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Didanosine

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use didanosine safely and effectively. See full prescribing information for didanosine for oral solution.Didanosine for Oral Solution, USPInitial U.S. Approval: 1991RECENT MAJOR CHANGES(5.7)BOXED WARNINGWARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS See full prescribing information for complete boxed warning. Fatal and nonfatal pancreatitis. Didanosine should be suspended in patients with suspected pancreatitis and discontinued in patients with confirmed pancreatitis. (5.1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine. (5.2) INDICATIONS AND USAGEDidanosine 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) DOSAGE AND ADMINISTRATION Adult patients: Administered on an empty stomach at least 30 minutes before or 2 hours after eating. Dosing is based on body weight. (2.1) at least 60 kg less than 60 kg Preferred dosing 200 mg twice daily 125 mg twice daily Dosing for patients whose management requires once-daily frequency 400 mg once daily 250 mg once daily Pediatric patients (2 weeks old to 18 years old): Administered on an empty stomach at least 30 minutes before or 2 hours after eating. - Between 2 weeks and 8 months old, dosing is 100 mg/m2 twice daily. - For those greater than 8 months old, dosing is 120 mg/m2 twice daily but not to exceed the adult dosing recommendation. (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) DOSAGE FORMS AND STRENGTHS 4 ounce bottle of 2 grams of Didanosine (3) 8 ounce bottle of 4 grams of Didanosine (3) CONTRAINDICATIONS(4.14.2)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) Side Effects In adults, the most common adverse reactions (greater than 10%, all grades) are diarrhea, peripheral neurologic symptoms/neuropathy, abdominal pain, nausea, headache, rash, and vomiting. (6.1) Adverse reactions in pediatric patients were consistent with those in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS(4,712.3)USE IN SPECIFIC POPULATIONSPregnancy: 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.

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS
1 DIDANOSINE INDICATIONS AND USAGE
2 DIDANOSINE DOSAGE AND ADMINISTRATION
- 2.1 Recommended Dosage (Adult and Pediatric Patients)
- 2.2 Renal Impairment
- 2.3 Dosage Adjustment
3 DOSAGE FORMS AND STRENGTHS
4 DIDANOSINE CONTRAINDICATIONS
- 4.1 Allopurinol
- 4.2 Ribavirin
5 WARNINGS AND PRECAUTIONS
- 5.1 Pancreatitis
- 5.2 Lactic Acidosis/Severe Hepatomegaly with Steatosis
- 5.3 Hepatic Toxicity
- 5.4 Non-cirrhotic Portal Hypertension
- 5.5 Peripheral Neuropathy
- 5.6 Retinal Changes and Optic Neuritis
- 5.7 Immune Reconstitution Syndrome
- 5.8 Fat Redistribution
6 DIDANOSINE ADVERSE REACTIONS
- 6.1 Clinical Trials Experience
- 6.2 Postmarketing Experience
7 DRUG INTERACTIONS
- 7.1 Established Drug Interactions
- 7.2 Predicted Drug Interactions
8 USE IN SPECIFIC POPULATIONS
- 8.1 Pregnancy
- 8.3 Nursing Mothers
- 8.4 Pediatric Use
- 8.5 Geriatric Use
- 8.6 Renal Impairment
10 OVERDOSAGE
11 DIDANOSINE DESCRIPTION
12 CLINICAL PHARMACOLOGY
- 12.1 Mechanism of Action
- 12.3 Pharmacokinetics
- 12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
- 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
- 13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
- 14.1 Adult Patients
- 14.2 Pediatric Patients
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
- 17.1 Pancreatitis
- 17.2 Peripheral Neuropathy
- 17.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis
- 17.4 Hepatic Toxicity
- 17.5 Non-cirrhotic Portal Hypertension
- 17.6 Retinal Changes and Optic Neuritis
- 17.7 Fat Redistribution
- 17.8 Concomitant Therapy
- 17.9 General Information
Medication Guide
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL (2 g Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL Carton (2 g Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL (4 g Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL Carton (4 g Bottle)

FULL PRESCRIBING INFORMATION

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Didanosine should be suspended in patients with suspected pancreatitis and discontinued in patients with confirmed pancreatitis [see Warnings and Precautions (5.1)].

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

[see Clinical Studies (14)]

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage (Adult and Pediatric Patients)

[see Clinical Studies (14)]

Table 1: Recommended Dosage (Adult)
	at least 60 kg	less than 60 kg
Preferred dosing	200 mg twice daily	125 mg twice daily
Dosing for patients whose management requires once-daily frequency	400 mg once daily	250 mg once daily

Pediatric Patients (2 weeks old to 18 years old): ²²

2.2 Renal Impairment

Adult Patients

Table 2: Recommended Dosage in Patients with Renal Impairment
Creatinine Clearance (mL/min)	Recommended Didanosine for Oral Solution Dose by Patient Weight
Creatinine Clearance (mL/min)	at least 60 kg	less than 60 kg
^a 400 mg once daily (at least 60 kg) or 250 mg once daily (less than 60 kg) for patients whose management requires once-daily frequency of administration.
at least 60	200 mg twice daily^a	125 mg twice daily^a
30-59	200 mg once daily or 100 mg twice daily	150 mg once daily or 75 mg twice daily
10-29	150 mg once daily	100 mg once daily
less than 10	100 mg once daily	75 mg once daily

Pediatric Patients

Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis

2.3 Dosage Adjustment

Concomitant Therapy with Tenofovir Disoproxil Fumarate

[See Drug Interactions (7) and Clinical Pharmacology (12.3)]

Hepatic Impairment

[see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Allopurinol

[see Clinical Pharmacology (12.3)]

4.2 Ribavirin

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

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.[see Use in Specific Populations (8.1)]

5.3 Hepatic Toxicity

[See Adverse Reactions (6).]

5.4 Non-cirrhotic Portal Hypertension

5.5 Peripheral Neuropathy

[See Adverse Reactions (6).]

5.6 Retinal Changes and Optic Neuritis

[see Adverse Reactions (6)]

5.7 Immune Reconstitution Syndrome

Mycobacterium aviumPneumocystis jiroveci

5.8 Fat Redistribution

6 ADVERSE REACTIONS

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)]

6.1 Clinical Trials Experience

Adults

Table 3: Selected Clinical Adverse Reactions from Monotherapy Studies
Adverse Reactions	Percent of Patients*
	ACTG 116A		ACTG 116B/117
	didanosine n=197	zidovudine n=212	didanosine n=298	zidovudine n=304
* The incidences reported included all severity grades and all reactions regardless of causality.
Diarrhea Peripheral Neurologic Symptoms/Neuropathy Abdominal Pain Rash/Pruritus Pancreatitis	19 17 13 7 7	15 14 8 8 3	28 20 7 9 6	21 12 8 5 2

Table 4: Selected Clinical Adverse Reactions from Combination Studies
Adverse Reactions	Percent of Patients^a,c
	AI454-148^b		START 2^b
	didanosine + stavudine + nelfinavir n=482	zidovudine + lamivudine + nelfinavir n=248	didanosine + stavudine + indinavir n=102	zidovudine + lamivudine + indinavir n=103
^a Percentages based on treated subjects. ^b Median duration of treatment 48 weeks. ^c The incidences reported included all severity grades and all reactions regardless of causality. * This event was not observed in this study arm.
Diarrhea Nausea Peripheral Neurologic Symptoms/Neuropathy Headache Rash Vomiting Pancreatitis (see below)	70 28 26 21 13 12 1	60 40 6 30 16 14 *	45 53 21 46 30 30 less than 1	39 67 10 37 18 35 *

[see Warnings and Precautions (5)]

Table 5: Selected Laboratory Abnormalities from Monotherapy Studies
Parameter	Percent of Patients
	ACTG 116A		ACTG 116B/117
	didanosine n=197	zidovudine n=212	didanosine n=298	zidovudine n=304
ULN = upper limit of normal.
SGOT (AST) (greater than 5 x ULN) SGPT (ALT) (greater than 5 x ULN) Alkaline phosphatase (greater than 5 x ULN) Amylase (at least 1.4 x ULN) Uric acid (greater than 12 mg/dL)	9 9 4 17 3	4 6 1 12 1	7 6 1 15 2	6 6 1 5 1

Table 6: Selected Laboratory Abnormalities from Combination Studies (Grades 3 to 4)
Parameter	Percent of Patients^a
	AI454-148^b		START 2^b
	didanosine + stavudine + nelfinavir n=482	zidovudine + lamivudine + nelfinavir n=248	didanosine + stavudine + indinavir n=102	zidovudine + lamivudine + indinavir n=103
ULN = upper limit of normal. NC = Not Collected. ^a Percentages based on treated subjects. ^b Median duration of treatment 48 weeks.
Bilirubin (greater than 2.6 x ULN) SGOT (AST) (greater than 5 x ULN) SGPT (ALT) (greater than 5 x ULN) GGT (greater than 5 x ULN) Lipase (greater than 2 x ULN) Amylase (greater than 2 x ULN)	less than 1 3 3 NC 7 NC	less than 1 2 3 NC 2 NC	16 7 8 5 5 8	8 7 5 2 5 2

Table 7: Selected Laboratory Abnormalities from Combination Studies (All Grades)
Parameter	Percent of Patients^a
	AI454-148^b		START 2^b
	didanosine + stavudine + nelfinavir n=482	zidovudine + lamivudine + nelfinavir n=248	didanosine + stavudine + indinavir n=102	zidovudine + lamivudine + indinavir n=103
NC = Not Collected. ^a Percentages based on treated subjects. ^b Median duration of treatment 48 weeks.
Bilirubin SGOT (AST) SGPT (ALT) GGT Lipase Amylase	7 42 37 NC 17 NC	3 23 24 NC 11 NC	68 53 50 28 26 31	55 20 18 12 19 17

²²²[see Clinical Studies (14)]

6.2 Postmarketing Experience

Blood and Lymphatic System Disorders

Body as a Whole [see Warnings and Precautions (5.8)]

Digestive Disorders

Exocrine Gland Disorders [see Boxed Warning, Warnings and Precautions (5.1)]

Hepatobiliary Disorders [see Boxed Warning, Warnings and Precautions (5.2)][see Warnings and Precautions (5.4)]

Metabolic Disorders

Musculoskeletal Disorders

Ophthalmologic Disorders [see Warnings and Precautions (5.6)]

Use with Stavudine- and Hydroxyurea-Based Regimens

[see Warnings and Precautions (5)]

7 DRUG INTERACTIONS

7.1 Established Drug Interactions

[see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3)]

Table 8: Established Drug Interactions with Didanosine
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules.
ciprofloxacin	↓ ciprofloxacin concentration	Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine	↓ delavirdine concentration	Administer didanosine 1 hour after delavirdine.
ganciclovir	↓ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
indinavir	↓ indinavir concentration	Administer didanosine 1 hour after indinavir.
methadone	↓ didanosine concentration	Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir	↓ No interacion 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate	↓ didanosine concentration	A dose reduction of didanosine to the following dosage once daily is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Didanosine and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, didanosine should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.

[Table 8 and see Clinical Pharmacology (12.3, Table 12)][see Dosage and Administration (2.3) , Warnings and Precautions (5) ]

7.2 Predicted Drug Interactions

Table 9: Predicted Drug Interactions with Didanosine
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)]. ^b [See Warnings and Precautions (5.6).]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution^b
Antacids containing magnesium or aluminum	↑ side effects associated with antacid components	Use caution with Didanosine Pediatric Powder for Oral Solution
Azole antifungals	↓ ketoconazole or Itraconazole concentration	Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine.
Quinolone antibiotics (see also ciprofloxacin in Table 8)	↓ quinolone concentration	Consult package insert of the quinolone.
Tetracycline antibiotics	↓ antibiotic concentration	Consult package insert of the tetracycline.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

[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.

Antiretroviral Pregnancy Registry

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.mothers should be instructed not to breastfeed if they are receiving didanosine.

10 OVERDOSAGE

[see Clinical Pharmacology (12.3)]

11 DESCRIPTION

[see How Supplied/Storage and Handling (16)]

₁₀₁₂₄₃

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

[see Clinical Pharmacology (12.4)]

12.3 Pharmacokinetics

in vitroin vitro

Table 10: Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients
Parameter	Adult Patients^a	n	Pediatric Patients^b
Parameter	Adult Patients^a	n	8 months to 19 years	n	2 weeks to 4 months	n
CSF = cerebrospinal fluid, ND = not determined. ^a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m². ^bIn 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m² and half-life was 2 ± 0.7 h. ^c Following IV administration. ^d Following IV administration in adults and IV or oral administration in pediatric patients. ^eMean ± SE. ^f Following oral administration. ^g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate.
Oral bioavailability (%)	42 ± 12	6	25 ± 20	46	ND
Apparent volume of distribution^c (L/m²)	43.7 ± 8.9	6	28 ± 15	49	ND
CSF-plasma ratio^d	21 ± 0.03%^e	5	46% (range 12 to 85%)	7	ND
Systemic clearance^c (mL/min/m²)	526 ± 64.7	6	516 ± 184	49	ND
Renal clearance^f (mL/min/m²)	223 ± 85	6	240 ± 90	15	ND
Apparent oral clearance^g(mL/min/m²)	1252 ± 154	6	2064 ± 736	48	1353 ± 759	41
Elimination half-life^f (h)	1.5 ± 0.4	6	0.8 ± 0.3	60	1.2 ± 0.3	21
Urinary recovery of didanosine^f (%)	18 ± 8	6	18 ± 10	15	ND

Effect of Food

_max[see Dosage and Administration (2)]

Special Populations

Renal Insufficiency: [See Dosage and Administration (2.2).]

Table 11: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose
ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CL_R = renal clearance.
Parameter	Creatinine Clearance (mL/min)
Parameter	at least 90 n=12	60-90 n=6	30-59 n=6	10-29 n=3	Dialysis Patients n=11
CLcr (mL/min)	112 ± 22	68 ± 8	46 ± 8	13 ± 5	ND
CL/F (mL/min)	2164 ± 638	1566 ± 833	1023 ± 378	628 ± 104	543 ± 174
CL_R (mL/min)	458 ± 164	247 ± 153	100 ± 44	20 ± 8	less than 10
T½ (h)	1.42 ± 0.33	1.59 ± 0.13	1.75 ± 0.43	2 ± 0.3	4.1 ± 1.2

Hepatic Impairment: _max_max[See Dosage and Administration (2.3).]

Pediatric Patients:²²[see Clinical Studies (14.2) and Use in Specific Populations (8.4)]

[see Use in Specific Populations (8.5)]

Drug Interactions

_max[see Dosage and Administration (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4.1), and Drug Interactions (7.1 and 7.2)]

Table 12: Results of Drug Interaction Studies with Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and C_max Values
			% Change of Didanosine Pharmacokinetic Parameters^a
Drug	Didanosine Dosage	n	AUC of Didanosine (95% CI)	C_max of Didanosine (95% CI)
↑ Indicates increase. ↓ Indicates decrease. ↔ Indicates no change, or mean increase or decrease of less than 10%. ^aThe 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. ^bHIV-infected patients. ^c 90% CI. ^d Comparisons are made to a parallel control group not receiving methadone (n=10) ^eComparisons are made to historical controls (n=68, pooled from 3 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and C_max is 15 and 16, respectively. ^f For results of drug interaction studies between the enteric-coated formulation of didanosine (didanosine delayed-release capsules) and methadone, see the complete prescribing information for didanosine delayed-release capsules. ^gTenofovir disoproxil fumarate. ^h For results of drug interaction studies between the enteric-coated formulation of didanosine (didanosine delayed-release capsules) and tenofovir disoproxil fumarate, see the complete prescribing information for didanosine delayed-release capsules. ⁱ Patients less than 60 kg with creatinine clearance of at least 60 mL/min. NA = Not available.
allopurinol,
renally impaired, 300 mg/day	200 mg single dose	2	↑ 312%	↑ 232%
healthy volunteer, 300 mg/day for 7 days	400 mg single dose	14	↑ 113%	↑ 69%
ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine	200 mg every 12 hours for 3 days	8^b	↓ 16%	↓ 28%
ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine indinavir, 800 mg single dose,	200 mg every 12 hours	12	↑ 111%	NA
simultaneous	200 mg single dose	16	↔	↔
1 hour before didanosine	200 mg single dose	16	↓ 17% (-27, -7%)^c	↓ 13% (-28, 5%)^c
ketoconazole, 200 mg/day for 4 days, 2 hours before didanosine	375 mg every 12 hours for 4 days	12^b	↔	↓ 12%
methadone, chronic maintenance dose^f	200 mg single dose	16^d	↓ 57%	↓ 66%
methadone, chronic maintenance dose^f	400 mg single dose	15, 16^e	↓ 29% (-40, -16%)^c	↓ 41% (-54, -26%)^c
tenofovir,^g,h 300 mg once daily, 1 hour after didanosine	250ⁱ mg or 400 mg once daily for 7 days	14	↑ 44% (31, 59%)^c	↑ 28% (11, 48%)^c
loperamide, 4 mg every 6 hours for 1 day	300 mg single dose	12^b	↔	↓ 23%
metoclopramide, 10 mg single dose	300 mg single dose	12^b	↔	↑ 13%
ranitidine, 150 mg single dose, 2 hours before didanosine	375 mg single dose	12^b	↑ 14%	↑ 13%
rifabutin, 300 or 600 mg/day for 12 days	167 mg or 250 mg every 12 hours for 12 days	11	↑ 13% (-1, 27%)	↑ 17% (-4, 38%)
ritonavir, 600 mg every 12 hours for 4 days	200 mg every 12 hours for 4 days	12	↓ 13% (0, 23%)	↓ 16% (5, 26%)
stavudine, 40 mg every 12 hours for 4 days	100 mg every 12 hours for 4 days	10	↔	↔
sulfamethoxazole, 1000 mg single dose	200 mg single dose	8^b	↔	↔
trimethoprim, 200 mg single dose	200 mg single dose	8^b	↔	↑ 17% (-23, 77%)
zidovudine, 200 mg every 8 hours for 3 days	200 mg every 12 hours for 3 days	6^b	↔	↔

Table 13: Results of Drug Interaction Studies with Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and C_max Values
			% Change of Coadministered Drug Pharmacokinetic Parameters^a
Drug	Didanosine Dosage	n	AUC of Coadministered Drug (95% CI)	C_max of Coadministered Drug (95% CI)
↑ Indicates increase. ↓ Indicates decrease. ↔ Indicates no change, or mean increase or decrease of less than 10%. ^a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. ^b HIV-infected patients. ^c Tenofovir disoproxil fumarate. ^d Patients less than 60 kg with creatinine clearance of at least 60 mL/min. NA = Not available.
ciprofloxacin
750 mg every 12 hours for 3 days, 2 hours before didanosine	200 mg every 12 hours for 3 days	8^b	↓ 26%	↓ 16%
750 mg single dose	buffered placebo tablet	12	↓ 98%	↓ 93%
delavirdine, 400 mg single dose simultaneous	125 mg or 200 mg every 12 hours	12^b	↓ 32%	↓ 53%
1 hour before didanosine	125 mg or 200 mg every 12 hours	12^b	↑ 20%	↑ 18%
ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine	200 mg every 12 hours	12^b	↓ 21%	NA
indinavir, 800 mg single dose simultaneous	200 mg single dose	16	↓ 84%	↓ 82%
1 hour before didanosine	200 mg single dose	16	↓ 11%	↓ 4%
ketoconazole, 200 mg/day for 4 days, 2 hours before didanosine	375 mg every 12 hours for 4 days	12^b	↓ 14%	↓ 20%
nelfinavir, 750 mg single dose, 1 hour after didanosine	200 mg single dose	10^b	↑ 12%	↔
dapsone, 100 mg single dose	200 mg every 12 hours for 14 days	6^b	↔	↔
ranitidine, 150 mg single dose, 2 hours before didanosine	375 mg single dose	12^b	↓ 16%	↔
ritonavir, 600 mg every 12 hours for 4 days	200 mg every 12 hours for 4 days	12	↔	↔
stavudine, 40 mg every 12 hours for 4 days	100 mg every 12 hours for 4 days	10^b	↔	↑ 17%
sulfamethoxazole, 1000 mg single dose	200 mg single dose	8^b	↓ 11% (-17, -4%)	↓ 12% (-28, 8%)
tenofovir,^c 300 mg once daily 1 hour after didanosine	250^d mg or 400 mg once daily for 7 days	14	↔	↔
trimethoprim, 200 mg single dose	200 mg single dose	8^b	↑ 10% (-9, 34%)	↓ 22% (-59, 49%)
zidovudine, 200 mg every 8 hours for 3 days	200 mg every 12 hours for 3 days	6^b	↓ 10% (-27, 11%)	↓ 16.5% (-53, 47%)

12.4 Microbiology

Mechanism of Action

Antiviral Activity in Cell Culture

₅₀

Resistance

Cross-resistance

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Escherichia coliin vitroin vitroin vitroSalmonellain vivo

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Adult Patients

Combination Therapy

³³₁₀₁₀³

Table 14: Outcomes of Randomized Treatment Through Week 48, AI454-148
Week 48 Status	Percent of Patients with HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL)
Week 48 Status	didanosine/stavudine/nelfinavir n=503	lamivudine/zidovudine/ nelfinavir n=253
* p less than 0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. ^a Patients achieved virologic response [two consecutive viral loads less than 400 (less than 50) copies/mL] and maintained it to Week 48. ^b Includes viral rebound and failing to achieve confirmed less than 400 (less than 50) copies/mL by Week 48. ^c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy.
Responder^a	50* (34*)	59 (47)
Virologic failure^b	36 (57)	32 (48)
Death or disease progression	less than 1 (less than 1)	1 (less than 1)
Discontinued due to adverse events	4 (2)	2 (less than 1)
Discontinued due to other reasons^c	6 (3)	4 (2)
Never initiated treatment	4 (4)	2 (2)

Monotherapy

14.2 Pediatric Patients

²²²²

16 HOW SUPPLIED/STORAGE AND HANDLING

Didanosine for Oral Solution, USP

20 mg/mL Initial Solution

10 mg/mL Final Admixture

Immediately mix one part of the 20 mg/mL initial solution with one part of Maximum Strength Mylanta^® Liquid for a final dispensing concentration of 10 mg didanosine per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures.
Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator.

Storage

Store

^®

17 PATIENT COUNSELING INFORMATION

See Medication Guide.

17.1 Pancreatitis

17.2 Peripheral Neuropathy

17.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

17.4 Hepatic Toxicity

17.5 Non-cirrhotic Portal Hypertension

17.6 Retinal Changes and Optic Neuritis

17.7 Fat Redistribution

17.8 Concomitant Therapy

17.9 General Information

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 or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not breastfeed. 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 breastfeed because HIV-1 can be passed to the baby in breast milk.

Aurobindo Pharma USA, Inc.

Aurobindo Pharma Limited

Medication Guide

Didanosine for Oral Solution, USP

What is the most important information I should know about didanosine for oral solution?

Didanosine for oral solution 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 for oral solution.

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

Build-up of acid in your blood (lactic acidosis). Lactic acidosis must be treated in the hospital as it may cause death.

have liver problems
are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking didanosine for oral solution and ZERIT (stavudine).
are overweight
have been treated for a long time with other medicines to treat HIV

It is important to call your health care 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

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 for oral solution?

Who should not take didanosine for oral solution?

Do not take didanosine for oral solution if you take:

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

What should I tell my healthcare provider before taking didanosine for oral solution?

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 for oral solution will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking didanosine for oral solution. You and your healthcare provider will decide if you should take didanosine for oral solution 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 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,

Especially tell your healthcare provider if you take:

VIREAD^® (tenofovir disoproxil fumarate)
DROXIA^®, HYDREA^® (hydroxyurea)
RESCRIPTOR^® (delavirdine mesylate)
CYTOVENE^®, VALCYTE^® (ganciclovir)
CRIXIVAN^® (indinavir)
DOLOPHINE^® HYDROCHLORIDE, METHADOSE^® (methadone)
VIRACEPT^® (nelfinavir)
antacids
antifungal medicines such as NIZORAL^® (ketoconazole) or SPORANOX^® (itraconazole)
quinolone antibiotics such as CIPRO^®, PROQUIN^® XR (ciprofloxacin)
tetracycline antibiotics such as BRISTACYCLINE^®, SUMYCIN^® (tetracycline)
alcoholic beverages

How should I take didanosine for oral solution?

Take didanosine for oral solution exactly as your healthcare provider tells you to take it.
Your healthcare provider will tell you how much didanosine for oral solution to take and when to take it.
Your healthcare provider may change your dose. Do not change your dose of didanosine for oral solution without talking to your healthcare provider.
Do not take didanosine for oral solution with food. Take didanosine for oral solution on an empty stomach at least 30 minutes before or 2 hours after you eat.
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 didanosine for oral solution. 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 for oral solution. Your healthcare provider may also lower your dosage of didanosine for oral solution if your kidneys are not working well.
If you take too much didanosine for oral solution, contact a poison control center or emergency room right away.

What should I avoid while taking didanosine for oral solution?

Alcohol. Do not drink alcohol while you take didanosine for oral solution. 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 for oral solution?

“What is the most important information I should know about didanosine for oral solution?”

Vision changes. You should have regular eye exams while you take didanosine for oral solution.
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 your 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

less fat in your

diarrhea
stomach pain
nausea
vomiting
headache
rash

How should I store didanosine for oral solution?

Safely throw away any unused didanosine for oral solution after 30 days.

Keep didanosine for oral solution and all medicines out of the reach of children and pets.

General information about the safe and effective use of didanosine for oral solution

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 or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.

What are the ingredients in didanosine for oral solution?

Active Ingredient:

Inactive Ingredients:

Pediatric Oral Solution: ^®

Aurobindo Pharma USA, Inc.

Aurobindo Pharma Limited

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL (2 g Bottle)

NDC 65862-109-02
Didanosine for Oral Solution, USP
2 g
PHARMACIST: Dispense the Medication
Guide provided separately to each patient.
Rx only
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL Carton (2 g Bottle)

NDC 65862-109-02
Didanosine for Oral Solution, USP
2 g
PHARMACIST: Dispense the Medication Guide
provided separately to each patient.
Rx only
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL (4 g Bottle)

NDC 65862-110-04
Didanosine for Oral Solution, USP
4 g
PHARMACIST: Dispense the Medication
Guide provided separately to each patient.
Rx only
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL Carton (4 g Bottle)

NDC 65862-110-04
Didanosine for Oral Solution, USP
4 g
PHARMACIST: Dispense the Medication Guide
provided separately to each patient.
Rx only
AUROBINDO

Didanosine

Didanosine POWDER, FOR SOLUTION

Product Information
Product Type	Human prescription drug label	Item Code (Source)	NDC:65862-109
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
DIDANOSINE didanosine		10 mg

Product Characteristics
Color
WHITE (White to almost white)

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1		200 in 1 BOTTLE
2	NDC:65862-109-02	1 in 1 CARTON

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078112	2007-03-08

Didanosine

Didanosine POWDER, FOR SOLUTION

Product Information
Product Type	Human prescription drug label	Item Code (Source)	NDC:65862-110
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
DIDANOSINE didanosine		10 mg

Product Characteristics
Color
WHITE (White to almost white)

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1		400 in 1 BOTTLE
2	NDC:65862-110-04	1 in 1 CARTON

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078112	2007-03-08

PLEASE, BE CAREFUL!

Be sure to consult your doctor before taking any medication!

Didanosine description, usages, side effects, indications, overdosage, supplying and lots more!

Didanosine

FULL PRESCRIBING INFORMATION: CONTENTS*

FULL PRESCRIBING INFORMATION

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage (Adult and Pediatric Patients)

2.2 Renal Impairment

2.3 Dosage Adjustment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Allopurinol

4.2 Ribavirin

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

5.2 Lactic Acidosis/Severe Hepatomegaly with Steatosis

5.3 Hepatic Toxicity

5.4 Non-cirrhotic Portal Hypertension

5.5 Peripheral Neuropathy

5.6 Retinal Changes and Optic Neuritis

5.7 Immune Reconstitution Syndrome

5.8 Fat Redistribution

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Established Drug Interactions

7.2 Predicted Drug Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Adult Patients

14.2 Pediatric Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Pancreatitis

17.2 Peripheral Neuropathy

17.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

17.4 Hepatic Toxicity

17.5 Non-cirrhotic Portal Hypertension

17.6 Retinal Changes and Optic Neuritis

17.7 Fat Redistribution

17.8 Concomitant Therapy

17.9 General Information

Medication Guide

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL (2 g Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL Carton (2 g Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL (4 g Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 10 mg/mL Carton (4 g Bottle)

Didanosine

Product Information

Active Ingredient/Active Moiety

Product Characteristics

Packaging

Marketing Information

Didanosine

Product Information

Active Ingredient/Active Moiety

Product Characteristics

Packaging

Marketing Information