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Dinex

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Dinex uses


WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

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

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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) ].

Dinex (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

Dinex should be administered on an empty stomach. Dinex Delayed-Release Capsules should be swallowed intact.


Body Weight


Dose


20 kg to less than 25 kg

200 mg once daily

25 kg to less than 60 kg

250 mg once daily

at least 60 kg

400 mg once daily

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 Dinex to pediatric patients weighing less than 20 kg or who can not swallow capsules.


Body Weight


Dose


20 kg to less than 25 kg

200 mg once daily

25 kg to less than 60 kg

250 mg once daily

at least 60 kg

400 mg once daily

2.2 Renal Impairment

Dosing recommendations for Dinex and VIDEX Pediatric Powder for Oral Solution are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX Pediatric Powder for Oral Solution to patients with renal impairment.

Adult Patients

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

Creatinine Clearance

(mL/min)

Dosage (mg)
at least 60 kg less than 60 kg
a Based on studies using a buffered formulation of Dinex.

b Not suitable for use in patients less than 60 kg with CLcr less than 10 mL/min. An alternate formulation of Dinex should be used.

at least 60

400 once daily

250 once daily

30-59

200 once daily

125 once daily

10-29

125 once daily

125 once daily

less than 10

125 once daily

b

Pediatric Patients

Urinary excretion is also a major route of elimination of Dinex in pediatric patients, therefore the clearance of Dinex may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of Dinex 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 Dinex 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 Dinex to 250 mg 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 Dinex 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) ].

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3 DOSAGE FORMS AND STRENGTHS

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


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

4.2 Ribavirin

Coadministration of Dinex and ribavirin is contraindicated because exposures of the active metabolite of Dinex (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 Dinex and ribavirin.

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5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

Fatal and nonfatal pancreatitis has occurred during therapy with Dinex used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Dinex should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with Dinex 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 Dinex (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, Dinex 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 Dinex 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 Dinex and stavudine with other antiretroviral agents. The combination of Dinex 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 ]. Particular caution should be exercised when administering Dinex 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 Dinex 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 Dinex 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, Dinex, 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 Dinex therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.

Patients receiving Dinex should be monitored for early signs of portal hypertension 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. Dinex 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 Dinex 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 Dinex 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 Dinex. Periodic retinal examinations should be considered for patients receiving Dinex [see Adverse Reactions ].

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Dinex. 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.

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6 ADVERSE REACTIONS

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


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 Dinex 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.

Adverse Reactions Percent of Patientsb,c
Dinex + stavudine

+ nelfinavir

n=258

zidovudine/lamivudined

+ nelfinavir

n=253

a Median duration of treatment was 62 weeks in the Dinex + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.

b Percentages based on treated patients.

c The incidences reported included all severity grades and all reactions regardless of causality.

d Zidovudine/lamivudine combination tablet.

* This event was not observed in this study arm.

Diarrhea

57

58

Peripheral Neurologic Symptoms/Neuropathy

25

11

Nausea

24

36

Headache

22

17

Rash

14

12

Vomiting

14

19

Pancreatitis


less than 1

*

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

Percent of Patientsb
Dinex + stavudine

+ nelfinavir

n=258

zidovudine/lamivudinec

+ nelfinavir

n=253

Parameter Grades 3-4d All Grades Grades 3-4d All Grades
a Median duration of treatment was 62 weeks in the Dinex + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.

b Percentages based on treated patients.

c Zidovudine/lamivudine combination tablet.

d Greater than 5 × ULN for SGOT and SGPT, at least 2.1 × ULN for lipase, and at least 2.6 × ULN for bilirubin (ULN = upper limit of normal).

SGOT (AST)

5

46

5

19

SGPT (ALT)

6

44

5

22

Lipase

5

23

2

13

Bilirubin

less than 1

9

less than 1

3

Pediatric Patients

In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with Dinex. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of Dinex 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 Dinex 120 mg/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received Dinex 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 Dinex. 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 Dinex, or a combination of these factors.

Use with Stavudine- and Hydroxyurea-Based Regimens

When Dinex is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Dinex is used alone. Thus, patients treated with Dinex 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 Dinex and hydroxyurea, with or without stavudine, should be avoided.

7 DRUG INTERACTIONS

Coadministration of Dinex can alter the concentration of other drugs and other drugs may alter the concentration of Dinex. The potential drug-drug interactions must be considered prior to and during therapy.

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) ].

Drug Effect Clinical Comment
↑ Indicates increase.

↓ Indicates decrease.

a Coadministration of Dinex with food decreases Dinex concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce Dinex concentrations further.

ganciclovir

↑ Dinex concentration

If there is no suitable alternative to ganciclovir, then use in combination with Dinex with caution. Monitor for didanosine-associated toxicity.

methadone

↓ Dinex concentration

If coadministration of methadone and Dinex is necessary, the recommended formulation of Dinex is Dinex. Patients should be closely monitored for adequate clinical response when Dinex is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in Dinex concentrations.


nelfinavir

No interaction 1 hour after Dinex

Administer nelfinavir 1 hour after Dinex.

tenofovir disoproxil fumarate

↑ Dinex concentration

A dose reduction of Dinex to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state 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)

Patients should be monitored for didanosine-associated toxicities and clinical response.

Exposure to Dinex 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 Dinex should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. Dinex 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 Dinex at a dose of 400 mg daily.

7.2 Predicted Drug Interactions

Predicted drug interactions with Dinex are listed in Table 6.

Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.

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 Dinex 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

8 USE IN SPECIFIC POPULATIONS

Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both Dinex 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. 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 Dinex. At approximately 12 times the estimated human exposure, Dinex 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 Dinex 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 Dinex in pregnant women. Dinex 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 Dinex 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 Dinex 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 Dinex 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 Dinex 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, Dinex and/or its metabolites were excreted into the milk of lactating rats. It is not known if Dinex 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 Dinex.

8.4 Pediatric Use

Use of Dinex in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of Dinex in adult and pediatric patients [see Dosage and Administration, Adverse Reactions (6.1), Clinical Pharmacology (12.3) , and Clinical Studies (14) ]. Additional pharmacokinetic studies in pediatric patients support use of Dinex in pediatric patients who weigh at least 20 kg.

8.5 Geriatric Use

In an Expanded Access Program using a buffered formulation of Dinex 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 Dinex, including those for Dinex, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Dinex 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 Dinex 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 Dinex overdosage. In phase 1 studies, in which buffered formulations of Dinex were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Dinex 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 Dinex, USP, a synthetic purine nucleoside analogue active against HIV-1. Dinex Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of Dinex. 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.

Dinex 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 Dinex is 2′,3′-dideoxyinosine. The structural formula is:

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

didanosine-structure.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dinex is an antiviral agent [see Clinical Pharmacology ].

12.3 Pharmacokinetics

The pharmacokinetic parameters of Dinex in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Dinex 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 Dinex 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 Dinex 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 Dinex 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 Dinex in man occurs by the same pathways responsible for the elimination of endogenous purines.

a The pharmacokinetic parameters (mean ± standard deviation) of Dinex were determined by a population pharmacokinetic model based on combined clinical studies.

Parametera


Pediatrics


Adults


20 kg to less than 25 kg

n=10


25 kg to less than 60 kg

n=17


At least 60 kg

n=7


At least 60 kg

n=44


Apparent clearance (L/h)

89.5 ± 21.6

116.2 ± 38.6

196.0 ± 55.8

174.5 ± 69.7

Apparent volume of distribution (L)

98.1 ± 30.2

154.7 ± 55.0

363 ± 137.7

308.3 ± 164.3

Elimination half-life (h)

0.75 ± 0.13

0.92 ± 0.09

1.26 ± 0.19

1.19 ± 0.21

Steady-state AUC (mg-h/L)

2.38 ± 0.66

2.36 ± 0.70

2.25 ± 0.89

2.65 ± 1.07

Comparison of Dinex Formulations

In Dinex, the active ingredient, Dinex, 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 Dinex, 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 Dinex administered as the Dinex formulation relative to a buffered tablet formulation. The peak plasma concentration of Dinex, administered as Dinex, is reduced approximately 40% relative to Dinex buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for Dinex buffered tablets to 2.0 hours for Dinex.

Effect of Food

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

Special Populations

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

Parameter Creatinine Clearance (mL/min) Dialysis Patients

n=11

at least 90

n=12

60-90

n=6

30-59

n=6

10-29

n=3

ND = not determined due to anuria.

CLcr = creatinine clearance.

CL/F = apparent oral clearance.

CLR = renal clearance.

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

CLR (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 ± 0.3

4.1 ± 1.2

Hepatic Impairment: The pharmacokinetics of Dinex 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 Cmax values following a single 400 mg dose of Dinex 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 Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [See Dosage and Administration (2.3) .]

Pediatric Patients: The pharmacokinetics of Dinex have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.

A population pharmacokinetic analysis was conducted on pooled Dinex 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. Dinex 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: Dinex 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 Dinex pharmacokinetics have not been studied.

Drug Interactions

Tables 9 and 10 summarize the effects on AUC and Cmax, with a 90% confidence interval (CI) when available, following coadministration of Dinex 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) .

% Change of Dinex

Pharmacokinetic Parametersa

Drug Dinex Dosage n AUC of

Dinex

(90% CI)

Cmax of

Dinex

(90% CI)

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no change, or mean increase or decrease of less than 10%.

a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.

c Tenofovir disoproxil fumarate.

d 373 kcalories, 8.2 grams fat.

e Compared with Dinex 250 mg administered alone under fasting conditions.

f Compared with Dinex 400 mg administered alone under fasting conditions.

g Comparisons are made to historical controls (n=148, pooled from 5 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.

tenofovir,b,c 300 mg

once daily with a light meald


400 mg single dose fasting

2 hours before tenofovir

26

↑ 48%

(31, 67%)

↑ 48%

(25, 76%)

tenofovir,b,c 300 mg

once daily with a light meald


400 mg single dose

with tenofovir and a light meal

25

↑ 60%

(44, 79%)

↑ 64%

(41, 89%)

tenofovir,b,c 300 mg

once daily with a light meald


200 mg single dose

with tenofovir and a light meal

33

↑ 16%

(6, 27%)e


↓ 12%

(-25, 3%)e




250 mg single dose

with tenofovir and a light meal

33

↔

(-13, 5%)f


↓ 20%

(-32, -7%)f




325 mg single dose

with tenofovir and a light meal

33

↑ 13%

(3, 24%)f


↓ 11%

(-24, 4%)f


methadone, chronic maintenance dose


400 mg single dose

15, 16g


↓ 17%

(-29, -2%)

↓ 16%

(-33, 4%)
% Change of Coadministered Drug

Pharmacokinetic Parametersa,b

Drug Dinex Dosage n AUC of Coadministered Drug

(90% CI)

Cmax of Coadministered Drug

(90% CI)

↔ Indicates no change, or mean increase or decrease of less than 10%.

a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.

c Tenofovir disoproxil fumarate.

d 373 kcalories, 8.2 grams fat.

ciprofloxacin, 750 mg

single dose

400 mg single dose

16

↔

↔

indinavir, 800 mg

single dose

400 mg single dose

23

↔

↔

ketoconazole, 200 mg

single dose

400 mg single dose

21

↔

↔

tenofovir,c 300 mg

once daily with a light meald


400 mg single dose

fasting 2 hours before tenofovir

25

↔

↔

tenofovir,c 300 mg

once daily with a light meald


400 mg single dose

with tenofovir and a light meal

25

↔

↔

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

% Change of Dinex

Pharmacokinetic Parametersa

Drug Dinex Dosage n AUC of Dinex

(95% CI)

Cmax of Dinex

(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 90% CI.

c HIV-infected patients.

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%

ganciclovir, 1000 mg every 8 hours,

2 hours after Dinex

200 mg every 12 hours

12

↑ 111%

NA

ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before Dinex

200 mg every 12 hours

for 3 days

8c


↓ 16%

↓ 28%

indinavir, 800 mg single dose









simultaneous

200 mg single dose

16

↔

↔

1 hour before Dinex

200 mg single dose

16

↓ 17%

(-27, -7%)b


↓ 13%

(-28, 5%)b


ketoconazole, 200 mg/day for 4 days,

2 hours before Dinex

375 mg every 12 hours

for 4 days

12c


↔

↓ 12%

loperamide, 4 mg every 6 hours for 1 day

300 mg single dose

12c


↔

↓ 23%

metoclopramide, 10 mg single dose

300 mg single dose

12c


↔

↑ 13%

ranitidine, 150 mg single dose,

2 hours before Dinex

375 mg single dose

12c


↑ 14%

↑ 13%

rifabutin, 300 mg 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

8c


↔

↔

trimethoprim, 200 mg single dose

200 mg single dose

8c


↔

↑ 17%

(-23, 77%)

zidovudine, 200 mg every 8 hours for 3 days

200 mg every 12 hours

for 3 days

6c


↔

↔
% Change of Coadministered Drug

Pharmacokinetic Parametersa

Drug Dinex Dosage n AUC of Coadministered Drug

(95% CI)

Cmax 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.

NA = Not available.

dapsone, 100 mg single dose

200 mg every 12 hours for 14 days

6b


↔

↔

ganciclovir, 1000 mg every 8 hours,

2 hours after Dinex

200 mg every 12 hours

12b


↓ 21%

NA

nelfinavir, 750 mg single dose,

1 hour after Dinex

200 mg single dose

10b


↑ 12%

↔

ranitidine, 150 mg single dose,

2 hours before Dinex

375 mg single dose

12b


↓ 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

10b


↔

↑ 17%

sulfamethoxazole, 1000 mg single dose

200 mg single dose

8b


↓ 11%

(-17, -4%)

↓ 12%

(-28, 8%)

trimethoprim, 200 mg single dose

200 mg single dose

8b


↑ 10%

(-9, 34%)

↓ 22%

(-59, 49%)

zidovudine, 200 mg every 8 hours for 3 days

200 mg every 12 hours

for 3 days

6b


↓ 10%

(-27, 11%)

↓ 16.5%

(-53, 47%)

12.4 Microbiology

Mechanism of Action

Dinex is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly, Dinex 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 Dinex 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% 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 Dinex have been selected in cell culture and were also obtained from patients treated with Dinex. 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 Dinex monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to Dinex in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in Dinex susceptibility harbored one or more Dinex resistance-associated substitutions.

Cross-resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with Dinex and zidovudine exhibited decreased susceptibility to Dinex, 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 Dinex.

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.

Dinex induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.

Dinex 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 Dinex at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of Dinex to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of Dinex and other nucleoside analogues.

14 CLINICAL STUDIES

14.1 Adult Patients

Study AI454-152 was a 48-week, randomized, open-label study comparing Dinex 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.

Outcome Percent of Patients with HIV-1 RNA less than 400 copies/mL

(less than 50 copies/mL)

Dinex + stavudine

+ nelfinavir

n=258

zidovudine/lamivudinea

+ nelfinavir

n=253

a Zidovudine/lamivudine combination tablet.

b Corresponds to rates at Week 48 in Figure 1.

c Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.

d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.

e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons.

Responderb,c


55% (33%)

56% (33%)

Virologic failured


22% (45%)

21% (43%)

Death or discontinued due to disease progression

1% (1%)

2% (2%)

Discontinued due to adverse event

6% (6%)

7% (7%)

Discontinued due to other reasonse


16% (16%)

15% (16%)
Dinex figure

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), Dinex (120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus Dinex (90 mg/m2 every 12 hours). Patients treated with Dinex or Dinex 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

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


125 mg capsule imprinted with “BMS 125 mg 6671” in Tan


NDC No. 0087-6671-17

30 capsules/bottle

200 mg capsule imprinted with “BMS 200 mg 6672” in Green


NDC No. 0087-6672-17

30 capsules/bottle

250 mg capsule imprinted with “BMS 250 mg 6673” in Blue


NDC No. 0087-6673-17

30 capsules/bottle

400 mg capsule imprinted with “BMS 400 mg 6674” in Red


NDC No. 0087-6674-17

30 capsules/bottle

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 Dinex, 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 Dinex. 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 Dinex 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 Dinex 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 Dinex 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 Dinex, 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 Dinex is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when Dinex 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 Dinex toxicities.

17.9 General Information

Dinex 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 Dinex.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.


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 Dinex 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 Dinex 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 Dinex before you start taking it and at regular check-ups. You should stay under your healthcare provider’s care when taking Dinex.

What is the most important information I should know about Dinex?

Dinex 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 Dinex. Before you start taking Dinex, tell your healthcare provider if you:


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


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 Dinex, tell your healthcare provider if you:


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


3. Liver problems. Serious liver problems have happened in some people (including pregnant women) who take Dinex. 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 Dinex. Your healthcare provider should check your liver function while you are taking Dinex. 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:


What is Dinex?

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

Dinex will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking Dinex, 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 Dinex?

Do not take Dinex if you take:


What should I tell my healthcare provider before taking Dinex?

Before you take Dinex, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Dinex may affect the way other medicines work, and other medicines may affect how Dinex works.

Especially tell your healthcare provider if you take:


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 Dinex?


What should I avoid while taking Dinex?


What are the possible side effects of Dinex?

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


Tell your healthcare provider if you have any of the symptoms listed above.

The most common side effects of Dinex include:


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 Dinex. 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 Dinex?


Keep Dinex and all medicines out of the reach of children and pets.

General Information about the safe and effective use of Dinex

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


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

This Medication Guide summarizes the most important information about Dinex. If you would like more information about Dinex, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Dinex 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 Dinex?

Active Ingredients: Dinex

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

Dinex 125 mg Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of Dinex.

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

Dinex 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

Dinex 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

Dinex 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

Dinex pharmaceutical active ingredients containing related brand and generic drugs:


Dinex available forms, composition, doses:


Dinex destination | category:


Dinex Anatomical Therapeutic Chemical codes:


Dinex pharmaceutical companies:


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References

  1. Dailymed."VIDEX EC (DIDANOSINE) CAPSULE, DELAYED RELEASE [BRISTOL-MYERS SQUIBB COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."DIDANOSINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "didanosine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Dinex?

Depending on the reaction of the Dinex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Dinex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Dinex addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Dinex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Dinex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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