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Didanosine

Class: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 2′,3′-Dideoxyinosine
CAS Number: 69655-05-6
Brands: Videx

Warning(s)

  • Fatal and nonfatal pancreatitis reported in both antiretroviral-naive and antiretroviral-experienced patients, regardless of degree of immunosuppression.1 217 Temporarily interrupt didanosine in patients with suspected pancreatitis; discontinue in patients with confirmed pancreatitis.1 217 (See Pancreatitis under Cautions.)

  • Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals.1 217 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  • Fatal lactic acidosis reported in pregnant women who received didanosine and stavudine with other antiretrovirals.1 217 Didanosine in conjunction with stavudine should be used with caution in pregnant women and only if potential benefits outweigh potential risks.1 217 (See Pregnancy under Cautions.)

Introduction

Antiretroviral; nucleoside reverse transcriptase inhibitor (NRTI).1 3 8 30 40 72 200

Uses for Didanosine

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.1 200 201 217

Used with another NRTI (dual NRTIs) in conjunction with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or an HIV protease inhibitor (PI) in NNRTI- or PI-based regimens.200 201

Not included in preferred, alternative, or acceptable antiretroviral regimens recommended for initial treatment in HIV-infected adults and adolescents.200

Dual NRTI option of didanosine and either emtricitabine or lamivudine not recommended for initial antiretroviral regimens in adults or adolescents because of inferior virologic efficacy and limited clinical trial experience.200

Slideshow: Flashback: FDA Drug Approvals 2013

When PI- or NNRTI-based regimens used for initial treatment in HIV-infected children, some experts state that didanosine and zidovudine or didanosine and either lamivudine or emtricitabine are alternative (not preferred) dual NRTI options.201

Dual NRTI option of didanosine and tenofovir not recommended at any time because such regimens are associated with early virologic failure, rapid selection of resistant mutants, potential for immunologic nonresponse or decline in CD4+ T-cell counts, and increased risk of didanosine toxicities.200 Consider altering the NRTIs in those clinically stable on a regimen that contains both didanosine and tenofovir.200

Dual NRTI option of stavudine and didanosine not recommended at any time because of high incidence of toxicity (e.g., lactic acidosis, peripheral neuropathy, pancreatitis).200 202 (See Pregnancy under Cautions.)

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.199 Used in conjunction with other antiretrovirals.199

Postexposure prophylaxis of HIV infection in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Didanosine Dosage and Administration

Administration

Oral Administration

Delayed-release capsules containing enteric-coated pellets of didanosine: Administer orally once daily without food.217 Swallow whole capsule; do not open, crush, chew, or dissolve.217

Didanosine pediatric oral solution admixed with antacid: Administer orally at least 30 minutes before or 2 hours after a meal.1 Administer oral solution twice daily in children.1 201 Twice-daily regimen also preferred in adults and adolescents,1 200 but once-daily regimen can be considered in adults and adolescents if needed.1

Reconstitution and Dilution

Pediatric powder for oral solution must be reconstituted and admixed with an antacid at time of dispensing.1 Reconstitute by adding 100 or 200 mL of water to the bottle containing 2 or 4 g of didanosine, respectively, to provide a solution containing 20 mg/mL.1 Immediately after reconstitution, mix the 20-mg/mL solution with an equal amount of Maximum Strength Mylanta oral liquid to provide a final admixture containing 10 mg/mL.1 Shake final admixture thoroughly prior to removing each dose.1

Dosage

Adult dosage is based on weight.1 217 Pediatric dosage is based on body surface area or weight.1 217

Delayed-release capsules are used in adults and also can be used in children weighing ≥20 kg who can swallow capsules.217 Pediatric oral solution generally used in children, but may be used in adults.1

Pediatric Patients

Treatment of HIV Infection
Oral

Neonates and infants 2 weeks through 8 months of age (pediatric oral solution admixed with antacid): 100 mg/m2 twice daily.1 201 Some experts recommend 50 mg/m2 every 12 hours in those 2 weeks to <3 months of age.201

Children >8 months of age (pediatric oral solution admixed with antacid): 120 mg/m2 twice daily.1 201

Children and adolescents weighing 20 to <25 kg (delayed-release capsules): 200 mg once daily.201 217

Children and adolescents weighing 25 to <60 kg (delayed-release capsules): 250 mg once daily.201 217

Children and adolescents weighing ≥60 kg (delayed-release capsules): 400 mg once daily.201 217

Adults

Treatment of HIV Infection
Treatment in Adults Weighing <60 kg
Oral

Delayed-release capsules: 250 mg once daily.200 217

Pediatric oral solution admixed with antacid: 125 mg twice daily.1 If once-daily administration required, 250 mg once daily.1

Treatment in Adults Weighing ≥60 kg
Oral

Delayed-release capsules: 400 mg once daily.200 217

Pediatric oral solution admixed with antacid: 200 mg twice daily.1 If once-daily administration required, 400 mg once daily.1

Postexposure Prophylaxis of HIV
Occupational Exposure
Oral

Adults weighing <60 kg (delayed-release capsules): 250 mg once daily.199 200

Adults weighing ≥60 kg (delayed-release capsules): 400 mg once daily.199 200

Initiate postexposure prophylaxis as soon as possible following exposure and continue for 4 weeks, if tolerated.199

Nonoccupational Exposure
Oral

Adults weighing <60 kg (delayed-release capsules): 250 mg once daily.198 200

Adults weighing ≥60 kg (delayed-release capsules): 400 mg once daily.198 200

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.198

Special Populations

Renal Impairment

Treatment of HIV Infection
Oral
Didanosine Dosage in Adults with Renal Impairment (Delayed-release Capsules)217

Clcr (mL/minute)

Weighing <60 kg

Weighing ≥60 kg

≥60

250 mg once daily

400 mg once daily

30–59

125 mg once daily

200 mg once daily

10–29

125 mg once daily

125 mg once daily

<10

Not recommended; use alternative didanosine formulation

125 mg once daily

Hemodialysis or CAPD patients

Not recommended; use alternative didanosine formulation

125 mg once daily; supplemental doses unnecessary after hemodialysis

Didanosine Dosage in Adults with Renal Impairment (Pediatric Oral Solution Admixed with Antacid)1

Clcr (mL/minute)

Weighing <60 kg

Weighing ≥60 kg

≥60

125 mg twice daily or 250 mg once daily

200 mg twice daily or 400 mg once daily

30–59

150 mg once daily or 75 mg twice daily

200 mg once daily or 100 mg twice daily

10–29

100 mg once daily

150 mg once daily

<10

75 mg once daily

100 mg once daily

Hemodialysis or CAPD patients

75 mg once daily; supplemental doses unnecessary after hemodialysis

100 mg once daily; supplemental doses unnecessary after hemodialysis

Didanosine clearance may be decreased in pediatric patients with impaired renal function.1 217 Although data are insufficient to date to make specific dosage recommendations for pediatric patients with impaired renal function,1 217 manufacturer recommends that dosage reduction be considered.1 217

Hepatic Impairment

Dosage adjustment not needed.1 217

Cautions for Didanosine

Contraindications

  • Concomitant use with allopurinol.1 217 (See Specific Drugs under Interactions.)

  • Concomitant use with ribavirin.1 217 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Pancreatitis

Fatal and nonfatal pancreatitis reported in patients receiving didanosine alone or in conjunction with other antiretrovirals in both treatment-naive and previously treated patients, regardless of degree of immunosuppression.1 29 34 36 39 41 44 47 49 69 145 217

Interrupt didanosine therapy in patients with signs or symptoms of pancreatitis; discontinue the drug in patients with confirmed pancreatitis.1 217

Use with extreme caution and only if clearly needed in patients at increased risk for pancreatitis, including those receiving didanosine in conjunction with stavudine and those with advanced HIV infection (especially geriatric individuals).1 217 Patients with renal impairment also are at increased risk for pancreatitis if didanosine dosage is not reduced.1 217

Discontinue didanosine if treatment with a life-sustaining drug known to cause pancreatic toxicity is required.1 217

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving NRTIs (including didanosine) alone or in conjunction with other antiretrovirals.1 65 82 129 217 Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.1 217 Has been reported in patients with no known risk factors.1 217

Reported in pregnant women receiving didanosine in conjunction with stavudine.1 217 (See Pregnancy under Cautions.)

Use caution in patients with known risk factors for liver disease.1 217

Interrupt didanosine therapy if there are clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1 217

Other Warnings and Precautions

Noncirrhotic Portal Hypertension

Rare, but serious, cases of noncirrhotic portal hypertension reported in patients 10–66 years of age receiving didanosine; some cases resulted in liver transplantation or death.1 217 268 271

Didanosine-associated noncirrhotic portal hypertension was confirmed by liver biopsy in patients with no evidence of viral hepatitis or other alternative etiologies.1 217 268

Onset of signs and symptoms ranged from months to years after initiation of didanosine therapy; common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.1 217 268 271 Medical interventions consisted of banding or ligation of esophageal varices, transjugular intrahepatic portosystemic shunting (TIPSS), and liver transplantation.268 There were 4 deaths among 42 reported postmarketing cases.268

Although a causal relationship is difficult to determine, after excluding other causes of portal hypertension (e.g., alcohol-related cirrhosis, HCV infection), FDA concluded that there is an association between use of didanosine and development of noncirrhotic portal hypertension.268 However, FDA states that the clinical benefits of the drug for some patients continue to outweigh potential risks and that the decision to use didanosine must be made on an individual basis.268

Monitor patients for early signs of portal hypertension (e.g., thrombocytopenia, splenomegaly) and esophageal varices; consider use of appropriate laboratory tests (e.g., liver enzymes, serum bilirubin, albumin, CBC, INR, ultrasonography).1 217 271 Discontinue didanosine in patients with evidence of noncirrhotic portal hypertension.1 217 271

Peripheral Neuropathy

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, reported; these effects occur more frequently in patients with advanced HIV, a history of neuropathy, or those receiving other neurotoxic drugs, including stavudine.1 217

Consider discontinuing didanosine if peripheral neuropathy occurs.1 217

Ocular Effects

Retinal changes and optic neuritis reported in adults and pediatric patients.1 66 82 217 Consider periodic retinal examinations.1 217

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1 217

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1 217

The mechanisms and long-term consequences of these adipogenic effects are unknown.1 217 A causal relationship has not been established.1 217

Cardiovascular Effects

There is some evidence that recent use of didanosine (within 6 months) is associated with an increased risk of MI.267

Specific Populations

Pregnancy

Category B.1 217

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 217

Experts state use in dual NRTI options in multiple-drug antiretroviral regimens in pregnant women only in special circumstances when preferred and alternative NRTIs cannot be used.202

Although the manufacturers state use dual NRTI option of stavudine and didanosine with caution and only if potential benefits clearly outweigh potential risks,1 217 220 experts state do not use dual NRTI option of stavudine and didanosine at any time, including during pregnancy.200 202

Fatal lactic acidosis reported in pregnant women receiving didanosine and stavudine with other antiretrovirals.1 202 217 Unclear whether pregnancy potentiates risk of lactic acidosis and severe hepatotoxicity with steatosis that occurs in NRTI-treated individuals.1 217

Clinicians caring for pregnant patients receiving didanosine should be alert for early diagnosis of lactic acidosis and hepatitis steatosis syndrome.1 217

Lactation

Didanosine and/or its metabolites distributed into milk in rats; not known whether distributed into human milk.1 217

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 217

Pediatric Use

Delayed-release capsules: Use in children weighing ≥20 kg supported by pharmacokinetic data.217

Pediatric oral solution admixed with antacid: Safety and efficacy in pediatric patients 2 weeks of age through adolescence supported by evidence from adequate and well-controlled studies in adult and pediatric patients.1

Adverse effects reported in pediatric patients 2 weeks through 18 years of age are similar to those in adults and include pancreatitis, peripheral neuropathy, ophthalmic effects, GI effects, and hepatic effects.1 35 45 131 237

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 217

Substantially eliminated by kidneys; risk of toxic reactions may be greater in patients with decreased renal function.1 217 Consider age-related decreases in renal function when selecting dose.1 217 Monitor renal function and adjust dosage as necessary.1 217

Hepatic Impairment

Safety and efficacy not evaluated in patients with clinically important underlying liver disease; risk of liver function abnormalities, including severe and potentially fatal adverse hepatic events, in patients with underlying liver dysfunction (e.g., chronic active hepatitis).1 217

Use caution and monitor patients with liver disease.1 217 Interrupt or discontinue if liver disease worsens.1 217

Because noncirrhotic portal hypertension reported rarely in patients receiving didanosine,1 217 268 271 monitor patients for early signs of portal hypertension (e.g., thrombocytopenia, splenomegaly) and esophageal varices; consider obtaining appropriate laboratory tests (e.g., liver enzymes, serum bilirubin, albumin, CBC, INR, ultrasonography).1 217 271 Discontinue didanosine if there is evidence of noncirrhotic portal hypertension.1 217 271 (See Noncirrhotic Portal Hypertension under Cautions.)

Renal Impairment

Risk of toxic reactions may be greater in patients with decreased renal function.1 217

Dosage adjustment needed based on degree of renal impairment.1 217 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (diarrhea, nausea, vomiting, abdominal pain), peripheral neurologic symptoms/neuropathy, rash/pruritus, headache, pancreatitis.1 217

Interactions for Didanosine

Drug interaction studies have used buffered didanosine (chewable/dispersible, buffered tablets [no longer commercially available in the US], pediatric oral solution admixed with antacid) or didanosine delayed-release capsules.217 With a few exceptions (e.g., ciprofloxacin, indinavir, ketoconazole),48 217 results of interaction studies that used buffered preparations are expected to apply to delayed-release capsules.217

Specific Drugs

Drug

Interaction

Comments

Allopurinol

Substantially increased didanosine concentrations and AUC;1 217 possible increased risk of didanosine toxicity1 217

Concomitant use contraindicated1 200 217

Antacids

Aluminum- and magnesium-containing antacids increase oral bioavailability of didanosine1 2 3 38 39 62

Possible increased antacid adverse effects if additional antacids are used in patients receiving didanosine pediatric oral solution admixed with antacid1

Used to therapeutic advantage; didanosine pediatric oral solution is admixed with antacid prior to administration1

Additional antacids should be used with caution in patients receiving didanosine pediatric oral solution admixed with antacid1

Antifungals, azoles

Itraconazole: Decreased itraconazole concentrations with buffered didanosine1 132

Ketoconazole: Decreased ketoconazole peak plasma concentrations and AUC with buffered didanosine;1 no changes in ketoconazole concentrations with didanosine delayed-release capsules48 217

Administer itraconazole or ketoconazole at least 2 hours before buffered didanosine (pediatric oral solution admixed with antacid)1

Antimycobacterials

Rifabutin: Slightly increased didanosine concentrations;1 no clinically important pharmacokinetic interactions238

Atazanavir

Buffered didanosine: Decreased atazanavir concentrations and AUC;203 decreased didanosine concentrations and AUC203

Didanosine delayed-release capsules: Decreased didanosine concentrations and AUC if given with atazanavir and food;200 203 no change in atazanavir concentrations200

No in vitro evidence of antagonistic antiretroviral effects203

Administer atazanavir (with food) 2 hours before or 1 hour after buffered or delayed-release didanosine preparations (without food)200 203

Buprenorphine

No clinically important pharmacokinetic interactions200

Dosage adjustments not needed200

Dapsone

No effect on dapsone concentrations or AUC1 181 217

Some reports of failure of dapsone to prevent Pneumocystis carinii pneumonia in HIV-infected patients receiving didanosine concomitantly71

Some clinicians suggest didanosine be administered at least 2 hours after dapsone71

Darunavir

Didanosine delayed-release capsules: No change in didanosine or darunavir concentrations204

No in vitro evidence of antagonistic antiretroviral effects204

Administer didanosine (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food)204

Delavirdine

Buffered didanosine: Decreased delavirdine and didanosine concentrations if given simultaneously;1 212 slightly increased delavirdine concentrations if delavirdine given 1 hour before didanosine1

In vitro evidence of additive or synergistic antiretroviral effects212

Administer delavirdine at least 1 hour before or at least 1 hour after buffered didanosine (pediatric oral solution admixed with antacid)1 212

Drugs associated with pancreatitis (pentamidine, co-trimoxazole)

Increased risk of pancreatitis1 36 39 217

Use with extreme caution and only if other alternative agents are not available; if clearly indicated, consider discontinuing didanosine1 36 39 217

Drugs associated with neurotoxicity

Increased risk of neuropathy1 217

Use caution1 217

Efavirenz

In vitro evidence of additive antiretroviral effects213

Etravirine

No clinically important effect on plasma concentrations or AUC of either drug214

No in vitro evidence of antagonistic antiretroviral effects214

Dosage adjustments not needed214

Fluoroquinolones (ciprofloxacin, levofloxacin moxifloxacin, ofloxacin)

Decreased absorption and lower concentrations of fluoroquinolones with buffered didanosine1 262 263 264

Studies using ciprofloxacin indicate didanosine delayed-release capsules do not affect pharmacokinetics of the fluoroquinolone48 217

Ciprofloxacin: Administer 2 hours before or 6 hours after buffered didanosine (pediatric oral solution admixed with antacid)1

Levofloxacin: Administer at least 2 hours before or 2 hours after buffered didanosine (pediatric oral solution admixed with antacid)262

Moxifloxacin: Administer at least 4 hours before or 8 hours after buffered didanosine (pediatric oral solution admixed with antacid)263

Ofloxacin: Administer at least 2 hours before or 2 hours after buffered didanosine (pediatric oral solution admixed with antacid)264

Fosamprenavir

In vitro evidence of synergistic antiretroviral effects205

Ganciclovir and valganciclovir

Didanosine given 2 hours before ganciclovir results in increased didanosine AUC1 217 and decreased ganciclovir AUC1

Concomitant administration of didanosine with IV ganciclovir results in increased didanosine AUC and peak plasma concentrations; no change in ganciclovir pharmacokinetics250

Because valganciclovir is rapidly and completely converted to ganciclovir, didanosine interaction reported with ganciclovir is expected to occur with valganciclovir251

If no suitable alternatives to ganciclovir are available, use caution and monitor for didanosine toxicity1 217

Histamine H2-receptor antagonists

Ranitidine: Slightly increased didanosine AUC and slightly decreased ranitidine AUC if given 2 hours prior to buffered didanosine1

Hydroxyurea

Concomitant use of didanosine and hydroxyurea: Potential for increased risk of pancreatitis1 217 228

Concomitant use of didanosine, hydroxyurea, and stavudine: Potential for increased risk of fatal hepatotoxicity1 217

In vitro evidence of synergistic antiretroviral effects227 229 235 274

Avoid concomitant use of didanosine and hydroxyurea (with or without stavudine)1 217

Indinavir

Buffered didanosine (Videx): Substantially decreased indinavir concentrations and AUC if administered simultaneously1

Delayed-release capsules (Videx EC): No effect on indinavir concentrations and AUC217

In vitro evidence of synergistic antiretroviral effects206

Buffered didanosine (Videx): Administer 1 hour after indinavir1

Loperamide

Buffered didanosine: Decreased didanosine concentrations; no effect on didanosine AUC1

Lopinavir/ritonavir

Lopinavir/ritonavir oral solution: Conflicting administration instructions regarding food207

Lopinavir/ritonavir oral solution: Administer didanosine (without food) 1 hour before or 2 hours after lopinavir/ritonavir (with food)207

Lopinavir/ritonavir tablets: May be administered at the same time as didanosine207

Macrolides (clarithromycin)

Clarithromycin: Pharmacokinetic interaction unlikely158

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects224

Methadone

Buffered didanosine: Substantially decreased didanosine concentrations and AUC;1 243 no change in methadone concentrations243

Didanosine delayed-release capsules: Decreased didanosine concentrations and AUC217

Didanosine pediatric oral solution: Concomitant use not recommended1

Didanosine delayed-release capsules: Dosage adjustments not needed;200 monitor closely for adequate clinical response to didanosine (e.g., changes in viral load)217

Metoclopramide

Buffered didanosine: Slightly increased didanosine concentrations; no effect on didanosine AUC1

Nelfinavir

No change in nelfinavir concentrations when didanosine administered 1 hour before nelfinavir1 208 217

In vitro evidence of additive or synergistic antiretroviral effects186 208

Administer didanosine (without food) 1 hour before or 2 hours after nelfinavir (with food)1 208 217

Nevirapine

No effect on nevirapine or didanosine pharmacokinetics215

In vitro evidence of additive or synergistic antiretroviral effects215

Raltegravir

In vitro evidence of additive to synergistic antiretroviral effects225

Ribavirin

Increased intracellular concentrations of active didanosine metabolite1 200 217

Serious adverse effects (fatal hepatic failure, peripheral neuropathy, pancreatitis, hyperlactatemia/lactic acidosis) reported with concomitant use1 200 217

Concomitant use contraindicated1 200 217

Rilpivirine

No effect on rilpivirine or didanosine concentrations when administered 2 hours apart226

No in vitro evidence of antagonistic antiretroviral effects226

Administer didanosine (without food) at least 2 hours before or 4 hours after rilpivirine (with food);226 dosage adjustments not needed226

Ritonavir

Full-dose ritonavir: Decreased didanosine concentrations and AUC;1 209 217 no clinically important effect on ritonavir pharmacokinetics209 217

In vitro evidence of additive or synergistic antiretroviral effects1 186 209

Saquinavir

In vitro evidence of additive or synergistic antiretroviral effects186 210

Stavudine

No clinically important pharmacokinetic interactions1

Concomitant use of didanosine and stavudine (with or without hydroxyurea): Increased risk of toxicities (pancreatitis, peripheral neuropathy, hyperlactatemia)1 200 217

In vitro evidence of additive or synergistic antiretroviral effects;189 antagonism also reported162

Experts state concomitant use of didanosine and stavudine not recommended at any time, including in pregnant women200 202

Manufacturers state use concomitantly with caution; avoid concomitant use during pregnancy unless potential benefits outweigh risks1 217 220

Avoid concomitant use of didanosine, hydroxyurea, and stavudine1 217

Sulfamethoxazole

Pharmacokinetic interaction unlikely1

Tenofovir

Buffered or delayed-release didanosine: Increased didanosine concentrations and AUC;1 217 221 no effect on tenofovir pharmacokinetics1 217 221

Early virologic failure, rapid selection of resistant mutants, potential for immunologic nonresponse or decline in CD4+ T-cell counts reported200

Increased risk of didanosine-associated adverse effects (e.g., pancreatitis, lactic acidosis, neuropathy)1 200 217 221

In vitro evidence of additive to synergistic antiretroviral effects221

Experts state concomitant use of didanosine and tenofovir not recommended at any time200

Manufacturers state use concomitantly with caution and reduced didanosine dosage; closely monitor for didanosine-associated adverse effects; discontinue didanosine if necessary1 217 221

In adults or adolescents weighing ≥60 kg with Clcr ≥60 mL/minute, reduce didanosine dosage to 250 mg once daily; in those weighing <60 kg with Clcr ≥60 mL/minute, reduce didanosine dosage to 200 mg once daily1 217

If using didanosine delayed-release capsules, administer didanosine and tenofovir at same time without food or with a light meal;217 if using didanosine pediatric oral solution, administer didanosine and tenofovir at same time without food or administer didanosine on an empty stomach (i.e., ≥30 minutes before or 2 hours after food) if tenofovir is taken with food1

Tetracyclines

Buffered didanosine: Possible decreased tetracycline concentrations1

Buffered didanosine (pediatric oral solution): Some clinicians recommend giving didanosine oral solution 1–2 hours before or after tetracycline dose82

Tipranavir

Ritonavir-boosted tipranavir: Decreased didanosine concentrations;200 211 clinical importance unknown211

In vitro evidence of additive antiretroviral effects211

Administer ritonavir-boosted tipranavir at least 2 hours before or 2 hours after didanosine200 211

Trimethoprim

Pharmacokinetic interaction unlikely1

Zidovudine

Buffered didanosine: Decreased zidovudine concentrations and AUC;1 217 no effect on didanosine concentrations or AUC1 217

In vitro evidence of synergistic antiretroviral effects70 222

Didanosine Pharmacokinetics

Absorption

Bioavailability

Extent of absorption is variable and depends on several factors including dosage form administered, gastric pH, and presence of food in GI tract.1 37 38 39 44 61 62 63 120 217 Bioavailability is 42%.217

Rapidly degraded at acidic pH; gastric secretions may inactivate the drug following oral administration.1 2 3 29 34 39 40 45 61 62 63

Delayed-release capsules contain enteric-coated pellets of the drug to maximize GI absorption.217

Powder for oral solution must be admixed with antacids prior to administration.1 39 40 62

Following administration of delayed-release capsules, AUC is similar to, but peak plasma concentrations are 40% lower than, values reported following administration of chewable/dispersible tablets (no longer commercially available in the US).217

No clinically important changes in pharmacokinetics of didanosine during pregnancy.202

Food

Presence of food in GI tract decreases rate and extent of absorption.1 62 217

Distribution

Extent

Distributed into CSF;1 concentrations in CSF may be 46% of concurrent plasma concentrations.1

Crosses placenta and is distributed into cord blood and amniotic fluid.60 Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

<5%.1

Elimination

Metabolism

Metabolism presumably occurs via same pathways responsible for elimination of endogenous purines.1 217

Intracellularly, didanosine is phosphorylated and converted by cellular enzymes to the active metabolite, dideoxyadenosine 5′-triphosphate.1

Elimination Route

Eliminated in urine by glomerular filtration and active tubular secretion.63

Half-life

Adults: 0.97–1.6 hours.1 37 44 55 63 217 249

Plasma half-life averages 1.2 hours in neonates and children 2 weeks to 4 months of age and 0.8 hours in children 8 months to 19 years of age.1

Special Populations

The apparent oral clearance of didanosine decreases and half-life of the drug increases as Clcr decreases.1 Mean half-life is 1.42 hours in patients with Clcr ≥90 mL/minute or 1.59, 1.75, or 2 hours in those with Clcr 60–90, 30–59, or 10–29 mL/minute, respectively.1 In dialysis patients, mean half-life is 4.1 hours.1

Removed by hemodialysis.1 122 239 Absolute bioavailability not affected in patients requiring dialysis.1 Does not appear to be removed by peritoneal dialysis.1 239

Peak plasma concentrations and AUC in individuals with moderate or severe hepatic impairment (Child-Pugh class B or C) similar to values in individuals without hepatic impairment.217

Stability

Storage

Oral

Delayed-release Capsules

25°C (may be exposed to 15–30°C); tight containers.217

Pediatric Powder for Oral Solution

15–30°C.1

Following reconstitution with water and admixture with a liquid antacid as directed, stable for 30 days when refrigerated at 2–8°C.1 Discard unused portions of reconstituted and admixed pediatric didanosine oral solutions after 30 days.1

Actions and Spectrum

  • Analog of inosine, a naturally occurring purine nucleoside.40

  • Pharmacologically related to other NRTIs (e.g., abacavir, emtricitabine, lamivudine, stavudine, zidovudine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.1

  • Active in vitro against HIV-11 4 5 6 8 10 16 17 21 30 34 40 58 70 76 and HIV-2.1 16 34

  • Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1 217

  • Strains of HIV-1 with reduced susceptibility to didanosine have been produced in vitro and have emerged during therapy with the drug.1 156

  • Strains of HIV resistant to didanosine may be cross-resistant to some other NRTIs.111 112 113 114 125 155

Advice to Patients

  • Didanosine medication guide must be provided to the patient each time the drug is dispensed;269 importance of patient reading the medication guide prior to initiating didanosine therapy and each time prescription is refilled.1 217

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician during therapy.1 217 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 217

  • Importance of using in conjunction with other antiretrovirals–not for monotherapy.1 217

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 217

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.226

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200 217

  • If a dose is missed, it should be taken as soon as possible;1 217 if it is almost time for the next dose, the missed dose should be skipped and the next dose taken at the regularly scheduled time.1 217

  • Possibility of pancreatitis, including fatal pancreatitis.1 217

  • Possibility of peripheral neuropathy; manifestations include numbness, tingling, or pain in hands or feet.1 217 Advise patients that peripheral neuropathy occurs most frequently in patients with advanced HIV disease or a history of peripheral neuropathy, and that discontinuance of the drug may be required if peripheral neuropathy occurs.1 217

  • Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported.1 217

  • Advise patients that hepatotoxicity, including fatal events, have been reported in patients with preexisting liver dysfunction and that safety and efficacy not established in HIV-infected individuals with substantial underlying liver disease.1 217

  • Advise patients that noncirrhotic portal hypertension (sometimes resulting in liver transplantation or death) have been reported.1 217 268

  • Possibility of retinal changes and optic neuritis.1 217

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 217

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1 217

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 217 Advise HIV-infected women not to breast-feed.1 217

  • Importance of advising patients of other important precautionary information.1 217 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Didanosine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release (containing enteric-coated pellets)

125 mg*

Didanosine Delayed-release Capsules

Videx EC

Bristol-Myers Squibb

200 mg*

Didanosine Delayed-release Capsules

Videx EC

Bristol-Myers Squibb

250 mg*

Didanosine Delayed-release Capsules

Videx EC

Bristol-Myers Squibb

400 mg*

Didanosine Delayed-release Capsules

Videx EC

Bristol-Myers Squibb

For solution

2 g/bottle*

Didanosine for Oral Solution

Videx Pediatric

Bristol-Myers Squibb

4 g/bottle*

Didanosine for Oral Solution

Videx Pediatric

Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Didanosine 200MG Delayed-release Capsules (TEVA PHARMACEUTICALS USA): 30/$158.99 or 90/$438.95

Didanosine 250MG Delayed-release Capsules (TEVA PHARMACEUTICALS USA): 30/$173.99 or 90/$479.97

Didanosine 400MG Delayed-release Capsules (TEVA PHARMACEUTICALS USA): 30/$253.42 or 90/$730.95

Videx 4GM Solution (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 200/$119.99 or 600/$339.99

Videx EC 250MG Delayed-release Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 30/$259.99 or 90/$747.94

Videx EC 400MG Delayed-release Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 30/$376.38 or 90/$1,109.77

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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82. Reviewers’ comments (personal observations).

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181. Sahai J, Garber G, Gallicano K et al. Effects of the antacids in didanosine tablets on dapsone pharmacokinetics. Ann Intern Med. 1995; 123:584-7. [IDIS 354303] [PubMed 7677298]

182. Shafer RW, Iversen AKN, Winters MA et al. Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. J Infect Dis. 1995; 172:70-8. [IDIS 350663] [PubMed 7541064]

183. Kozal MJ, Kroodsma K, Winters MA et al. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med. 1994; 121:263-8. [IDIS 333949] [PubMed 7518658]

184. Moyle GJ. Resistance to antiretroviral compounds: implications for the clinical management of HIV infection. Immunol Infect Dis. 1995; 5:170-82.

185. Arts EJ, Wainberg MA. Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription. Antimicrob Agents Chemother. 1996; 40:527-40. [IDIS 364368] [PubMed 8851566]

186. Craig JC, Duncan IB, Whittaker L et al. Antiviral synergy between inhibitors of HIV proteinase and reverse transcriptase. Antiviral Chem Chemother. 1993; 4:161-6.

187. Englund JA, Baker CJ, Raskino C et al. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. N Engl J Med. 1997; 336:1704-12. [IDIS 385977] [PubMed 9182213]

189. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis. 1996; 173:355-64. [IDIS 362747] [PubMed 8568296]

198. Smith DK, Grohskopf LA, Black RJ et al. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep. 2005; 54(RR-2):1-20. [PubMed 15660015]

199. Panlilio AL, Cardo DM, Grohskopf LA et al. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep. 2005; 54(RR-9):1-17.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 18, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (August 11, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (July 31, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

203. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.

204. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Jun.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.

206. Merck Sharp & Dohme. Crixivan (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

207. Abbott Laboratories. Kaletra (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

208. ViiV Healthcare. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2012 Apr.

209. Abbott Laboratories. Norvir (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

210. Genentech USA. Invirase (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.

212. ViiV Healthcare. Rescriptor (delavirdine mesylate) tablets prescribing information. Research Triangle Park, NC; 2010 Sep.

213. Bristol-Myers Squibb. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2012 Jun.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.

215. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2011 Nov.

217. Bristol-Myers Squibb. Videx EC (didanosine) delayed-release capsules enteric-coated beadlets prescribing information. Princeton, NJ; 2011 Feb.

218. Gilead Sciences. Emtriva (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2012 Jul.

220. Bristol-Myers Squibb. Zerit (stavudine) capsules and oral solution prescribing information. Princeton, NJ; 2012 Jan.

221. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2012 Jan.

222. ViiV Healthcare. Retrovir (zidovudine) tablets, capsules, and syrup prescribing information. Research Triangle Park, NC; 2012 May.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

226. Tibotec Therapeutics. Edurant (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.

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251. Genentech USA, Inc. Valcyte (valganciclovir hydrochloride) tablets and for oral solution prescribing information. South San Francisco, CA; 2009 Nov.

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263. Bayer Corporation. Avelox (moxifloxacin hydrochloride) tablets and I.V. prescribing information. Wayne, NJ; 2010 Mar.

264. Ortho-McNeil Pharmaceutical. Floxin (ofloxacin) tablets prescribing information. Raritan, NJ; 2008 Jan.

267. D:A:D study group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study; a multi-cohort collaboration. Lancet. 2008; 371:1417-26.

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