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DIDANOSINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Didanosine is a synthetic purine nucleoside analogue with activity against Human Immunodeficiency Virus (HIV). Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5-triphosphate (ddATP). The active metabolite inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5-triphosphate (dATP), and by its incorporation into viral DNA. Viral DNA growth is terminated.

Specific Substances

    1) 2,3-dideoxyinosine
    2) ddl
    3) Dideoxyinosine
    4) DDINO
    5) DIDIOXYINOSINE
    6) Molecular formula: C10H12N4O3
    7) CAS 69655-05-6

Available Forms Sources

    A) FORMS
    1) Didanosine is available as 125 mg, 200 mg, 250 mg and 400 mg delayed-release capsules. Didanosine pediatric powder is available as 2 gram and 4 gram bottles of powder for oral solution (final concentration of 10 mg/mL) (Prod Info VIDEX(R) oral powder for solution, 2014; Prod Info didanosine oral delayed-release capsules, 2014; Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012) .
    B) USES
    1) Didanosine is indicated in patients 2 weeks of age or older for the treatment of HIV infection in combination with other antiretroviral agents (Prod Info didanosine oral delayed-release capsules, 2014; Prod Info VIDEX(R) oral powder for solution, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Didanosine is used in the treatment of HIV-1 infection, in combination with other antiretroviral agents.
    B) PHARMACOLOGY: Didanosine terminates HIV RNA to DNA transcription by acting as a substrate for the HIV reverse transcriptase and terminating DNA elongation. Didanosine prevents cell infection, but has no effect on already infected cells.
    C) TOXICOLOGY: Toxicological effects are generally extensions of adverse effects.
    D) EPIDEMIOLOGY: Overdose is uncommon and severe sequelae from acute overdose are rare. Adverse effects and drug interactions, however, are common.
    E) WITH THERAPEUTIC USE
    1) Diarrhea and transaminitis are common. Peripheral neuropathy is dose-dependent. Pancreatitis occurs in 3% to 4% of patients. Hepatic failure/steatosis and lactic acidosis are rare. There is a possible increased risk of coronary heart disease.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There are limited data regarding overdose of didanosine. However, overdose appears to be largely well tolerated with very few reports of severe clinical effects despite 2 decades of availability. Nausea or vomiting, peripheral neuropathy, signs of bone marrow toxicity (ie, anemia, leukopenia, thrombocytopenia), or an increase in liver enzymes have all been reported with chronic toxicity of didanosine.
    2) SEVERE TOXICITY: Severe toxicity has been reported after therapeutic use but not after acute overdose, and may be manifested by pancreatitis, hepatic steatosis, neuropsychiatric abnormalities, or acidosis. Chronic therapeutic administration may lead to mitochondrial toxicity leading to lactic acidosis, with or without hepatic microsteatosis. Pancreatitis, neuropathy, and myopathy often accompany the syndrome. Seizures have been reported. Lactic acidosis has been reported in patients receiving both single and dual nucleoside analogue regimens, including didanosine, for HIV infection. This is thought to cause multiorgan failure and most commonly occurs in persons on prolonged (more than 6 months) therapy.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Therapeutic use of didanosine has been associated with the development of ophthalmic changes including blurred vision, retinal depigmentation, photophobia, and optic neuritis. Other adverse effects include rhinitis, epistaxis, rhinorrhea, sinusitis, congestion, and pharyngitis.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Didanosine has been associated with the development of heart failure, palpitations, dysrhythmias, thrombophlebitis, and vasodilation.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Dyspnea, cough, or bronchitis may occur.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Seizures, peripheral neuropathy, or headache may occur.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Diarrhea is common. Fatal and non-fatal pancreatitis (dose-related) have occurred following therapeutic use.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Elevated liver enzymes and hepatic failure have occurred.
    2) Lactic acidosis and hepatomegaly with steatosis, sometimes fatal, have been reported with the use of didanosine alone or in combination therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Didanosine has been associated with the development of thrombocytopenia and leukopenia.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Dermatologic effects include the development of skin rashes, eczema, impetigo, pruritus, excoriation, sweating, erythema, and Stevens-Johnson syndrome.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Didanosine has been associated with muscle atrophy, myalgia, arthritis, and decreased strength.
    0.2.17) METABOLISM
    A) WITH THERAPEUTIC USE
    1) Hypertriglyceridemia and/or hyperuricemia may occur.
    0.2.20) REPRODUCTIVE
    A) FDA Pregnancy Category B
    B) Didanosine crosses the placenta and appears in amniotic fluid.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor serum electrolytes and hepatic enzymes.
    B) Monitor serum lipase in patients with abdominal pain or severe acidosis.
    C) Lactic acid concentration and serum pH should be monitored in acidotic patients.
    D) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain.
    E) Sources of infection should be sought in patients with neutropenia or significant acidosis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive therapy remains the mainstay of care. Benzodiazepines or antipsychotics may be used for agitation or manic symptoms. Mild transaminitis can be monitored, discontinuation of therapy is not usually necessary. Therapy should be changed for persistently rising transaminases or evidence of hepatic synthetic dysfunction. Nausea and vomiting should be treated with antiemetics. Peripheral neuropathies are generally reversible with drug withdrawal and can be treated with pain management as needed. Asymptomatic elevation of lactic acid without systemic acidemia does not require discontinuation of the medication.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care is the mainstay of care. Aggressive fluid resuscitation should be initiated for severe lactic acidosis. Granulocyte colony stimulating factor may be considered for patients with agranulocytosis complicated by infection. Vasopressors may be necessary in cases with multi-organ failure. Withdrawal of the agent is imperative to improvement in severe adverse reactions. Riboflavin and L-carnitine may be useful in treating nucleoside reverse transcriptase inhibitor (NRTI)-associated lactic acidosis.
    C) DECONTAMINATION
    1) PREHOSPITAL: No prehospital decontamination is indicated. Prehospital care should focus on assessment of vital signs and general supportive care.
    2) HOSPITAL: Activated charcoal may be considered for patients that present early after overdose if they are awake, alert, and willing to drink the charcoal. Gastric lavage has no role in the management of didanosine overdose.
    D) AIRWAY MANAGEMENT
    1) Respiratory depression is not expected with overdose of didanosine. However, coingestants must be considered and airway protection should be employed as needed for airway protection.
    E) ANTIDOTE
    1) There is no specific antidote for didanosine toxicity.
    F) ACIDOSIS
    1) Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Anecdotal evidence suggests that riboflavin and L-carnitine may be useful in reversing NRTI-associated lactic acidosis. Riboflavin has been used at a dose of 50 mg/day orally or intravenously. L-carnitine has been used at a dose of 50 mg/kg/day as a 2-hour infusion divided in 3 doses for patients not receiving dialysis, or a continuous infusion of 100 mg/kg/day in patients receiving dialysis.
    G) ENHANCED ELIMINATION
    1) Hemodialysis would likely remove significant amounts of didanosine given its limited protein binding and small volume of distribution, however patients generally do well with supportive care so hemodialysis is rarely if ever indicated.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Suicidal patients and those with symptoms should be referred to a healthcare facility. Asymptomatic patients with inadvertent ingestion of didanosine can be observed at home.
    2) OBSERVATION CRITERIA: Asymptomatic or mildly symptomatic patients should be observed for 4 to 6 hours, primarily monitoring signs of coingestant toxicity.
    3) ADMISSION CRITERIA: Patients with severe toxicity should be admitted. Patients with severe lactic acidosis, hepatic failure, or renal failure should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Infectious disease should be consulted if a change to anti-retroviral therapy is indicated. Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Failure to consider toxicity of co-medications due to drug-drug interactions. Failure to remove the offending agent in patients with severe adverse drug reactions.
    J) PHARMACOKINETICS
    1) Bioavailability 21% to 43%. Cmax is decreased by 40% as compared with buffered tablet formulation (Tmax of about 0.67 hours for buffered tablets versus 2 hours for delayed-release capsules). Protein binding less than 5%, volume of distribution 1 L/kg, renal excretion 18%, half-life 1.3 to 1.5 hours.
    K) TOXICOKINETICS
    1) No data are available regarding toxicokinetics.
    L) DIFFERENTIAL DIAGNOSIS
    1) Other etiologies of hepatic failure (ie, acetaminophen, iron, carbon tetrachloride, etc.) should be considered. Medical etiologies (ie, portal vein thrombosis, viral hepatitis, hepatic abscess, or Budd-Chiari malformation) should be ruled out in cases of hepatitis. Infection must be ruled out in cases predominated by lactic acidosis and organ dysfunction.

Range Of Toxicity

    A) TOXICITY: At doses 10 times the recommended dose, reported toxicities in adults included pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction.
    B) THERAPEUTIC DOSE: ADULT: Less than 60 kg: 125 mg twice daily OR 250 mg once daily (delayed release); 60 kg or more: 200 mg twice daily OR 400 mg once daily (delayed release). PEDIATRIC: 2 weeks to 8 months of age: 100 mg/m(2) twice daily; 8 months or older: 120 mg/m(2) twice daily.

Clinical Effects

Summary Of Exposure

    A) USES: Didanosine is used in the treatment of HIV-1 infection, in combination with other antiretroviral agents.
    B) PHARMACOLOGY: Didanosine terminates HIV RNA to DNA transcription by acting as a substrate for the HIV reverse transcriptase and terminating DNA elongation. Didanosine prevents cell infection, but has no effect on already infected cells.
    C) TOXICOLOGY: Toxicological effects are generally extensions of adverse effects.
    D) EPIDEMIOLOGY: Overdose is uncommon and severe sequelae from acute overdose are rare. Adverse effects and drug interactions, however, are common.
    E) WITH THERAPEUTIC USE
    1) Diarrhea and transaminitis are common. Peripheral neuropathy is dose-dependent. Pancreatitis occurs in 3% to 4% of patients. Hepatic failure/steatosis and lactic acidosis are rare. There is a possible increased risk of coronary heart disease.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There are limited data regarding overdose of didanosine. However, overdose appears to be largely well tolerated with very few reports of severe clinical effects despite 2 decades of availability. Nausea or vomiting, peripheral neuropathy, signs of bone marrow toxicity (ie, anemia, leukopenia, thrombocytopenia), or an increase in liver enzymes have all been reported with chronic toxicity of didanosine.
    2) SEVERE TOXICITY: Severe toxicity has been reported after therapeutic use but not after acute overdose, and may be manifested by pancreatitis, hepatic steatosis, neuropsychiatric abnormalities, or acidosis. Chronic therapeutic administration may lead to mitochondrial toxicity leading to lactic acidosis, with or without hepatic microsteatosis. Pancreatitis, neuropathy, and myopathy often accompany the syndrome. Seizures have been reported. Lactic acidosis has been reported in patients receiving both single and dual nucleoside analogue regimens, including didanosine, for HIV infection. This is thought to cause multiorgan failure and most commonly occurs in persons on prolonged (more than 6 months) therapy.

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Therapeutic use of didanosine has been associated with the development of ophthalmic changes including blurred vision, retinal depigmentation, photophobia, and optic neuritis. Other adverse effects include rhinitis, epistaxis, rhinorrhea, sinusitis, congestion, and pharyngitis.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Ophthalmic effects seen with therapeutic use of didanosine include retinal depigmentation, photophobia, blurred vision, and optic neuritis. Retinal changes and optic neuritis have been reported in both adults and pediatric patients (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010).
    2) Retinal depigmentation occurred in 4 pediatric patients receiving didanosine at doses above 300 mg/m(2)/day (Prod Info Videx(R), didanosine, 2000). Similar lesions have been reported in children taking didanosine 270 mg/m(2)/day (Whitcup et al, 1992).
    3) Photophobia occurred in 5% of children in phase I trials (Prod Info Videx(R), didanosine, 1996).
    4) CASE REPORT: Administration of didanosine was associated with visual impairment in a 40-year-old man being treated for AIDS. Six weeks after starting didanosine the visual acuity was 3/10 in both eyes. The visual acuity stabilized when didanosine was discontinued for 6 weeks. When didanosine was restarted, the visual acuity decreased to 1/20 in both eyes. The decrease in visual acuity was thought to be caused by optic neuritis because eye exam revealed no changes (Lafeuillade et al, 1991).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Didanosine has been reported to cause epistaxis (13%), rhinitis (48%), rhinorrhea (21%), sinusitis (7%), and congestion (3%) in children during phase I trials (Prod Info Videx(R), didanosine, 2000).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Didanosine has been reported to cause pharyngitis (17%) in children during phase I trials (Prod Info Videx(R), didanosine, 2000).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Didanosine has been associated with the development of heart failure, palpitations, dysrhythmias, thrombophlebitis, and vasodilation.
    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Didanosine was associated with left-ventricular failure in a 33-year-old man. The patient also had cardiomyopathy related to the HIV infection; however, the left-ventricular failure appeared to be exacerbated by the didanosine. This effect is possibly caused by the sodium content of the didanosine formulation (Willocks et al, 1992).
    B) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations, without EKG changes, were reported in 1 of 37 subjects involved in a Phase I twice daily dose-escalation trial (Lambert et al, 1990).
    C) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Phlebitis was noted in 3 of 37 subjects involved in a Phase I twice daily dose-escalation trial. This was resolved with a more dilute solution for intravenous administration (Lambert et al, 1990).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Didanosine has been associated with the induction of dysrhythmias. This adverse effect is believed to be secondary to electrolyte abnormalities (Anon, 1990). Dysrhythmias were reported in 6% of pediatric patients in phase I trials (Prod Info Videx(R), didanosine, 2000).
    E) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Vasodilation was reported in 22% of pediatric patients in phase I trials (Prod Info Videx(R), didanosine, 2000).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dyspnea, cough, or bronchitis may occur.
    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) Didanosine has been reported to cause asthma (21%), cough (85%), dyspepsia (23%), epistaxis (14%), hypoventilation (8%), pharyngitis (14%), rhinitis (48%), rhinorrhea (21%), rhonchi or rales (6%), sinusitis (7%), and congestion (3%) in children during phase I trials (Prod Info Videx(R), didanosine, 2000).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Seizures, peripheral neuropathy, or headache may occur.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Didanosine has been associated with the induction of seizures. This adverse effect is believed to be secondary to electrolyte abnormalities caused by the drug (Anon, 1990).
    b) Three patients receiving more than 9.6 mg/kg/day developed seizures; however, each had an underlying cerebral disorder (HIV dementia, CNS toxoplasmosis, undiagnosed EEG abnormality) (Yarchoan et al, 1990).
    B) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Painful distal symmetrical peripheral neuropathy is a major dose-limiting toxicity of didanosine. It often progresses to severe, opioid-requiring pain. It generally has an abrupt onset and rapid progression. Histologically, axonal degeneration is evident. The frequency is related to didanosine dose and stage of disease (Moore et al, 2000; Prod Info Videx(R), didanosine, 2000; Anon, 1989; Cooley et al, 1990; Lambert et al, 1990; Yarchoan et al, 1990; Schindzielorz et al, 1994). Peripheral neuropathy occurred in 34% of patients in phase I trials receiving less than or equal to 12.5 mg/kg/day and in 51% of patients receiving more than 12.5 mg/kg/day (Prod Info Videx(R), didanosine, 2000). Peripheral neuropathy and pancreatitis are dosing-limiting toxicities of this drug (Moyle & Sadler, 1998)
    b) Moore et al (2000) suggest an incidence of 6.8 cases of peripheral neuropathy per 100 person-years for didanosine therapy alone (Moore et al, 2000).
    c) The painful neuropathic syndrome consists of tingling, burning, or aching in the lower extremities, particularly at nighttime but gradually progressing to interfere with walking, sleep, and routine daily activities. There are no associated neurologic deficits except for occasional diminished vibratory sensation and decreased ankle reflexes (Lambert et al, 1990). The onset of neuropathy ranges from 55 to 201 days after initiation of therapy (Cooley et al, 1990; Lambert et al, 1990). Patients with a history of neuropathy or neurotoxic drug therapy may be at an increased risk of neuropathy during didanosine therapy (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 32% to 55% of patients in phase I trials; dizziness (17%), lethargy (4%), nervousness (27%), and poor coordination (6%) were also reported in pediatric patients (Prod Info Videx(R), didanosine, 2000).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia has been reported in 8% of pediatric patients and 22% of adult patients in phase I trials (Prod Info Videx(R), didanosine, 2000).
    b) Twenty-nine patients maintained for 12 to 21 months at a dose of 9.6 mg/kg/day presented with insomnia. Irritability and anxiety were noted in 13 and 5 patients, respectively, while on maintenance didanosine given at a dose of 9.6 mg/kg/day for 12 to 21 months. There were insufficient data to verify if these complaints were drug-related or merely part of the disease process (Yarchoan et al, 1990).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Diarrhea is common. Fatal and non-fatal pancreatitis (dose-related) have occurred following therapeutic use.
    3.8.2) CLINICAL EFFECTS
    A) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) The major toxicity of didanosine is pancreatitis, which has been fatal in some cases, and has been posted as a warning in the product insert. Pancreatitis is often accompanied by severe lactic acidosis. Frequency of pancreatitis is dose-related, with an incidence in phase 3 adult studies ranging from 1% to 10% with high dose and 1% to 7% with recommended dose. In pediatric studies, pancreatitis occurred in 13% (5/38) patients treated at higher doses (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010). Other nucleoside reverse transcriptase inhibitors have been reported to cause pancreatitis, however, it appears most often following didanosine or stavudine therapy (Frippiat et al, 2000).
    1) Moore et al (2001) reported a risk of pancreatitis in didanosine-treated patients to be 4 fold higher when concurrent hydroxyurea is used (Moore et al, 2001).
    b) Pancreatitis has been reported to occur in 9% of patients in phase I trials when patients were treated at or below the recommended dose (12.5 mg/kg/day); with doses greater than 12.5 mg/kg/day, the incidence of fatality was 0.2% (Anon, 1990). The development of pancreatitis appears to be associated with cumulative dose (Seidlin et al, 1992). Incidence of pancreatitis in the didanosine Expanded Access Program (n=21,198) was reported to be 5.0% (Schindzielorz et al, 1994).
    c) It has been suggested that the development of hypertriglyceridemia may serve as a marker for patients at risk of developing pancreatitis (Tal & Dall, 1993).
    d) A warning has been added to the manufacturers labeling for didanosine about fatal and non-fatal pancreatitis which has occurred at an incidence of 1% to 7% in advanced HIV disease in phase III clinical trials following higher than recommended didanosine doses ((Anon, 1999)).
    e) CASE SERIES: Ninety-five HIV-infected children ranging from 3 months to 18 years of age were observed during didanosine treatment. Seven children (7%) had a total of 10 episodes of clinical pancreatitis. This incidence is comparable to that of adults developing pancreatitis in clinical trials (Butler et al, 1993).
    f) CASE REPORT: A 46-year-old HIV infected male presented to the ED 4 weeks after starting didanosine therapy with complaints of nausea, vomiting, diarrhea, and sharp abdominal pain. He was also taking acyclovir, which he began several months prior to admission. Elevated serum amylase, AST, and LDH were reported. A diagnosis of didanosine-induced acute pancreatitis was made. The patient died approximately 26 hours following initial presentation. Autopsy results revealed cause of death to be acute hemorrhagic pancreatitis (Pelucio et al, 1995).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) The citrate/phosphate buffer used in the didanosine oral solution formulation is thought to be the cause of diarrhea associated with didanosine. The oral solution was associated with diarrhea in 34% of patients in phase 1 adult studies (Prod Info Videx(R), didanosine, 2000). A trial of oral tablets is recommended if the patient develops diarrhea with the buffered powder for oral solution.
    b) Incidences of diarrhea and nausea/vomiting were reported to be 17.2% and 8.3%, respectively, in the didanosine Expanded Access Program (n=21,198) (Schindzielorz et al, 1994).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was reported in 12% to 13% of patients in phase I trials (Prod Info Videx(R), didanosine, 2000).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Didanosine has been reported to cause dyspepsia (23%), in children during phase I trials (Prod Info Videx(R), didanosine, 2000).
    E) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Xerostomia was reported in 8% of patients receiving didanosine in phase I trials (Prod Info Videx(R), didanosine, 2000).
    b) The resting saliva flow rate has been shown to be decreased in AIDS patients receiving didanosine treatment. However, the stimulated saliva flow was not significantly decreased (Dodd et al, 1992).
    F) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain was reported in 22% to 35% of patients in phase I trials. Nausea and vomiting (25%), diarrhea (29%), constipation (13%), and stomatitis (11%) have also been reported in phase I trials (Prod Info Videx(R), didanosine, 2000).
    b) Transient abdominal pain was noted in 15 patients maintained on didanosine 9.6 mg/kg/day for 12 to 21 months (Yarchoan et al, 1990).
    c) A 6 week open-label trial showed that there may be less gastrointestinal side effects, primarily nausea, diarrhea, gas, and abdominal pain, when the enteric-coated formulation of didanosine is used. Enteric-coated didanosine is absorbed in the small intestine instead of in the stomach (Kunches et al, 2001).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Elevated liver enzymes and hepatic failure have occurred.
    2) Lactic acidosis and hepatomegaly with steatosis, sometimes fatal, have been reported with the use of didanosine alone or in combination therapy.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes, primarily serum aminotransferase, were noted with didanosine in 13 of 37 patients in a twice-daily dose-escalation trial and in 5 of 34 patients on a once-daily regimen (Cooley et al, 1990; Lambert et al, 1990).
    B) LARGE LIVER
    1) WITH THERAPEUTIC USE
    a) Lactic acidosis and hepatomegaly with steatosis, sometimes fatal, have been reported following the use of antiretroviral nucleoside analogues alone or in combination therapies, including didanosine. Women appear to be at more increased risk for these effects (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010; (Anon, 2001)) .
    C) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 36-year-old male AIDS patient died of fulminant hepatic failure associated with didanosine (Lai et al, 1991).
    b) Liver failure, of unknown etiology, has occurred in less than 0.2% of patients in phase I trials (Prod Info Videx(R), didanosine, 2000).
    D) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) Therapeutic didanosine has been reported to induce hepatitis with hepatic necrosis and inflammation. Severe hepatic necrosis is predominantly reported in children. In most cases, hepatic injury has been described as steatosis with minimal hepatic necrosis (Ware et al, 2000).
    b) CASE REPORT: Ware et al (2000) describe a patient who developed clinically severe liver injury while on didanosine combination (including hydroxyurea) therapy. On re-exposure to didanosine, liver disease recurred. Liver biopsy revealed extensive hepatocellular necrosis with collapse-fibrosis and inflammation. The role that hydroxyurea may have played in this reaction is unknown (Ware et al, 2000).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Lactic acidosis and hepatomegaly with steatosis, which may be fatal, has been reported with the therapeutic use of NRTIs alone or in combination, including didanosine. Many of these cases have been reported in women (Falco et al, 2002; Coghlan et al, 2001; Masia et al, 2005; Prod Info VIDEX(R) EC delayed-release oral capsules, 2008). Cumulative exposure to didanosine or other NRTIs may increase the risk for symptomatic lactic acidosis. The lactic acidosis is considered to be type B lactic acidosis (eg, not resulting from tissue hypoxia (type A)).
    b) Hyperlactatemia from NRTIs generally manifest in 1 of 3 forms (Falco et al, 2002):
    1) Fulminant lactic acidosis, often associated with gastrointestinal symptoms and respiratory distress.
    2) Symptomatic hyperlactatemia often presents with nausea, vomiting, weakness, fatigue, and weight loss.
    3) Asymptomatic hyperlactatemia, which is the most common form occurring in up to 21% of patients on NRTIs.
    c) CASE REPORT: A 31-year-old male AIDS patient presented to the ED with complaints of dyspnea. Medications included zidovudine (500 mg/day) and didanosine (400 mg/day), which were added to his therapy regimen 5 months previously. Other medications included fluconazole, acetaminophen and monthly aerosolized pentamidine. Laboratory results showed an elevated serum lactate (13.7 mEq/L) and an anion gap of 28 mEq/L. Hemodialysis was initiated when IV sodium bicarbonate and thiamine failed to reverse the acidosis. Muscle biopsy results and Southern blot analysis of muscle tissue, which revealed a marked reduction of mitochondrial DNA, was consistent with an adverse antiviral drug effect. Both zidovudine and didanosine were stopped. Within 4 weeks serum lactate levels returned to normal (Roy et al, 1999).
    d) CASE REPORT: Three cases of fatal lactic acidosis, with and without pancreatitis, were reported in pregnant women taking stavudine and didanosine in combination with other antiretroviral drugs. Several nonfatal cases in pregnant women (with and without pancreatitis) were also reported. Although it has been suggested that women may be at an increased risk of developing lactic acidosis and liver toxicity, it is unclear if pregnancy potentiates these known adverse events ((Anon, 2001)). The FDA has issued a warning concerning an increased risk of severe or fatal lactic acidosis in pregnant women who take the combination of HIV drugs, stavudine and didanosine, with other antiretroviral agents.

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Didanosine has been associated with the development of thrombocytopenia and leukopenia.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia developed in 3 of the 37 patients while receiving didanosine at doses of 1.6, 7, and 66 mg/kg/day.
    b) CASE REPORT: Didanosine was associated with thrombocytopenia in a 42-year-old male with AIDS. Prior to the episode of thrombocytopenia the patient had been treated with alternating courses of zidovudine and didanosine. During the last course of didanosine the platelet count dropped to 16 X 10(9)/L. Didanosine was discontinued and the platelet count returned to normal within 3 weeks. Zidovudine was started again without thrombocytopenia (Lor & Liu, 1993).
    B) HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Ecchymosis (15%), hemorrhage (10%), and petechiae (7%) were reported in phase I trials (Prod Info Videx(R), didanosine, 2000).
    b) When light-density nonadherent bone marrow cells from 3 normal subjects were cultured in vitro with various concentrations of didanosine, dose-dependent inhibition of myelopoiesis and erythropoiesis occurred only at very high concentrations of didanosine (Johnson et al, 1988). Very minimal inhibition of bone marrow progenitor cells was demonstrated at didanosine concentrations of 5 to 10 micromoles.
    C) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Results of the didanosine Expanded Access Program, assessing the safety of didanosine in 21,198 patients refractory to zidovudine, demonstrated that patients with CD4 lymphocyte counts of <0.10 x 10(9)/L or with a diagnosis of AIDS were less tolerant of didanosine and more likely to develop adverse clinical reactions and myelosuppression than other patients (Schindzielorz et al, 1994). Leukopenia was documented in 8% of patients taking didanosine.

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dermatologic effects include the development of skin rashes, eczema, impetigo, pruritus, excoriation, sweating, erythema, and Stevens-Johnson syndrome.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) MACULOPAPULAR RASHES were noted in 2 of 37 subjects of a Phase I twice-daily dose-escalation trial (Lambert et al, 1990). These resolved spontaneously and did not require discontinuation of the drug.
    b) A patient receiving a single daily dose of didanosine of 4 mg/kg/day discontinued treatment for resolution of RASHES which progressed with a rechallenge at 2 mg/kg/day (Cooley et al, 1990).
    c) Two patients had mild erythematous maculopapular eruptions while on maintenance dose of didanosine of 9.6 mg/kg/day for 12 to 21 months (Yarchoan et al, 1990).
    d) Impetigo (6%), eczema (12%), rash or pruritus (70%), excoriation (4%), sweating (71%), and erythema (4%) were reported in pediatric patients during phase I trials (Prod Info Videx(R), didanosine, 2000).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Stevens-Johnson syndrome was reported in a 35-year-old male being treated with didanosine for HIV infection. The symptoms developed 21 days after didanosine was initiated and resolved rapidly after it was discontinued (Parneix-Spake et al, 1992).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Didanosine has been associated with muscle atrophy, myalgia, arthritis, and decreased strength.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Muscle atrophy (8%), myalgia (9%), arthritis (11%), and decreased strength (6%) were reported in pediatric patients during phase I trials. Myalgia and arthritis occurred in 13% and 11% of adults, respectively (Prod Info Videx(R), didanosine, 2000).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ABNORMAL GLUCOSE TOLERANCE TEST
    1) WITH THERAPEUTIC USE
    a) Seven of 151 patients in one study developed abnormal serum glucose. Glucose determinations prior to the study were within normal limits for all patients. Standard 75 gram glucose tolerance test indicated diabetes mellitus in 6 of the 7 patients. Didanosine was discontinued and glucose tolerance returned to normal in 3 of the patients. The remaining 4 patients continued to have mildly abnormal glucose tolerance, not requiring treatment (Moyle et al, 1993).

Reproductive

    3.20.1) SUMMARY
    A) FDA Pregnancy Category B
    B) Didanosine crosses the placenta and appears in amniotic fluid.
    3.20.2) TERATOGENICITY
    A) PLACENTAL BARRIER
    1) Didanosine crosses the placenta and appears in amniotic fluid.
    2) After a single oral dose of 375 mg in 2 women, maternal blood levels were 295 and 629 ng/mL; corresponding fetal blood levels were 42 and 121 ng/mL, amniotic fluid levels were less than 5 ng/mL and 135 ng/mL, respectively (Pons et al, 1991).
    a) Fetal effects of the drug are not known.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Didanosine is classified as FDA Pregnancy Category B (Prod Info Videx(R), didanosine, 2000).
    B) PLACENTAL BARRIER
    1) Didanosine crosses the placenta by simple diffusion and appears in amniotic fluid in rat studies (Taylor & Low-Beer, 2001; Prod Info Videx(R), didanosine, 2000).
    C) ACIDOSIS LACTIC
    1) The FDA has issued a warning concerning an increased risk of severe or fatal lactic acidosis in pregnant women who take the combination of HIV drugs, stavudine and didanosine, with other antiretroviral agents. Pancreatitis is also a well-documented complication of stavudine and didanosine.
    a) Three cases of fatal lactic acidosis, with and without pancreatitis, were reported in pregnant women taking stavudine and didanosine in combination with other antiretroviral drugs. Several nonfatal cases in pregnant women (with and without pancreatitis) were also reported. Although it has been suggested that women may be at an increased risk of developing lactic acidosis and liver toxicity, it is unclear if pregnancy potentiates these known adverse events ((Anon, 2001)).
    D) ANIMAL STUDIES
    1) RABBITS - In rabbit studies, no effect on fertility and no harm to fetuses was seen at didanosine doses of greater than 10 times that used in human therapy (Taylor & Low-Beer, 2001).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether didanosine is excreted in human milk. Rat studies indicate that didanosine and/or metabolites do appear in rat milk. Nursing mothers taking didanosine are advised to discontinue breast feeding (Prod Info Videx(R), didanosine, 2000).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) No significant increase in neoplastic lesions in mice or rats were seen at maximally tolerated doses (Prod Info Videx(R), didanosine, 2000). In life-long rodent didanosine studies, no evidence of carcinogenicity was noted (Taylor & Low-Beer, 2001).

Genotoxicity

    A) Tests indicate that didanosine is not mutagenic at pharmacologic doses (Prod Info Videx(R), didanosine, 2000). No mutagenicity has been reported in bacterial assays; effects on mammalian cells have been seen only at higher concentrations (Taylor & Low-Beer, 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes and hepatic enzymes.
    B) Monitor serum lipase in patients with abdominal pain or severe acidosis.
    C) Lactic acid concentration and serum pH should be monitored in acidotic patients.
    D) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain.
    E) Sources of infection should be sought in patients with neutropenia or significant acidosis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes and hepatic enzymes.
    2) Monitor serum lipase in patients with abdominal pain or severe acidosis.
    3) Lactic acid concentration and serum pH should be monitored in acidotic patients.
    4) Serum potassium should be monitored in patients taking didanosine, particularly in those with pre-existing diarrhea or low baseline potassium (Katlama et al, 1991).
    B) HEMATOLOGIC
    1) The following hematologic tests should be monitored in patients receiving didanosine: hemoglobin, neutrophil count, WBC, and platelets.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain.

Methods

    A) CHROMATOGRAPHY
    1) Reversed-phase high-performance liquid chromatography has been used to quantitate didanosine in human plasma and urine (Knupp et al, 1990).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe toxicity should be admitted. Patients with severe lactic acidosis, hepatic failure, or renal failure should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Suicidal patients and those with symptoms should be referred to a healthcare facility. Asymptomatic patients with inadvertent ingestion of didanosine can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Infectious disease should be consulted if a change to anti-retroviral therapy is indicated. Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Asymptomatic or mildly symptomatic patients should be observed for 4 to 6 hours, primarily monitoring signs of coingestant toxicity.

Monitoring

    A) Monitor serum electrolytes and hepatic enzymes.
    B) Monitor serum lipase in patients with abdominal pain or severe acidosis.
    C) Lactic acid concentration and serum pH should be monitored in acidotic patients.
    D) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain.
    E) Sources of infection should be sought in patients with neutropenia or significant acidosis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital decontamination is indicated. Prehospital care should focus on assessment of vital signs and general supportive care.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There are no specific antidotes for antiretroviral agents. Seizures may rarely occur and should be treated aggressively. Cardiac failure has been reported and cardiac monitoring is recommended. Dose-related pancreatitis, which has been fatal in some cases, and hepatic dysfunction, may occur. Monitor liver function and serum amylase. Monitor for signs of peripheral neuropathy following overdose.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) MONITORING OF PATIENT
    1) Monitor serum electrolytes and hepatic enzymes.
    2) Monitor serum lipase in patients with abdominal pain or severe acidosis.
    3) Lactic acid concentration and serum pH should be monitored in acidotic patients.
    4) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain.
    5) Sources of infection should be sought in patients with neutropenia or significant acidosis.
    D) TRANSFUSION
    1) In the presence of bone marrow suppression, transfusions and protective measures for granulocytopenia may be needed until recovery.
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    E) ACIDOSIS
    1) Untreated patients with lactic acidosis may develop confusion, hypotension, coma, and circulatory collapse.
    2) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    3) Monitor serum sodium to avoid overload. Increase minute ventilation in intubated patients.
    4) RIBOFLAVIN: Fouty et al (1998) have proposed a riboflavin deficiency in AIDS patients taking these drugs and developing lactic acidosis and hepatic steatosis (Fouty et al, 1998). These authors have treated 3 patients with this syndrome with riboflavin 50 mg and reported return of serum lactate levels to normal. Other authors have reported resistant lactic acidosis which improved after treatment with riboflavin 50 mg/day orally or intravenously (Shiber, 2005; Luzzati et al, 1999).
    5) L-CARNITINE: Preliminary data from a pilot study of 6 patients suggested that L-carnitine may be helpful for patients with symptomatic nucleoside-analog-related lactic acidosis (Claessens et al, 2003). The dose used by these authors was L-carnitine 50 milligrams/kilogram/day as a 2 hour infusion 3 times/day in patients not receiving dialysis. For patients receiving continuous hemodiafiltration the dose was 100 mg/kg/day by continuous infusion.
    F) CONSULTATION
    1) HOTLINE: Health and Human Services (HHS) has launched the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline), a national toll-free hotline for assisting health care providers counsel and treat health care workers with job-related exposure to blood-borne diseases and infections, including hepatitis and HIV infection. The toll free number is: 1-888-448-4911 ((Anon, 1997)).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis would likely remove significant amounts of didanosine given its limited protein binding and small volume of distribution, however patients generally do well with supportive care so hemodialysis is rarely if ever indicated.
    2) Approximately 20% of total body didanosine is removed by 4 hours of hemodialysis (Morse et al, 1993). The manufacturer reports some clearance of didanosine via hemodialysis, with the drug having low plasma protein binding (<5%) (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010).
    B) PERITONEAL DIALYSIS
    1) Didanosine is NOT dialyzable by peritoneal dialysis (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010).

Range Of Toxicity

Summary

    A) TOXICITY: At doses 10 times the recommended dose, reported toxicities in adults included pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction.
    B) THERAPEUTIC DOSE: ADULT: Less than 60 kg: 125 mg twice daily OR 250 mg once daily (delayed release); 60 kg or more: 200 mg twice daily OR 400 mg once daily (delayed release). PEDIATRIC: 2 weeks to 8 months of age: 100 mg/m(2) twice daily; 8 months or older: 120 mg/m(2) twice daily.

Therapeutic Dose

    7.2.1) ADULT
    A) DELAYED-RELEASE CAPSULES AND ENTERIC-COATED BEADLETS
    1) 20 KG TO LESS THAN 25 KG: 200 mg once daily (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    2) 25 KG TO LESS THAN 60 KG: 250 mg once daily (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    3) 60 KG OR GREATER: 400 mg once daily (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    B) POWDER FOR SOLUTION
    1) 60 KG OR GREATER: 200 mg twice daily OR 400 mg once daily in patients requiring once-daily dosing (Prod Info VIDEX(R) oral powder for solution, 2014)
    2) LESS THAN 60 KG: 125 mg twice daily OR 250 mg once daily in patients requiring once-daily dosing (Prod Info VIDEX(R) oral powder for solution, 2014)
    7.2.2) PEDIATRIC
    A) DELAYED-RELEASE CAPSULES AND ENTERIC-COATED BEADLETS
    1) 2 WEEKS OR OLDER
    a) UNDER 20 KG: Dosage recommendations cannot be made (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    b) 20 KG TO LESS THAN 25 KG: 200 mg once daily (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    c) 25 KG TO LESS THAN 60 KG: 250 mg once daily (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    d) 60 KG OR GREATER: 400 mg once daily (Prod Info VIDEX(R) EC oral delayed-release capsules, enteric-coated beadlets, 2012; Prod Info didanosine oral delayed-release capsules, 2014)
    B) POWDER FOR SOLUTION
    1) LESS THAN 2 WEEKS: Dosing recommendations cannot be made (Prod Info VIDEX(R) oral powder for solution, 2014)
    2) 2 WEEKS TO 8 MONTHS: 100 mg/m(2) twice daily (Prod Info VIDEX(R) oral powder for solution, 2014)
    3) 8 MONTHS AND OLDER: 120 mg/m(2) twice daily; MAX: 125 mg twice daily (Prod Info VIDEX(R) oral powder for solution, 2014)

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Doses administered at 10 times the recommended daily doses resulted in some patients experiencing pancreatitis, peripheral neuropathies, diarrhea, hyperuricemia, and increased liver function tests. Pancreatitis is the major clinical toxic effect, and has been fatal in some cases (Prod Info VIDEX(R) EC delayed-release oral capsules, enteric-coated beadlets, 2010).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) >2 g/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) >2 g/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Didanosine, a purine nucleoside analogue, inhibits HIV replication in vitro in both T cells and monocytes (Lambert et al, 1990; Perno et al, 1989). Didanosine is converted within the target cell to the active metabolite, 2',3'-dideoxyadenosine-5'-triphosphate (ddATP). ddATP binds to the triphosphate binding site of the reverse transcriptase complex and functions as a chain terminator of proviral DNA synthesis (Prod Info didanosine oral delayed-release capsules, 2014).

Physicochemical

Physical Characteristics

    A) Didanosine is a white crystalline powder. It is unstable in acidic solutions (Prod Info Videx(R), didanosine, 2000).

Ph

    A) pH approximately 6 at 25 degrees C and in aqueous solution of 27.3 mg/mL (Prod Info Videx(R), didanosine, 2000).

Molecular Weight

    A) 236.2 (Prod Info Videx(R), didanosine, 2000)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Anon: "Compassionate" release of DDI. Lancet 1989; 2:1079-1080.
    3) Anon: Dear Health Care Provider (letter). U.S. Food and Drug Administration. Rockville, MD, USA. 1999. Available from URL: http://ww.fda.gov. As accessed Accessed November 23, 1999.
    4) Anon: FDA Talk Paper: FDA/Bristol Myers Squibb issues caution for HIV combination therapy with Zerit and Videx in pregnant women. U.S. Food and Drug Administration. Rockville, MD, USA. 2001. Available from URL: http://www.fda.gov/bbs/topics/ANSWERS/ANS01063.html. As accessed Accessed January 8, 2001.
    5) Anon: HHS launches national toll-free hotline for clinicians reporting exposure to blood-borne pathogens. United States Department of Health and Human Services. Washington, DC, USA. 1997. Available from URL: http://www.dhhs.gov. As accessed Accessed December 5, 1997.
    6) Anon: NIAID updates dideoxyinosine toxicity profile, suggests ways to reduce risk of pancreatitis. Clin Pharm 1990; 9:832-838.
    7) Balis FM, Pizzo PA, & Butler KM: Clinical pharmacology of 2',3'-dideoxyinosine in human immunodeficiency virus-infected children. J Infect Dis 1992; 165:99-104.
    8) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    9) Blanchard JN, Wohlfeiler M, Canas A, et al: Pancreatitis treated with didanosinde and tenofovir disoproxil fumarate. Clin Infect Dis 2003; 37:e57-e62.
    10) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    11) Butler KM, Husson RN, & Balis FM: Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 324:137-144.
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