Kit (Didanosine) were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Retrodel-Kit (Didanosine) is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis [see Clinical Pharmacology (12.3) ].

11 DESCRIPTION

VIDEX^® EC is the brand name for an enteric-coated formulation of Retrodel-Kit (Didanosine), USP, a synthetic purine nucleoside analogue active against HIV-1. Retrodel-Kit (Didanosine) Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of Retrodel-Kit (Didanosine). The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain gelatin and titanium dioxide. The capsules are imprinted with edible inks.

Retrodel-Kit (Didanosine) is also available in a powder formulation. Please consult the prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information.

The chemical name for Retrodel-Kit (Didanosine) is 2′,3′-dideoxyinosine. The structural formula is:

Retrodel-Kit (Didanosine) is a white crystalline powder with the molecular formula C₁₀H₁₂N₄O₃ and a molecular weight of 236.2. The aqueous solubility of Retrodel-Kit (Didanosine) at 25° C and pH of approximately 6 is 27.3 mg/mL. Retrodel-Kit (Didanosine) is unstable in acidic solutions. For example, at pH less than 3 and 37° C, 10% of Retrodel-Kit (Didanosine) decomposes to hypoxanthine in less than 2 minutes. In Retrodel-Kit (Didanosine), an enteric coating is used to protect Retrodel-Kit (Didanosine) from degradation by stomach acid.

didanosine-structure.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Retrodel-Kit is an antiviral agent [see Clinical Pharmacology (12.4) ].

12.3 Pharmacokinetics

The pharmacokinetic parameters of Retrodel-Kit (Didanosine) in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Retrodel-Kit (Didanosine) is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma Retrodel-Kit (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 a buffered formulation is 42 (±12)%. After oral administration, the urinary recovery of Retrodel-Kit (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 a single dose. Binding of Retrodel-Kit (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 Retrodel-Kit (Didanosine) in man occurs by the same pathways responsible for the elimination of endogenous purines.

Comparison of Retrodel-Kit Formulations

In Retrodel-Kit (Didanosine), the active ingredient, Retrodel-Kit (Didanosine), is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of Retrodel-Kit (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 Retrodel-Kit (Didanosine) administered as the Retrodel-Kit (Didanosine) formulation relative to a buffered tablet formulation. The peak plasma concentration (C_max) of Retrodel-Kit (Didanosine), administered as Retrodel-Kit (Didanosine), is reduced approximately 40% relative to Retrodel-Kit (Didanosine) buffered tablets. The time to the peak concentration (T_max) increases from approximately 0.67 hours for Retrodel-Kit (Didanosine) buffered tablets to 2.0 hours for Retrodel-Kit (Didanosine).

Effect of Food

In the presence of food, the C_max and AUC for Retrodel-Kit were reduced by approximately 46% and 19%, respectively, compared to the fasting state [see Dosage and Administration (2) ]. Retrodel-Kit (Didanosine) should be taken on an empty stomach.

Special Populations

Renal Insufficiency: Data from two studies using a buffered formulation of Retrodel-Kit (Didanosine) indicated that the apparent oral clearance of Retrodel-Kit (Didanosine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. Following oral administration, Retrodel-Kit (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 a 3-4 hour dialysis period. The absolute bioavailability of Retrodel-Kit (Didanosine) was not affected in patients requiring dialysis. [See Dosage and Administration (2.2) .]

Hepatic Impairment: The pharmacokinetics of Retrodel-Kit (Didanosine) have been studied in 12 non-HIV-infected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and C_max values following a single 400 mg dose of Retrodel-Kit (Didanosine) were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and C_max values was observed for subjects with hepatic impairment and matched healthy controls. [See Dosage and Administration (2.3) .]

Pediatric Patients: The pharmacokinetics of Retrodel-Kit (Didanosine) have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.

A population pharmacokinetic analysis was conducted on pooled Retrodel-Kit (Didanosine) plasma concentration data from 9 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. Retrodel-Kit (Didanosine) exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme [see Dosage and Administration (2) ].

Geriatric Patients: Retrodel-Kit (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 Retrodel-Kit (Didanosine) pharmacokinetics have not been studied.

Drug Interactions

Tables 9 and 10 summarize the effects on AUC and C_max, with a 90% confidence interval when available, following coadministration of Retrodel-Kit (Didanosine) with a 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) .

Retrodel-Kit (Didanosine) Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and C_max, with a 90% or 95% CI when available, following coadministration of buffered formulations of Retrodel-Kit (Didanosine) with a variety of drugs. The results of these studies may be expected to apply to Retrodel-Kit (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) .

12.4 Microbiology

Mechanism of Action

Retrodel-Kit is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly, Retrodel-Kit (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 Retrodel-Kit (Didanosine) was evaluated in a 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 μM (1 μM = 0.24 μg/mL) in lymphoblastic cell lines and 0.01 to 0.1 μM in monocyte/macrophage cell cultures.

Resistance

HIV-1 isolates with reduced sensitivity to Retrodel-Kit have been selected in cell culture and were also obtained from patients treated with Retrodel-Kit (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 6 to 24 months of Retrodel-Kit (Didanosine) monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to Retrodel-Kit (Didanosine) in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in Retrodel-Kit (Didanosine) susceptibility harbored one or more Retrodel-Kit (Didanosine) resistance-associated substitutions.

Cross-resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with Retrodel-Kit (Didanosine) and zidovudine exhibited decreased susceptibility to Retrodel-Kit (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 Retrodel-Kit (Didanosine).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.

Retrodel-Kit induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.

Retrodel-Kit (Didanosine) was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.

13.2 Animal Toxicology and/or Pharmacology

Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with Retrodel-Kit (Didanosine) at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of Retrodel-Kit (Didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of Retrodel-Kit (Didanosine) and other nucleoside analogues.

14 CLINICAL STUDIES

14.1 Adult Patients

Study AI454-152 was a 48-week, randomized, open-label study comparing Retrodel-Kit (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, with a mean CD4 cell count of 411 cells/mm³ (range 39 to 1105 cells/mm³) and a mean plasma HIV-1 RNA of 4.71 log₁₀ copies/mL (range 2.8 to 5.9 log₁₀ copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 13, respectively.

14.2 Pediatric Patients

Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m² every 6 hours), Retrodel-Kit (Didanosine) (120 mg/m² every 12 hours), or zidovudine (120 mg/m² every 6 hours) plus Retrodel-Kit (Didanosine) (90 mg/m² every 12 hours). Patients treated with Retrodel-Kit (Didanosine) or Retrodel-Kit (Didanosine) plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.

16 HOW SUPPLIED/STORAGE AND HANDLING

Retrodel-Kit (Didanosine) (didanosine, USP) Delayed-Release Capsules are white, opaque capsules that are packaged in bottles with child-resistant closures as described in Table 14.

Storage

The capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° C and 30° C (59° F and 86° F) are permitted.

17 PATIENT COUNSELING INFORMATION

See Medication Guide.

17.1 Pancreatitis

Patients should be informed that a serious toxicity of Retrodel-Kit, 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 Retrodel-Kit (Didanosine) (didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or a history of peripheral neuropathy, and that discontinuation of Retrodel-Kit (Didanosine) 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 Retrodel-Kit 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 Retrodel-Kit (Didanosine) have 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 Retrodel-Kit, 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 Retrodel-Kit is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when Retrodel-Kit (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 Retrodel-Kit (Didanosine) toxicities.

17.9 General Information

Retrodel-Kit (Didanosine) is not a 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 a physician when using Retrodel-Kit (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 items 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 a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. It is not known if Retrodel-Kit (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 breastfeed because HIV-1 can be passed to the baby in breast milk.

Patients should be instructed to swallow the capsule as a whole and to not open the capsule.

Patients should be instructed to not miss a dose but if they do, patients should take Retrodel-Kit (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 a poison control center or emergency room right away in case of an overdose.

Medication Guide

VIDEX ^® EC (VY-dex Ee-see)

(didanosine, also known as ddI)

Delayed-Release Capsules

Enteric-Coated Beadlets

Read this Medication Guide before you start taking Retrodel-Kit (Didanosine) and each time you get a 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 Retrodel-Kit (Didanosine) before you start taking it and at regular check-ups. You should stay under your healthcare provider’s care when taking Retrodel-Kit (Didanosine).

What is the most important information I should know about Retrodel-Kit (Didanosine)?

Retrodel-Kit (Didanosine) may cause serious side effects, including:

1. Swelling of your pancreas (pancreatitis) that may cause death. Pancreatitis can happen at any time during your treatment with Retrodel-Kit (Didanosine). Before you start taking Retrodel-Kit (Didanosine), tell your healthcare provider if you:

• have had pancreatitis
• have advanced HIV (human immunodeficiency virus) infection
• have kidney problems
• drink alcoholic beverages
• take a medicine called ZERIT^® (stavudine)

It is important to call your healthcare provider right away if you have:

• stomach pain
• swelling of your stomach
• nausea and vomiting
• fever

2. 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 Retrodel-Kit (Didanosine), 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 Retrodel-Kit (Didanosine) and ZERIT (stavudine).
• are overweight
• have been treated for a 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 a fast or irregular heartbeat

3. Liver problems. Serious liver problems have happened in some people (including pregnant women) who take Retrodel-Kit (Didanosine). 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 Retrodel-Kit (Didanosine). Your healthcare provider should check your liver function while you are taking Retrodel-Kit (Didanosine). You should be especially careful if you have a 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 Retrodel-Kit (Didanosine)?

Retrodel-Kit (Didanosine) is a prescription medicine used with other antiretroviral medicines to treat human immunodeficiency virus (HIV) infection in children and adults. Retrodel-Kit (Didanosine) belongs to a class of drugs called nucleoside analogues.

Retrodel-Kit (Didanosine) will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking Retrodel-Kit (Didanosine), 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 Retrodel-Kit (Didanosine)?

Do not take Retrodel-Kit (Didanosine) if you take:

• ZYLOPRIM^®, LOPURIN^®, ALOPRIM^® (allopurinol)
• COPEGUS^®, REBETOL^®, RIBASPHERE^®, RIBAVIRIN^®, VIRAZOLE^® (ribavirin)

What should I tell my healthcare provider before taking Retrodel-Kit (Didanosine)?

Before you take Retrodel-Kit (Didanosine), 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 Retrodel-Kit (Didanosine) will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Retrodel-Kit (Didanosine). You and your healthcare provider will decide if you should take Retrodel-Kit (Didanosine) while you are pregnant.
  

  Pregnancy Registry: There is a 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.

• are breastfeeding or plan to breastfeed. Do not breastfeed. It is not known if Retrodel-Kit (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 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. Retrodel-Kit (Didanosine) may affect the way other medicines work, and other medicines may affect how Retrodel-Kit (Didanosine) works.

Especially tell your healthcare provider if you take:

• CYTOVENE^®, VALCYTE^® (ganciclovir)
• DOLOPHINE^® HYDROCHLORIDE, METHADOSE^® (methadone)
• VIRACEPT^® (nelfinavir)
• VIREAD^® (tenofovir disoproxil fumarate)
• alcoholic beverages

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

Ask your healthcare provider if you are not sure if you take one of the medicines listed above.

How should I take Retrodel-Kit (Didanosine)?

• Take Retrodel-Kit (Didanosine) exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much Retrodel-Kit (Didanosine) to take and when to take it.
• Your healthcare provider may change your dose. Do not change your dose of Retrodel-Kit (Didanosine) without talking to your healthcare provider.
• Do not take Retrodel-Kit (Didanosine) with food. Take Retrodel-Kit (Didanosine) on an empty stomach.
• Take Retrodel-Kit (Didanosine) capsules whole. Do not break, crush, dissolve, or chew Retrodel-Kit (Didanosine) capsules before swallowing. If you cannot swallow Retrodel-Kit (Didanosine) capsules whole, tell your healthcare provider. You may need a different medicine.
• Try not to miss a 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 Retrodel-Kit (Didanosine). 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 Retrodel-Kit (Didanosine). Your healthcare provider may also lower your dosage of Retrodel-Kit (Didanosine) if your kidneys are not working well.
• If you take too much Retrodel-Kit (Didanosine), contact a poison control center or emergency room right away.

What should I avoid while taking Retrodel-Kit (Didanosine)?

• Alcohol. Do not drink alcohol while taking Retrodel-Kit (Didanosine). 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 Retrodel-Kit (Didanosine)?

Retrodel-Kit (Didanosine) can cause pancreatitis, lactic acidosis, and liver problems. See “What is the most important information I should know about Retrodel-Kit (Didanosine)?” at the beginning of this Medication Guide.

• Vision changes. You should have regular eye exams while taking Retrodel-Kit (Didanosine).
• 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. A child may not notice these symptoms. Ask the child’s 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 a 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 Retrodel-Kit (Didanosine) 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 Retrodel-Kit (Didanosine). 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 I store Retrodel-Kit (Didanosine)?

• Store Retrodel-Kit (Didanosine) capsules in a tightly closed container between 59° F to 86° F (15° C to 30° C)
• Safely throw away any unused Retrodel-Kit (Didanosine)

Keep Retrodel-Kit (Didanosine) and all medicines out of the reach of children and pets.

General Information about the safe and effective use of Retrodel-Kit (Didanosine)

Avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items 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 a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Retrodel-Kit (Didanosine) for a condition for which it was not prescribed. Do not give Retrodel-Kit (Didanosine) 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 Retrodel-Kit (Didanosine) in an unrecognizable closed container in the household trash.

This Medication Guide summarizes the most important information about Retrodel-Kit (Didanosine). If you would like more information about Retrodel-Kit (Didanosine), talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Retrodel-Kit (Didanosine) that is written for health professionals. For more information, go to www.bms.com/products/Pages/prescribing.aspx or call 1-800-321-1335.

What are the ingredients in Retrodel-Kit (Didanosine)?

Active Ingredients: Retrodel-Kit (Didanosine)

Inactive Ingredients:

Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, talc, gelatin, and titanium dioxide.

VIDEX^® EC and Zerit^® are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

Product of Japan

This Medication Guide has been approved by the U.S. Food and Drug Administration.

1352585

Revised August 2015

Retrodel-Kit (Didanosine) 125 mg Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of Retrodel-Kit (Didanosine).

30 Capsules NDC 0087-6671-17

125 mg

VIDEX^®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Retrodel-Kit (Didanosine) 200 mg Representative Packaging

30 Capsules NDC 0087-6672-17

200 mg

VIDEX^®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Retrodel-Kit (Didanosine) 250 mg Representative Packaging

30 Capsules NDC 0087-6673-17

250 mg

VIDEX^®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Retrodel-Kit (Didanosine) 400 mg Representative Packaging

30 Capsules NDC 0087-6674-17

400 mg

VIDEX^®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Efavirenz:

• Retrodel-Kit (Efavirenz) reviews

Indication: For use in combination treatment of HIV infection (AIDS)

Retrodel-Kit (Efavirenz) (dideoxyinosine, ddI) is an oral nucleoside reverse transcriptase inhibitor (NRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Retrodel-Kit (Efavirenz) was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Retrodel-Kit (Efavirenz) be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or Retrodel-Kit (Efavirenz) when treating HIV infection.

Lamivudine:

• Retrodel-Kit Mcneil & Argus Pharmaceuticals information
• Retrodel-Kit Mcneil & Argus Pharmaceuticals warnings
• Retrodel-Kit Mcneil & Argus Pharmaceuticals side effects
• Retrodel-Kit Mcneil & Argus Pharmaceuticals overdose
• Retrodel-Kit Mcneil & Argus Pharmaceuticals usage guidelines
• Retrodel-Kit (Lamivudine) reviews

Retrodel-Kit Mcneil & Argus Pharmaceuticals information

Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals is an anti-HIV treatment in the class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTIs). The body breaks down these drugs into chemicals that stop HIV from infecting uninfected cells in the body, but they do not help cells that have already been infected with the virus. This product is an important part of combination anti-HIV treatment. Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals inhibits the reproduction of viruses in the body.

Retrodel-Kit Mcneil & Argus Pharmaceuticals warnings

Before taking the medication, tell your doctor if you have:

kidney disease

liver disease

pancreatitis

problems with your muscles

problems with your blood counts.

Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals does not reduce the risk of passing the HIV or hepatitis B virus to others. Avoid alcohol while taking the medicine. Alcohol may increase the risk of damage to the pancreas and / or liver. It is not known whether Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals will be harmful to an unborn baby. It is very important to treat HIV / AIDS during pregnancy to reduce the risk of infecting the baby. It is not known whether Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed. The drug may interact with other medications resulting in reduced effectiveness and / or side effects. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medications, including herbal products.

Retrodel-Kit Mcneil & Argus Pharmaceuticals side effects

The possible side effects of Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals are lactic acidosis and severe liver problems, including fatal cases, have been reported with the use of reverse transcriptase inhibitors, alone or in combination. Contact your doctor immediately if you experience nausea, vomiting, or unusual or unexpected stomach discomfort; weakness and tiredness; shortness of breath; weakness in the arms and legs; yellowing of the skin or eyes; or pain in the upper stomach area. These may be early symptoms of lactic acidosis or liver problems. Serious cases of pancreatitis (inflammation of the pancreas) have also been reported with the use of Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals. Notify your doctor immediately if you develop symptoms of pancreatitis including nausea, vomiting, diarrhea, abdominal pain. If you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives), stop taking this medication and seek emergency medical attention.

Retrodel-Kit Mcneil & Argus Pharmaceuticals overdose

Seek emergency medical attention. Symptoms of a Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals overdose are not known. Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication unless your doctor directs otherwise.

Retrodel-Kit Mcneil & Argus Pharmaceuticals usage guidelines

Take this medicine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you. Take each dose with a full glass of water. Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals can be taken with or without food. For the treatment of HIV or AIDS, this drug is usually taken twice a day and is often used in combination with other HIV medicines. Follow your doctor's instructions. For the treatment of chronic hepatitis B, this product is usually taken once a day. Follow your doctor's instructions. Store Retrodel-Kit (Lamivudine) Mcneil & Argus Pharmaceuticals at room temperature away from moisture and heat.