Didanosine

(BAN, USAN, rINN)
Didanosine Chemical formula
Synonyms: BMY-40900; ddI; ddIno; Didanocin; Didanosiini; Didanosin; Didanosina; Didanosinum; Didanozin; Didanozinas; Dideoxyinosine; NSC-612049. 2′,3′-Dideoxyinosine.
Cyrillic synonym: Диданозин.

💊 Chemical information

Chemical formula: C10H12N4O3 = 236.2.
CAS — 69655-05-6.
ATC — J05AF02.
ATC Vet — QJ05AF02.

Pharmacopoeias.

In Eur., Int., and US.

Ph. Eur. 6.2

(Didanosine). A white or almost white, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol and in methyl alcohol; freely soluble in dimethyl sulfoxide.

USP 31

(Didanosine). A white to off-white crystalline powder. Practically insoluble or insoluble in acetone and in methyl alcohol; very soluble in dimethyl sulfoxide. Store at a temperature of 20° to 25°, excursions permitted between 15° and 30°.

💊 Adverse Effects

The most common serious adverse effects of didanosine are peripheral neuropathy and potentially fatal pancreatitis. Other commonly reported adverse effects include abdominal pain, diarrhoea, fatigue, headache, nausea, rash, and vomiting. Abnormal liver function tests may occur and hepatitis or fatal hepatic failure has been reported rarely; fatalities were reported most often in patients taking didanosine with stavudine and hydroxycarbamide. Retinal and optic-nerve changes have been reported in children, particularly in those taking higher than recommended doses; retinal depigmentation has been reported in adult patients. Other adverse effects include alopecia, anaemia, asthenia, dry mouth, fever, flatulence, parotid gland enlargement, leucopenia, hypersensitivity reactions including anaphylaxis, hyperuricaemia, and thrombocytopenia. Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, and generally occurring after some months of treatment has been reported. Immune reconstitution syndrome (an inflammatory immune response resulting in clinical deterioration) has been reported during the initial phase of treatment with combination antiretroviral therapy, including didanosine, in HIV-infected patients with severe immune deficiency. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been seen in patients receiving antiretroviral therapy, including didanosine. Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia have also been reported. NRTIs have also been associated with mitochondrial dysfunction such as abnormal behaviour, anaemia, convulsions, hyperlipasaemia, hypertonia, and neutropenia. Elevated creatine phosphokinase, myalgia, myositis, and rarely rhabdomyolysis have been reported, particularly when nucleoside analogues have been given with HIV-protease inhibitors. For further information on adverse effects associated with NRTIs see Zidovudine.

Effects on the blood.

In general, haematological abnormalities are less common in patients taking didanosine than in those taking zidovudine. However, there have been reports of thrombocytopenia associated with didanosine.1-3
1. Butler KM, et al. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 324: 137–44
2. Lor E, Liu YQ. Didanosine-associated eosinophilia with acute thrombocytopenia. Ann Pharmacother 1993; 27: 23–5
3. Herranz P, et al. Cutaneous vasculitis associated with didanosine. Lancet 1994; 344: 680.

Effects on the eyes.

Retinal lesions with atrophy of the retinal pigment epithelium at the periphery of the retina were reported in 4 children receiving didanosine doses of 270 to 540 mg/m2daily.1
1. Whitcup SM, et al. Retinal lesions in children treated with dideoxyinosine. N Engl J Med 1992; 326: 1226–7.

Effects on the heart.

For the possible risk of myocardial infarction in patients taking didanosine, see Effects on the Heart under Adverse Effects of Zidovudine.

Effects on the liver.

Fatal fulminant hepatic failure was reported1 in a patient receiving didanosine. A further 14 cases had been noted by the manufacturer, and elevated liver enzymes have been recorded during clinical studies.2-5
1. Lai KK, et al. Fulminant hepatic failure associated with 2′,3′dideoxyinosine (ddI). Ann Intern Med 1991; 115: 283–4
2. Dolin R, et al. Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no experience with zidovudine. Arch Intern Med 1995; 155: 961–74
3. Jablonowski H, et al. A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine. AIDS 1995; 9: 463–9
4. Alpha International Coordinating Committee. The Alpha trial: European/Australian randomized double-blind trial of two doses of didanosine in zidovudine-intolerant patients with symptomatic HIV disease. AIDS 1996; 10: 867–80
5. Gatell JM, et al. Switching from zidovudine to didanosine in patients with symptomatic HIV infection and disease progression. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12: 249–58.

Effects on mental state.

Recurrent mania associated with didanosine treatment has been reported in a patient.1
1. Brouillette MJ, et al. Didanosine-induced mania in HIV infection. Am J Psychiatry 1994; 151: 1839–40.

Effects on metabolism.

Hyperuricaemia has been reported to be a common adverse effect during clinical studies of didanosine.1,2 Hypokalaemia occurred during didanosine therapy in 3 patients, 2 of whom had diarrhoea.3 There has also been a report of hypertriglyceridaemia occurring on 2 occasions in a patient given didanosine;4 it was suggested that this hyperlipidaemic effect might be a possible aetiological factor in the development of pancreatitis.
1. Cooley TP, et al. Once-daily administration of 2′,3′-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: results of a phase I trial. N Engl J Med 1990; 322: 1340–5
2. Montaner JSG, et al. Didanosine compared with continued zidovudine therapy for HIV-infected patients with 200 to 500 CD4 cells/mm : a double-blind, randomized, controlled trial. Ann Intern Med 1995; 123: 561–71
3. Katlama C, et al. Dideoxyinosine-associated hypokalaemia. Lancet 1991; 337: 183
4. Tal A, Dall L. Didanosine-induced hypertriglyceridemia. Am J Med 1993; 95: 247.

Effects on the mouth.

Xerostomia (dry mouth) may be a troublesome effect in patients receiving didanosine.1,2
1. Dodd CL, et al. Xerostomia associated with didanosine. Lancet 1992; 340: 790
2. Valentine C, et al. Xerostomia associated with didanosine. Lancet 1992; 340: 1542.

Effects on the nervous system.

Peripheral neuropathy is a well recognised adverse effect of didanosine and has been the subject of a review.1
1. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Safety 1998; 19: 481–94.

Effects on the pancreas.

Pancreatitis is recognised as being the most serious adverse effect of didanosine and can be fatal.1-3It appears to be dose-related, occurring in up to 13% of patients receiving 750 mg of didanosine daily.2,4 Pancreatitis can resolve if didanosine is withdrawn5 and cautious reintroduction of didanosine has been possible in some patients.6 Raised amylase concentrations3 and glucose intolerance have been reported in patients who subsequently developed pancreatitis.
1. Bouvet E, et al. Fatal case of 2′,3′-dideoxyinosine-associated pancreatitis. Lancet 1990; 336: 1515
2. Kahn JO, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581–7
3. Dolin R, et al. Zidovudine compared with didanosine in patients with advanced HIV-type 1 infection and little or no previous experience with zidovudine. Arch Intern Med 1995; 155: 961–74
4. Jablonowski H, et al. A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine. AIDS 1995; 9: 463–9
5. Nguyen B-Y, et al. Five-year follow-up of a phase I study of didanosine in patients with advanced human immunodeficiency virus infection. J Infect Dis 1995; 171: 1180–9
6. Butler KM, et al. Pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine. Pediatrics 1993; 91: 747–51.

Effects on the skin.

Didanosine has been implicated in a case of Stevens-Johnson syndrome1 and of cutaneous vasculitis.2
1. Parneix-Spake A, et al. Didanosine as probable cause of Stevens-Johnson syndrome. Lancet 1992; 340: 857–8
2. Herranz P, et al. Cutaneous vasculitis associated with didanosine. Lancet 1994; 344: 680.

💊 Precautions

Didanosine should be used with extreme caution in patients with a history of pancreatitis and those with increased triglyceride concentrations should be observed carefully for signs of pancreatitis and treatment with didanosine interrupted in all patients with signs and symptoms of possible pancreatitis, until it has been excluded. Use with other drugs likely to cause pancreatitis or peripheral neuropathy (see Interactions, below) should preferably be avoided; treatment with didanosine should be suspended if possible when use of such drugs is essential. It may be necessary to interrupt didanosine treatment in patients who develop peripheral neuropathy; on recovery from peripheral neuropathy a reduced dose may be tolerated. Treatment should also be interrupted if uric acid concentrations are elevated. Patients co-infected with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. Didanosine should be given with caution to patients with hepatomegaly or other risk factors for liver disease and patients with renal or hepatic impairment; dosage reduction may be necessary. Regular checks of liver function are recommended. If liver enzymes increase to 5 times the upper limit of normal during treatment then didanosine should be stopped. Treatment with didanosine may be associated with lactic acidosis and should also be stopped if there is a rapid increase in aminotransferase concentrations, progressive hepatomegaly, steatosis, or metabolic or lactic acidosis of unknown aetiology. Children should be monitored for retinal lesions and didanosine withdrawn if they occur. Monitoring should also be considered in adults.

💊 Interactions

Use of didanosine with other drugs known to cause pancreatitis (for example intravenous pentamidine) or with drugs that may cause peripheral neuropathy (for example metronidazole, isoniazid, and vincristine) should be avoided. If co-administration is unavoidable, patients should be monitored carefully for these adverse effects. An increase in the area under the plasma concentration-time curve for didanosine has been reported when allopurinol or other xanthine oxidase inhibitors are given concurrently. Plasma concentrations of didanosine may be reduced by methadone and increased by ganciclovir. Didanosine formulations (chewable or dispersible preparation) contain an antacid and other drugs that could be affected by an increased gastric pH (for example HIV-protease inhibitors, ketoconazole, fluoroquinolone antibacterials, and dapsone) should be given at least 2 hours before didanosine. Didanosine preparations containing magnesium or aluminium antacids should not be given with tetracyclines. Use of didanosine with tenofovir results in increased plasma concentrations of didanosine and consequently an increased risk of didanosine-related adverse effects such as peripheral neuropathy, pancreatitis, and lactic acidosis. Fatalities have been reported. There have also been reports of virological failure and emergence of resistance at an early stage of treatment when didanosine and tenofovir were given with lamivudine as part of a once daily triple nucleoside regimen. UK licensed product information for both didanosine and tenofovir does not recommend co-administration of these drugs either at standard or reduced doses of didanosine. A 250 mg daily dose of didanosine had been evaluated, but resulted in virological failure and the emergence of resistance. US product information for didanosine, however, recommends that co-administration may be undertaken with caution in patients with normal renal function. For patients weighing greater than 60 kg the dose of didanosine should be reduced to 250 mg daily, while for those weighing less than 60 kg a dose of 200 mg daily is recommended. US product information for tenofovir advises against using didanosine with tenofovir in patients under 60 kg due to a lack of data. Ribavirin has been shown in vitro to increase the intracellular triphosphate levels of didanosine and to potentially increase the risk of adverse effects related to didanosine. UK product information for didanosine recommends that co-administration be undertaken with caution, while the US information does not recommend use of the two drugs together. See also below for interactions with antivirals.

Antidiabetics.

Fatal lactic acidosis has been reported1 in a patient given metformin with didanosine, stavudine, and tenofovir.
1. Worth L, et al. A cautionary tale: fatal lactic acidosis complicating nucleoside analogue and metformin therapy. Clin Infect Dis 2003; 37: 315–16.

Antivirals.

Plasma concentrations of didanosine are roughly doubled when given ganciclovir.1-3 Valganciclovir, the prodrug of ganciclovir, inhibits purine nucleoside phosphorylase and increases didanosine concentrations. Significant CD4+ T lymphocyte count decline and symptoms of didanosine toxicity, despite complete viral suppression, occurred in an HIV-positive patient given an antiretroviral regimen containing didanosine plus valganciclovir for the treatment of CMV enteritis. Complete CD4+ count recovery and resolution of symptoms occurred when didanosine was replaced with abacavir.4 Changes in the pharmacokinetics of didanosine and zidovudine have occurred when these drugs are given together, but results of studies have not been consistent, and the effects have generally been of limited clinical significance. For further details, see under Interactions in Zidovudine. Tenofovir has been reported to significantly increase plasma concentrations of didanosine,5 and may increase the risk of pancreatitis associated with didanosine.6,7 There has also been a report of acute renal failure and fatal lactic acidosis when tenofovir was added to a regimen containing didanosine.8 Use of didanosine with delavirdine resulted in reductions in the area under the concentration-time curve for both drugs in a single-dose study.9 Licensed product information for delavirdine recommends that these two drugs should be given at least 1 hour apart. Absorption of some HIV-protease inhibitors may be reduced by the buffers in some didanosine formulations and doses should be at least 2 hours apart.
1. Griffy KG. Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons. AIDS 1996; 10 (suppl 4): S3–S6
2. Jung D, et al. Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients. J Clin Pharmacol 1998; 38: 1057–62
3. Cimoch PJ, et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17: 227–34
4. Tseng AL, Salit IE. CD4+ cell count decline despite HIV suppression: a probable didanosine-valganciclovir interaction. Ann Pharmacother 2007; 41: 512–17
5. Pecora Fulco P, Kirian MA. Effect of tenofovir on didanosine absorption in patients with HIV. Ann Pharmacother 2003; 37: 1325–8
6. Blanchard JN, et al. Pancreatitis with didanosine and tenofovir disoproxil fumarate. Clin Infect Dis 2003; 37: e57–e62. Correction. ibid.: 995. [title of paper corrected
7. Kirian MA, et al. Acute onset of pancreatitis with concomitant use of tenofovir and didanosine. Ann Pharmacother 2004; 38: 1660–3
8. Murphy MD, et al. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clin Infect Dis 2003; 36: 1082–5
9. Morse GD, et al. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997; 41: 169–74.

💊 Antiviral Action

Didanosine is converted intracellularly to its active form dideoxyadenosine triphosphate. This triphosphate halts the DNA synthesis of retroviruses, including HIV, through competitive inhibition of reverse transcriptase and incorporation into viral DNA. Didanosine-resistant strains of HIV emerge during didanosine therapy. Cross-resistance to other nucleoside reverse transcriptase inhibitors has been recognised.

Resistance.

Evidence for the development of didanosine-resistant HIV was reported in 36 of 64 patients with advanced HIV infection within 24 weeks of switching from zidovudine to didanosine monotherapy.1 Patients with the didanosine resistance mutation for HIV reverse transcriptase showed a greater decline in CD4+ T cell count and increase in viral burden than those without. Multiple-drug resistant mutations have been found in patients taking long-term combination antiretroviral therapy containing didanosine.2
1. Kozal MJ, et al. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med 1994; 121: 263–8
2. Kavlick MF, et al. Emergence of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 variants, viral sequence variation, and disease progression in patients receiving antiretroviral chemotherapy. J Infect Dis 1998; 98: 1506–13.

💊 Pharmacokinetics

Didanosine is rapidly hydrolysed in the acid medium of the stomach and is therefore given orally with pH buffers or antacids. Bioavailability is reported to range from 20 to 40% depending on the formulation used; the bioavailability is substantially reduced if taken with or after food. Maximum plasma concentrations are achieved about 1 hour after oral dosage. Binding to plasma proteins is reported to be less than 5%. Didanosine has been reported not to cross the blood brain barrier. Didanosine is metabolised intracellularly to the active antiviral metabolite dideoxyadenosine triphosphate. The plasma elimination half-life is reported to be about 1.5 hours. Renal clearance is by glomerular filtration and active tubular secretion; about 20% of an oral dose is recovered in the urine. Didanosine is partially cleared by haemodialysis but not by peritoneal dialysis.
1. Balis FM, et al. Clinical pharmacology of 2′,3′-dideoxyinosine in human immunodeficiency virus-infected children. J Infect Dis 1992; 165: 99–104
2. Morse GD, et al. Comparative pharmacokinetics of antiviral nucleoside analogues. Clin Pharmacokinet 1993; 24: 101–23
3. Mueller BU, et al. Clinical and pharmacokinetic evaluation of long-term therapy with didanosine in children with HIV infection. Pediatrics 1994; 94: 724–31.
4. Knupp CA, et al. Disposition of didanosine in HIV-seropositive patients with normal renal function or chronic renal failure: influence of hemodialysis and continuous ambulatory peritoneal dialysis. Clin Pharmacol Ther 1996; 60: 535–42
5. Wintergerst U, et al. Lack of absorption of didanosine after rectal administration in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1999; 43: 699–701
6. Abreu T, et al. Bioavailability of once- and twice-daily regimens of didanosine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother 2000; 44: 1375–6.

Pregnancy.

Fetal blood concentrations of 14 and 19% of the maternal serum-didanosine concentrations have been reported.1There is evidence of extensive metabolism in the placenta.2
1. Pons JC, et al. Fetoplacental passage of 2′,3′-dideoxyinosine. Lancet 1991; 337: 732
2. Dancis J, et al. Transfer and metabolism of dideoxyinosine by the perfused human placenta. J Acquir Immune Defic Syndr 1993; 6: 2–6.

💊 Uses and Administration

Didanosine is a nucleoside reverse transcriptase inhibitor structurally related to inosine with antiviral activity against HIV-1. It is used in the treatment of HIV infection and AIDS. Viral resistance emerges rapidly when didanosine is used alone, and it is therefore used with other antiretrovirals. Didanosine is given orally, usually as buffered chewable/dispersible tablets or enteric-coated capsules. Doses should be taken at least 30 minutes before, or 2 hours after, a meal. The total daily dose may be given as either a single dose or as two divided doses, the choice being dependent upon both the formulation and the strength used. For adults weighing more than 60 kg the recommended dose is 400 mg daily and for those under 60 kg, 250 mg daily is given. For details of doses in children, see below. Doses of didanosine may need to be amended when given with some other antiretrovirals. For further details see under Interactions, above. Dosage reduction may be necessary in patients with renal (see below) or hepatic impairment, although no specific dose reductions are recommended in patients with hepatic impairment and close monitoring is required.
1. Shelton MJ, et al. Didanosine. Ann Pharmacother 1992; 26: 660–70
2. Lipsky JJ. Zalcitabine and didanosine. Lancet 1993; 341: 30–2
3. Perry CM, Noble S. Didanosine: an updated review of its use in HIV infection. Drugs 1999; 58: 1099–1135
4. Moreno S, et al. Didanosine enteric-coated capsule: current role in patients with HIV-1 infection. Drugs 2007; 67: 1441–62.

Administration in children.

For the treatment of HIV infection in children, didanosine is given daily with other antiretroviral drugs in doses based on body-surface. Doses are taken on an empty stomach. In the USA an oral solution is available for paediatric use:
in children aged between 2 weeks and 8 months the recommended dose is 100 mg/m2 twice daily
in children over 8 months of age the recommended dose is 120 mg/m2 twice daily
In the UK chewable or dispersible tablets or enteric-coated capsules are available for use:
the chewable or dispersible tablets may be given orally to children older than 3 months of age, as either a single dose or as two divided doses, in a dose of 240 mg/m2 daily or 180 mg/m2daily if given with zidovudine
enteric-coated capsules may be given orally to children older than 6 years of age in a dose of 240 mg/m2 daily or 180 mg/m2daily if given with zidovudine

Administration in renal impairment.

Dosage of didanosine should be reduced in patients with renal impairment. The following doses are recommended based on the patient’s creatinine clearance (CC): Adults greater than 60 kg:
CC more than 60 mL/minute: usual adult doses
CC 30 to 59 mL/minute: 200 mg daily as a single dose or in two equally divided doses
CC 10 to 29 mL/minute: 150 mg once daily
CC less than 10 mL/minute: 100 mg once daily
Adults less than 60 kg:
CC more than 60 mL/minute: usual adult doses
CC 30 to 59 mL/minute: 150 mg daily as a single dose or in two equally divided doses
CC 10 to 29 mL/minute: 100 mg once daily
CC less than 10 mL/minute: 75 mg once daily

💊 Preparations

USP 31: Didanosine for Oral Solution; Didanosine Tablets for Oral Suspension.

Proprietary Preparations

Arg.: Aso DDI†; Bandotan†; Dibistic†; Megavir†; Ronvir†; Videx; Austral.: Videx; Austria: Videx; Belg.: Videx; Braz.: Didanox†; Videx; Canad.: Videx; Chile: Videx; Cz.: Videx; Denm.: Videx; Fin.: Videx; Fr.: Videx; Ger.: Videx; Gr.: Videx; Hong Kong: Videx; Hung.: Videx; India: Dinex; Indon.: Videx; Irl.: Videx; Israel: Videx†; Ital.: Videx; Malaysia: Videx; Mex.: Apodasi†; Didasten; Videx; Neth.: Videx; Norw.: Videx; NZ: Videx; Pol.: Videx; Port.: Videx; Rus.: Videx (Видекс); S.Afr.: Videx; Singapore: Videx; Spain: Videx; Swed.: Videx; Switz.: Videx; Thai.: Videx; Turk. : Videx; UK: Videx; USA: Videx; Venez.: Videx. Multi-ingredient: India: Odivir Kit.
Published November 03, 2018.