Didanosine Tablet, for suspension

Name: Didanosine Tablet, for suspension

Dosage Forms and Strengths


Didanosine Tablets for Oral Suspension, 100 mg are white to off-white, slightly mottled, round, flat faced beveled edge tablets with debossing “D” on one side and “45” on other side. The tablets are packaged in bottles with child-resistant closures.
 
Didanosine Tablets for Oral Suspension, 150 mg are white to off-white, slightly mottled, round, flat faced beveled edge tablets with debossing “D” on one side and “46” on other side. The tablets are packaged in bottles with child-resistant closures.
 
Didanosine Tablets for Oral Suspension, 200 mg are white to off-white, slightly mottled, round, flat faced beveled edge tablets with debossing “D” on one side and “47” on other side. The tablets are packaged in bottles with child-resistant closures.

Adverse Reactions


The following adverse reactions are discussed in greater detail in other sections: 
  • Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)]
  • Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.2)]
  • Hepatic toxicity [see Warnings and Precautions (5.3)]
  • Non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]
  • Peripheral neuropathy [see Warnings and Precautions (5.5)]
  • Retinal changes and optic neuritis [see Warnings and Precautions (5.6)]

Clinical Trials Experience


Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults
 
Selected clinical adverse reactions that occurred in adult patients in clinical studies with didanosine are provided in Tables 4 and 5. Table 4: Selected Clinical Adverse Reactions from Monotherapy Studies
Adverse Reactions Percent of Patients*
ACTG 116A ACTG 116B/117
didanosine
n=197
zidovudine
n=212
didanosine
n=298
zidovudine
n=304
* The incidences reported included all severity grades and all reactions regardless of causality.
   Diarrhea
19
15
28
21
   Peripheral Neurologic Symptoms/Neuropathy
17
14
20
12
   Abdominal Pain
13
8
7
8
   Rash/Pruritus
7
8
9
5
   Pancreatitis
7
3
6
2

Table 5: Selected Clinical Adverse Reactions from Combination Studies
Percent of Patientsa,c
AI454-148b START 2b
didanosine + stavudine + nelfinavir
n=482
zidovudine + lamivudine + nelfinavir
n=248
didanosine + stavudine + indinavir
n=102
zidovudine + lamivudine + indinavir
n=103
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
c The incidences reported included all severity grades and all reactions regardless of causality.
* This event was not observed in this study arm.
   Diarrhea
70
60
45
39
   Nausea
28
40
53
67
   Peripheral Neurologic Symptoms/Neuropathy
26
6
21
10
   Headache
21
30
46
37
   Rash
13
16
30
18
   Vomiting
12
14
30
35
   Pancreatitis (see below)
1
*
less than 1
*

Pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir in Study AI454-148 and in one patient who received didanosine plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial [see Warnings and Precautions (5)].
 
The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose.
 
Selected laboratory abnormalities in clinical studies with didanosine are shown in Tables 6 to 8.

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

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

Table 8: Selected Laboratory Abnormalities from Combination Studies (All Grades)
Parameter Percent of Patientsa
AI454-148b START 2b
didanosine + stavudine + nelfinavir
n=482
zidovudine + lamivudine + nelfinavir
n=248
didanosine + stavudine + indinavir
n=102
zidovudine + lamivudine + indinavir
n=103
NC = Not Collected.
a Percentages based on treated subjects.
b Median duration of treatment 48 weeks.
   Bilirubin
7
3
68
55
   SGOT (AST)
42
23
53
20
   SGPT (ALT)
37
24
50
18
   GGT
NC
NC
28
12
   Lipase
17
11
26
19
   Amylase
NC
NC
31
17

Pediatric Patients
 
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults.
 
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/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 didanosine 120 mg/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m2 every 12 hours in combination with zidovudine [see Clinical Studies (14)].
 
Retinal changes and optic neuritis have been reported in pediatric patients.

Postmarketing Experience


The following adverse reactions have been identified during postapproval use of didanosine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors.

Blood and Lymphatic System Disorders – anemia, leukopenia, and thrombocytopenia. 

Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat [see Warnings and Precautions (5.8)]. 

Digestive Disorders – anorexia, dyspepsia, and flatulence.

Exocrine Gland Disorders – pancreatitis (including fatal cases) [see Boxed Warning, Warnings and Precautions (5.1)], sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. 

Hepatobiliary Disorders – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Boxed Warning, Warnings and Precautions (5.2)]; non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]; hepatitis and liver failure. 

Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia. 

Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.

Ophthalmologic Disorders – retinal depigmentation and optic neuritis [see Warnings and Precautions (5.6)].

Use with Stavudine- and Hydroxyurea-Based Regimens
 
When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with didanosine in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5)]. The combination of didanosine and hydroxyurea, with or without stavudine, should be avoided.

Drug Interactions

Established Drug Interactions


Clinical recommendations based on the results of drug interaction studies are listed in Table 9. Pharmacokinetic results of drug interaction studies are shown in Tables 13 and 14 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3)]. Table 9: 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.


Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate [Table 9 and see Clinical Pharmacology (12.3, Table 13)]. 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 didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. 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 didanosine at a dose of 400 mg daily.

Predicted Drug Interactions


Predicted drug interactions with didanosine are listed in Table 10.

Table 10: 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 cautiona
   Neurotoxic drugs
↑ risk of neuropathy
   Use with cautionb
   Antacids containing magnesium or aluminum
↑ side effects associated
with antacid components
   Use caution with didanosine tablets for oral suspension and 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 9)
↓ quinolone concentration
   Consult package insert of the quinolone.
   Tetracycline antibiotics
↓ antibiotic concentration
   Consult package insert of the tetracycline.

How Supplied/Storage and Handling


Didanosine Tablets for Oral Suspension USP, 100 mg are white to off-white, slightly mottled, round, flat faced beveled edge tablets with debossing “D” on one side and “45” on other side. The tablets are packaged in bottles with child-resistant closures.
 
               Bottles of 60                 NDC 65862-092-60

Didanosine Tablets for Oral Suspension USP, 150 mg are white to off-white, slightly mottled, round, flat faced beveled edge tablets with debossing “D” on one side and “46” on other side. The tablets are packaged in bottles with child-resistant closures.
 
               Bottles of 60                 NDC 65862-093-60

Didanosine Tablets for Oral Suspension USP, 200 mg are white to off-white, slightly mottled, round, flat faced beveled edge tablets with debossing “D” on one side and “47” on other side. The tablets are packaged in bottles with child-resistant closures.
 
               Bottles of 60                 NDC 65862-094-60

Storage
 
Store in tightly closed bottles at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. If dispersed in water, the dose may be held for up to 1 hour at ambient temperature.

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 100 mg (60 Tablet Bottle)


NDC 65862-092-60
Didanosine Tablets for
Oral Suspension, USP
[Formerly: Didanosine Tablets
(Chewable, Dispersible, Buffered)]
100 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
Rx only                                            60 Tablets
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 200 mg (60 Tablet Bottle)


NDC 65862-094-60
Didanosine Tablets for
Oral Suspension, USP
[Formerly: Didanosine Tablets
(Chewable, Dispersible, Buffered)]
200 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
Rx only                                            60 Tablets
AUROBINDO 
DIDANOSINE 
Didanosine Tablet, for suspension
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:65862-092
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DIDANOSINE (DIDANOSINE) DIDANOSINE 100 mg
Inactive Ingredients
Ingredient Name Strength
CALCIUM CARBONATE  
MAGNESIUM HYDROXIDE  
ASPARTAME  
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
ORANGE  
SORBITOL  
Product Characteristics
Color WHITE (White to Off-white) Score no score
Shape ROUND (Flat Faced Beveled Edge) Size 20mm
Flavor ORANGE Imprint Code D;45
Contains     
Packaging
# Item Code Package Description
1 NDC:65862-092-60 60 TABLET, FOR SUSPENSION in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077275 08/14/2012
DIDANOSINE 
Didanosine Tablet, for suspension
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:65862-093
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DIDANOSINE (DIDANOSINE) DIDANOSINE 150 mg
Inactive Ingredients
Ingredient Name Strength
CALCIUM CARBONATE  
MAGNESIUM HYDROXIDE  
ASPARTAME  
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
ORANGE  
SORBITOL  
Product Characteristics
Color WHITE (White to Off-white) Score no score
Shape ROUND (Flat Faced Beveled Edge) Size 20mm
Flavor ORANGE Imprint Code D;46
Contains     
Packaging
# Item Code Package Description
1 NDC:65862-093-60 60 TABLET, FOR SUSPENSION in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077275 08/14/2012
DIDANOSINE 
Didanosine Tablet, for suspension
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:65862-094
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DIDANOSINE (DIDANOSINE) DIDANOSINE 200 mg
Inactive Ingredients
Ingredient Name Strength
CALCIUM CARBONATE  
MAGNESIUM HYDROXIDE  
ASPARTAME  
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
ORANGE  
SORBITOL  
Product Characteristics
Color WHITE (White to Off-white) Score no score
Shape ROUND (Flat Faced Beveled Edge) Size 20mm
Flavor ORANGE Imprint Code D;47
Contains     
Packaging
# Item Code Package Description
1 NDC:65862-094-60 60 TABLET, FOR SUSPENSION in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077275 08/14/2012
Labeler - Aurobindo Pharma Limited (650082092)
Establishment
Name Address ID/FEI Operations
Aurobindo Pharma Limited 918917642 ANALYSIS(65862-092, 65862-093, 65862-094), MANUFACTURE(65862-092, 65862-093, 65862-094)
Establishment
Name Address ID/FEI Operations
Aurobindo Pharma Limited 918917662 API MANUFACTURE(65862-092, 65862-093, 65862-094)
Revised: 08/2012   Aurobindo Pharma Limited
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