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ZIDOVUDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zidovudine (formerly called azidothymidine) is a systemic antiviral agent used in the therapy of human immunodeficiency virus (HIV). Zidovudine is a pyrimidine nucleoside analog.

Specific Substances

    1) 3'-azido-3'-deoxythymidine
    2) Azidothymidine
    3) AZT
    4) BW-A509
    5) Compound S
    6) Thymidine, 3'-azido-3'-deoxy-
    7) Molecular Formula: C10-H13-N5-O4
    8) CAS 30516-87-1
    9) A509U, BW
    10) BW A590U
    11) BWA509U
    1.2.1) MOLECULAR FORMULA
    1) C10H13N5O4

Available Forms Sources

    A) FORMS
    1) Retrovir(R) is available as 100 mg capsules, and 300 mg tablets, 50 mg/5 mL syrup, and single use vials containing 10 mg/mL of zidovudine (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    2) Combination products include: Combivir(R) tablets with each tablet containing 150 mg lamivudine and 300 mg zidovudine; Trizivir(R) tablets with each tablet containing 300 mg abacavir sulfate, 150 mg lamivudine and 300 mg zidovudine (Prod Info COMBIVIR oral tablets, 2015; Prod Info TRIZIVIR oral tablets, 2015).
    B) USES
    1) Zidovudine, a nucleoside analogue antiretroviral agent, is used in combination with other antiretroviral agents and is approved for treatment of HIV infection (Prod Info COMBIVIR oral tablets, 2015; Prod Info TRIZIVIR oral tablets, 2015; Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 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: Zidovudine is used in the treatment of HIV-1 infection, in combination with other antiretroviral agents.
    B) PHARMACOLOGY: Zidovudine terminates HIV RNA to DNA transcription by acting as a substrate for the HIV reverse transcriptase and terminating DNA elongation. Zidovudine 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) Macrocytosis occurs in 90% of patients. Anemia and neutropenia are common. Hepatotoxicity/steatosis, lactic acidosis, and rhabdomyolysis are rare.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There are limited data regarding overdose of zidovudine. However, overdose appears to be largely well tolerated with very few reports of severe clinical effects despite over 2 decades of availability. Nausea or vomiting, neurologic symptoms (ie, ataxia, lethargy, nystagmus, peripheral neuropathy), signs of bone marrow toxicity (ie, anemia, leukopenia, thrombocytopenia), or an increase in liver enzymes have all been reported with in zidovudine overdose or chronic toxicity.
    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. Severe neuropsychiatric effects (ie, seizures and mania) have been reported. Lactic acidosis has been reported in patients receiving both single and dual nucleoside analogue regimens, including zidovudine, for HIV infection. This is thought to cause multiorgan failure and most commonly occurs in persons on prolonged (more than 6 months) therapy.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported following the therapeutic use of zidovudine.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Seizures have been rarely reported following therapeutic use, and have occurred after overdose.
    2) Headache was experienced in a patient who took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified.
    3) Fatigue was experienced in a patient who took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Spontaneous nausea and vomiting may occur following overdose.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatotoxicity has been reported during therapeutic use; it tends to appear after several weeks of therapy. A syndrome of fatal lactic acidosis and hepatic failure has been reported after several months of therapy.
    0.2.11) ACID-BASE
    A) WITH THERAPEUTIC USE
    1) Severe lactic acidosis, refractory to bicarbonate infusions, has been reported as an adverse effect of zidovudine, after several months of therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) The most common dose-related adverse effect is bone marrow suppression, resulting in granulocytopenia and macrocytic anemia.
    B) WITH POISONING/EXPOSURE
    1) Acute overdoses up to 50 grams have resulted in transient, non-severe hematologic changes.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Transverse nail pigmentation has been reported.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Myalgia has been reported following therapeutic use in about 8% of patients; however, myopathy has been reported in AIDS patients not receiving zidovudine, making the connection to zidovudine questionable.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Manic syndrome has been reported during therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Passive diffusion across the placenta occurs following zidovudine dosing in pregnancy. Limited data suggests that there is no increased incidence of congenital abnormalities in infants born to women receiving antepartum zidovudine therapy. Zidovudine has been well-tolerated in pregnant women with no adverse effects to the fetus.
    0.2.21) CARCINOGENICITY
    A) Extremely large doses have been associated with vaginal neoplasms in mice and rats; the significance in humans is not known.

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. 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 zidovudine overdose.
    D) AIRWAY MANAGEMENT
    1) Respiratory depression is not expected with overdose of zidovudine. 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 zidovudine 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 and whole bowel irrigation have no role in the management of zidovudine overdose.
    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 zidovudine 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 64%, protein binding less than 38%, volume of distribution 1.6 L/kg, extensive hepatic metabolism, renal excretion 14%, half-life 0.5 to 3 hours.
    K) TOXICOKINETICS
    1) In one case of massive overdose, elimination half-life was 1 hour.
    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: Limited overdose data. Acute overdoses of up to 50 g have been survived by both adults and children with only adverse effects of fatigue, headache and vomiting reported.
    B) THERAPEUTIC DOSE: ADULT: 200 mg orally 3 times daily OR 300 mg orally twice daily; 1 mg/kg/dose IV 5 or 6 times daily. PEDIATRIC (at least 4-weeks-old): 4 kg to less than 9 kg: 12 mg/kg orally twice daily OR 8 mg/kg orally 3 times daily; 9 kg to less than 30 kg: 9 mg/kg orally twice daily OR 6 mg/kg orally 3 times daily; 30 kg or more: 300 mg orally twice daily OR 200 mg orally 3 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Zidovudine is used in the treatment of HIV-1 infection, in combination with other antiretroviral agents.
    B) PHARMACOLOGY: Zidovudine terminates HIV RNA to DNA transcription by acting as a substrate for the HIV reverse transcriptase and terminating DNA elongation. Zidovudine 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) Macrocytosis occurs in 90% of patients. Anemia and neutropenia are common. Hepatotoxicity/steatosis, lactic acidosis, and rhabdomyolysis are rare.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There are limited data regarding overdose of zidovudine. However, overdose appears to be largely well tolerated with very few reports of severe clinical effects despite over 2 decades of availability. Nausea or vomiting, neurologic symptoms (ie, ataxia, lethargy, nystagmus, peripheral neuropathy), signs of bone marrow toxicity (ie, anemia, leukopenia, thrombocytopenia), or an increase in liver enzymes have all been reported with in zidovudine overdose or chronic toxicity.
    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. Severe neuropsychiatric effects (ie, seizures and mania) have been reported. Lactic acidosis has been reported in patients receiving both single and dual nucleoside analogue regimens, including zidovudine, for HIV infection. This is thought to cause multiorgan failure and most commonly occurs in persons on prolonged (more than 6 months) therapy.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported following the therapeutic use of zidovudine.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: Chills and fever have been reported in 10% of patients receiving lamivudine plus zidovudine, and in 12% receiving zidovudine alone (Prod Info EPIVIR(R) oral tablets, solution, 2008).

Heent

    3.4.3) EYES
    A) NYSTAGMUS
    1) WITH POISONING/EXPOSURE
    a) Nystagmus was noted for 48 hours after ingestion of 10 to 20 grams, however phenobarbital and triazolam were coingested (Spear et al, 1988).
    3.4.4) EARS
    A) TINNITUS
    1) WITH POISONING/EXPOSURE
    a) Tinnitus was experienced in a patient that took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified (Gorman et al, 1992).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASAL SYMPTOMS
    a) ZIDOVUDINE/LAMIVUDINE: Nasal signs and symptoms have been reported in 20% of adult patients receiving lamivudine plus zidovudine therapy; 11% of patients receiving zidovudine alone experienced these adverse effects (Prod Info EPIVIR(R) oral tablets, solution, 2008).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Zidovudine has been reported to rarely cause dilated cardiomyopathy (Carr & Cooper, 2000).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CARDIOMYOPATHY
    a) RATS/MICE: High-dose zidovudine has been shown to cause mitochondrial cardiomyopathy in rats and a worsened cardiac dysfunction in adult mice with AIDS. Alterations in steady-state mitochondrial DNA and RNA in affected tissues correlated with molecular evidence of cardiac remodeling (Lewis, 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) ZIDOVUDINE/LAMIVUDINE: Cough has been reported in 18% of adult patients receiving lamivudine plus zidovudine as compared to 13% in patients receiving zidovudine alone (Prod Info EPIVIR(R) oral tablets, solution, 2008).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Seizures have been rarely reported following therapeutic use, and have occurred after overdose.
    2) Headache was experienced in a patient who took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified.
    3) Fatigue was experienced in a patient who took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 41-year-old man with AIDS developed a severe headache 48 hours after initiation of zidovudine, was later found unresponsive, and had tonic-clonic focal seizure activity. Symptoms resolved over 48 hours and recurred 72 hours after reintroduction of the drug. Focal seizures were unresponsive to intravenous lorazepam and phenytoin (Hagler & Frame, 1986).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A single grand mal seizure was reported in a 35-year-old man 3 hours after ingestion of 36 g (Routy et al, 1989).
    b) CASE REPORT: A 17-day-old healthy girl born to a HIV-1-infected mother was admitted to the hospital with seizures, neutropenia, anemia and sepsis. It was noted on admission that patient had received a 10-fold incorrect dose (received 20 mg/kg every 6 hours for 17 days instead of 0.2 mL/kg every 6 hours) of zidovudine. Her hospital course was complicated by severe Streptococcus agalactiae meningo-encephalitis with the development of severe cerebral palsy, salt wasting syndrome, and hypothermia. It was presumed that ZDV-induced neutropenia facilitated the patient's development of bacterial sepsis. Following long term care, the patient died at 8 months of age of ab ingestis pneumonia (Manini et al, 2007).
    B) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Grand mal seizures were reported 48 hours after initiation of zidovudine in a 46-year-old nonalcoholic man with AIDS. Autopsy findings were typical of acute Wernicke's encephalopathy (Davtyan & Vinters, 1987).
    C) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) Ataxia was noted for 48 hours after ingestion of 10 to 20 grams in combination with phenobarbital and triazolam (Spear et al, 1988).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Clinical trials have shown CNS effects of headache, malaise, and fatigue to be common adverse effects of zidovudine therapy (Gartland, 2001).
    2) WITH POISONING/EXPOSURE
    a) Following acute overdoses of up to 50 grams in both adults and children, with no fatalities, some patients experienced nonspecific CNS symptoms, including headache, dizziness, drowsiness, lethargy, and confusion. All patients recovered uneventfully (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010; Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ZIDOVUDINE/LAMIVUDINE: Headache is a common effect, occurring in 35% of patients on combination lamivudine and zidovudine, and 27% on zidovudine monotherapy (Prod Info EPIVIR(R) oral tablets, solution, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Headache was experienced in a patient who took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified (Gorman et al, 1992).
    F) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Fatigue was experienced in a patient who took an overdose of zidovudine, in combination with ketoconazole. The amount of zidovudine and ketoconazole ingested were not specified (Gorman et al, 1992).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Spontaneous nausea and vomiting may occur following overdose.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common side effects of zidovudine therapy, occurring in 66 of 145 (46%) of AIDS patients during clinical trials (Richman et al, 1987) Gartland, 2001).
    b) ZIDOVUDINE/LAMIVUDINE: Nausea has occurred in 33% of patients treated with lamivudine plus zidovudine and 29% of zidovudine mono therapy patients in one study (Prod Info EPIVIR(R) oral tablets, solution, 2008).
    2) WITH POISONING/EXPOSURE
    a) Following acute overdoses of up to 50 grams, the only consistent finding was spontaneous or induced nausea and vomiting (Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    b) Spontaneous vomiting occurred in a 36-year-old man following ingestion of a handful of ketoconazole and zidovudine (Gorman et al, 1995).
    B) ULCER OF ESOPHAGUS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Esophageal ulceration was associated with ingestion of zidovudine capsules without accompanying fluid bolus while lying in bed in the early morning hours in 3 patients with AIDS (Edwards et al, 1990).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatotoxicity has been reported during therapeutic use; it tends to appear after several weeks of therapy. A syndrome of fatal lactic acidosis and hepatic failure has been reported after several months of therapy.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevations in liver enzymes (aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase) were reported in patients after several weeks of receiving zidovudine for AIDS (Melamed et al, 1987; Bessen et al, 1988; Rachlis & Fanning, 1993).
    b) ZIDOVUDINE/LAMIVUDINE: Increased liver enzymes (5 times the upper limit) have been reported equally in patients receiving lamivudine plus zidovudine as compared to zidovudine alone. This is a small percent of patients, but may increase in overdose cases (Prod Info EPIVIR(R) oral tablets, solution, 2008).
    c) ZIDOVUDINE/ZALCITABINE: Two nurses, receiving zidovudine and zalcitabine for prophylaxis following needlestick injuries, developed elevated liver enzymes after 3 weeks of therapy associated with pruritic rashes and lymphocytopenia (Henry et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) Transient increases in AST and ALT were noted after inadvertent ingestion of twice the recommended therapeutic dose for 16 days (500 mg 5 times/day) (Staszewski et al, 1989).
    b) INFANT: CASE REPORT: A healthy 4-day-old infant (3.3 kg at birth) born to an HIV-infected mother developed an elevated ALT level (66 U/L (normal; 5 to 40 U/L)), mild acidosis, elevated serum lactate, and persistent neutropenia after he was administered 2 inadvertent 10-fold overdoses of oral zidovudine (AZT) totaling 134 mg (40.6 mg/kg). At presentation to the emergency department his vital signs were normal. He was admitted for observation and discharged to home within 24 hours when his serum lactate level normalized. At discharge he was restarted on AZT prophylaxis. Borderline neutropenia persisted for approximately 5 weeks during his 6-week course of therapy (Livshits et al, 2011).
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Acute cholestatic hepatitis was reported while on zidovudine and with rechallenge (Dubin & Braffman, 1989).
    C) LARGE LIVER
    1) WITH THERAPEUTIC USE
    a) A syndrome of zidovudine-induced fatal lactic acidosis and hepatic failure has been reported following several months of therapy with zidovudine. One report describes 2 patients who initially presented with abdominal complaints and weakness. Markedly enlarged livers were shown on abdominal ultrasounds. Both patients developed severe lactic, metabolic acidosis and progressively deteriorated. Autopsies revealed livers to be significantly enlarged with severe macrovesicular steatosis (Sundar et al, 1997).
    b) The manufacturer has issued a warning concerning lactic acidosis and severe hepatomegaly with steatosis, including fatalities, following the use of zidovudine alone or in combination with other antiretroviral drugs (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010; Prod Info Combivir(R), lamivudine and zidovudine, 2002; Prod Info Trizivir(R), abacavir sulfate, lamivudine, and zidovudine, 2002; Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).

Acid-Base

    3.11.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Severe lactic acidosis, refractory to bicarbonate infusions, has been reported as an adverse effect of zidovudine, after several months of therapy.
    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) A syndrome of nucleoside-induced potentially fatal lactic acidosis, in the absence of hypoxemia, and severe hepatomegaly with steatosis has been reported in the literature. Patients generally present with weakness, malaise, abdominal complaints, tachypnea or dyspnea (Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    1) In one report, 2 patients are described with a probable syndrome of zidovudine- induced fatal lactic acidosis and hepatic steatosis leading to hepatic failure. In 1 patient, a severe metabolic acidosis (pH, 7.16), with an anion gap due to L-lactate accumulation (29.4 mmol/L), was noted. The other patient was noted to have severe metabolic acidosis with anion gap of 33. Acidosis was refractory to sodium bicarbonate therapy (Sundar et al, 1997).
    b) INCIDENCE: CHILDREN: In a prospective study of 80 HIV-infected children (ages 9 months to 17 years) receiving antiretroviral treatment, 14 developed hyperlactatemia (elevated lactate and alanine concentrations, obtained at clinic visits every 6 months). None of these patients were symptomatic, and 4 were taking zidovudine(Noguera et al, 2003).
    c) INCIDENCE: INFANTS: In a prospective study of 38 consecutive infants born to mothers treated with at least 3 antiretroviral agents during pregnancy (n=35) and/or zidovudine during delivery and the neonatal period (n=38), lactate levels were determined at birth, 2 weeks, and 1,2,3,4 and 6 months of age. Lactate was above normal at least once in 35 of 38 infants (92%). In 25 (64%) lactate was mildly elevated (2.1 to 5 mmol/L) and in 10 (26%) it was seriously elevated (greater than 5 mmol/L, mean 6.1 mmol/L range 5.0 to 7.4). Two patients were symptomatic (recurrent vomiting and irritability)(Alimenti et al, 2003).
    d) CASE REPORT: A case of severe lactic acidosis (serum lactate 13.7 mEq/L) is reported in a 31-year-old man following chronic therapy with zidovudine and didanosine. Lactic acidosis was accompanied by dyspnea, tachypnea, and tender hepatomegaly. He was treated with 10 hours of hemodialysis, zidovudine and didanosine therapy were stopped, and serum lactate level returned to normal within 4 weeks (Roy et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) INFANT: CASE REPORT: A healthy 4-day-old infant (3.3 kg at birth) born to an HIV-infected mother developed mild acidosis, elevated serum lactate, and persistent neutropenia after he was administered 2 inadvertent 10-fold overdoses of oral zidovudine (AZT) totaling 134 mg (40.6 mg/kg). At presentation to the emergency department his vital signs were normal. Laboratory analysis showed a serum lactate of 5.6 mmol/L (normal; 0.6 to 2.2 mmol/L) and a pH of 7.32. ALT levels were also slightly elevated. He was admitted for observation and discharged to home within 24 hours when his serum lactate level normalized. At discharge he was restarted on AZT prophylaxis. Borderline neutropenia persisted for approximately 5 weeks during his 6-week course of therapy (Livshits et al, 2011).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) The most common dose-related adverse effect is bone marrow suppression, resulting in granulocytopenia and macrocytic anemia.
    B) WITH POISONING/EXPOSURE
    1) Acute overdoses up to 50 grams have resulted in transient, non-severe hematologic changes.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) GRANULOCYTOPENIA has been the most frequently reported adverse effect following therapeutic use, and is directly related to dose and duration of therapy. The manufacturer has issued a warning concerning hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced AIDS, following therapy with zidovudine (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010; Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    1) During clinical trials granulocytopenia occurred in 40% of patients with high pre-treatment CD4 (T4) lymphocytes (greater than 200/mm(3)), and in 55% of those with low CD4 lymphocytes (less than 200/mm(3)).
    b) CASE SERIES: Severe NEUTROPENIA (less than 500/mm(3)) was reported in 16% of 145 zidovudine recipients during a clinical trial using 250 mg every 4 hours (Richman et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) The nadir white count occurred 48 hours postingestion after a massive overdose (Pickus, 1988).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been the second most common adverse reaction during therapy. The manufacturer has issued a warning concerning hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced AIDS, following therapy with zidovudine (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010; Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    b) CASE SERIES: MACROCYTIC ANEMIA was reported in 10% of patients with normal CD4 (T4) lymphocytes, and in 45% of those with decreased CD4 (T4) lymphocytes. Anemia was due to impaired erythrocyte maturation. Anemia occurred as early as 2 to 4 weeks after initiation of therapy, most commonly 4 to 6 weeks (Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    2) WITH POISONING/EXPOSURE
    a) Acute overdoses of up to 50 grams, in both adults and children, have resulted in transient, non-severe hematologic changes (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010).
    b) INFANTS
    1) CASE REPORT: A healthy 4-day-old infant (3.3 kg at birth) born to an HIV-infected mother developed persistent neutropenia, mild acidosis, and an elevated serum lactate after he was administered 2 inadvertent 10-fold overdoses of oral zidovudine (AZT) totaling 134 mg (40.6 mg/kg). At presentation to the emergency department his vital signs were normal. Laboratory analysis showed elevated serum lactate and a pH of 7.32. ALT levels were slightly elevated. He was admitted for observation and discharged to home within 24 hours when his serum lactate level normalized. At discharge he was restarted on a 6-week course of AZT prophylaxis. While hospitalized, his WBC and absolute neutrophil counts (ANC) decreased by 20% but remained within normal limits. Ten days after the exposure he became neutropenic with his ANC decreasing by 75% to 1,200 cells/mm(3) (normal; 1,500 to 10,000 cells/mm(3)). Borderline neutropenia persisted for approximately 5 weeks during his 6-week course of AZT prophylaxis (Livshits et al, 2011).
    2) CASE REPORT: A 17-day-old healthy girl born to a HIV-1-infected mother was admitted to the hospital with seizures, neutropenia, anemia and sepsis. It was noted on admission that patient had received a 10-fold incorrect dose (received 20 mg/kg every 6 hours for 17 days instead of 0.2 mL/kg every 6 hours) of zidovudine. Her hospital course was complicated by severe Streptococcus agalactiae meningo-encephalitis with the development of severe cerebral palsy, salt wasting syndrome, and hypothermia. It was presumed that ZDV-induced neutropenia facilitated the patient's development of bacterial sepsis. Following long term care, the patient died at 8 months of age of ab ingestis pneumonia (Manini et al, 2007).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA MACROCYTIC
    a) Monkeys infected with strain SIVsm were treated with zidovudine (20 mg/kg/day for 9 weeks) and consequently exhibited hematologic changes including macrocytic anemia and leukopenia. Anemia was the most evident toxic effect, similar to that seen in AIDS patients (Bottiger et al, 1992).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Transverse nail pigmentation has been reported.
    3.14.2) CLINICAL EFFECTS
    A) NAIL FINDING
    1) WITH THERAPEUTIC USE
    a) Dark blue or brownish transverse fingernail & toenail discoloration may occur after weeks of zidovudine therapy (Furth & Kazakis, 1987; Bendick et al, 1989; Fisher & McPoland, 1989; Azon-Masoliver et al, 1988; Carr & Cooper, 2000).
    b) CASE SERIES: One study showed 39% of AZT patients had nail hyperpigmentation (Groark et al, 1989). Another showed a 42% incidence, with blacks having 67% incidence (Don et al, 1990).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Myalgia has been reported following therapeutic use in about 8% of patients; however, myopathy has been reported in AIDS patients not receiving zidovudine, making the connection to zidovudine questionable.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 8% of patients receiving zidovudine during clinical trials (Richman et al, 1987). In another study 8% of patients receiving lamivudine plus zidovudine experienced myalgias (Prod Info EPIVIR(R) oral tablets, solution, 2008)
    B) MYOSITIS
    1) WITH THERAPEUTIC USE
    a) POLYMYOSITIS-LIKE SYNDROME has been reported in several patients on months of therapy (Bessen et al, 1988). The manufacturer has issued a warning that patients on prolonged use of zidovudine may develop symptomatic myopathy (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010).
    b) Muscle fatigue, myalgia, profound weakness, and wasting is reported in approximately 17% of patients treated with zidovudine. This is potentially aggravated by corticosteroids (Carr & Cooper, 2000).

Reproductive

    3.20.1) SUMMARY
    A) Passive diffusion across the placenta occurs following zidovudine dosing in pregnancy. Limited data suggests that there is no increased incidence of congenital abnormalities in infants born to women receiving antepartum zidovudine therapy. Zidovudine has been well-tolerated in pregnant women with no adverse effects to the fetus.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) HUMANS
    a) In a long-term study of 234 uninfected children born to HIV-positive mothers taking zidovudine throughout pregnancy, Culnane et al (1999) reported no adverse outcomes regarding growth, cognitive/developmental function, immune function, cancers, or mortality during an average follow-up period of 4.2 years. One child was reported to have mild cardiomyopathy of unknown etiology.
    b) Lipshultz et al (2000) followed 48 infants with perinatal exposure to zidovudine (36 infants without HIV infection and 12 with HIV infection) for evidence of cardiac toxicity. Infants were followed up to 5 years of age. No acute or chronic abnormalities in left ventricular structure or function were associated with zidovudine in these children.
    B) ANIMAL STUDIES
    1) ANIMAL STUDIES
    a) Administration of doses up to 500 mg/kg/day to pregnant rats and rabbits resulted in no evidence of teratogenicity (Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001). Teratogenic effects have only been reported in rodents exposed to near-lethal maternal doses of zidovudine (Taylor & Low-Beer, 2001).
    b) MICE: Perinatal exposure to the combination of zidovudine and lamivudine in mice has resulted in minor, but more significant, effects on somatic and sensorimotor development than either of these drugs given separately; juvenile social behavior was also affected by this combination (Venerosi et al, 2001).
    2) ABACAVIR/LAMIVUDINE/ZIDOVUDINE
    a) Animal studies conducted with the individual components of this product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above described dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 500 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations were reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Zidovudine has been classified as FDA pregnancy category C (Prod Info Retrovir(R), zidovudine, 2001)
    2) The combination product of abacavir/lamivudine/zidovudine has been classified as FDA pregnancy category C. Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk. Physicians may register patients exposed to abacavir/lamivudine/zidovudine during pregnancy in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (Prod Info TRIZIVIR oral tablets, 2015).
    B) PLACENTAL BARRIER
    1) Passive diffusion across the placenta occurs following zidovudine dosing in pregnancy. Concentrations in the fetal circulation approximate to 85% of the maternal plasma concentrations. Incorporation of zidovudine into the DNA of the placenta and most fetal organs during short term IV infusion of zidovudine has been shown in pregnant monkeys. Incorporation into human lymphocyte DNA with in utero exposure has also been shown (Taylor & Low-Beer, 2001).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Zidovudine is excreted into human breast milk in quantities sufficiently high to decrease viral load in milk (Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001; Briggs et al, 1998).
    2) ABACAVIR/LAMIVUDINE/ZIDOVUDINE
    a) Due to the risk of postnatal transmission of HIV, the Centers for Disease Control and Prevention does not recommend breastfeeding for HIV-infected mothers, including those who are receiving combination antiretroviral therapy or prophylaxis (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Extremely large doses have been associated with vaginal neoplasms in mice and rats; the significance in humans is not known.
    3.21.3) HUMAN STUDIES
    A) NEOPLASM
    1) Doses far in excess of those administered to humans, have been associated with vaginal neoplasms in female mice and rats. The significance of these findings to humans is not known (Rachlis & Fanning, 1993).

Genotoxicity

    A) In vitro studies with zidovudine have demonstrated weak mutagenicity at high concentrations, and produced dose-related chromosomal abnormalities in human lymphocytes at concentrations of 3 mcg/mL and higher (Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    B) Zidovudine was negative in bacterial mutagenicity assay (Ayers, 1988).
    C) In mammalian cells, concentrations of 1000 to 5000 micrograms/mL were weakly mutagenic (Ayers, 1988).
    D) Aberrations in cultured human lymphocytes were seen at zidovudine concentrations of 3 micrograms/mL and higher (Ayers, 1988).

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) HEMATOLOGIC
    1) Complete blood counts (CBC's) should be monitored intensively in patients who overdose on zidovudine.
    B) 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.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Neonates taking prophylactic zidovudine have been reported to have large urinary peaks of thymine. It is speculated that zidovudine may be converted to thymine through a glucuronide/nucleoside pathway or thiol reduction pathway (Sewell, 1998).
    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.
    b) Patients taking prolonged courses of zidovudine are at risk for myopathy (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010). Monitor serum creatinine phosphokinase in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) AZT can be measured by high performance liquid chromatography (Hedaya & Sawchuk, 1988; Fauvelle et al, 1991).
    B) IMMUNOASSAY
    1) In-vivo quantification of individual phosphorylated zidovudine compounds requires a coupled high-performance liquid chromatography (HPLC)-radioimmunoassay (RIA). The HPLC column separates the mono-, di-, and triphosphate peaks, which are then eluted, exposed to phosphatases, and analyzed by RIA. O'Donnell et al (1994) showed evidence that samples treated with a bovine-derived alkaline phosphatase may cause RIA interference and assay variability (O'Donnell et al, 1994).

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 zidovudine 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) 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.
    B) 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.
    C) 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.
    4) RIBOFLAVIN: Fouty et al (1998) have proposed a riboflavin deficiency in AIDS patients taking these drugs and developing lactic acidosis and hepatic steatosis. These authors have treated 3 patients with this syndrome with riboflavin 50 mg and reported clinical recovery and return of serum lactate levels to normal (Fouty et al, 1998). 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.
    6) HEMODIALYSIS
    a) CASE REPORT: A case of severe lactic acidosis (serum lactate 13.7 mEq/L) is reported in a 31-year-old male following chronic therapy with zidovudine and didanosine. Lactic acidosis was accompanied by dyspnea, tachypnea, and tender hepatomegaly. He was treated with 10 hours of hemodialysis, zidovudine and didanosine therapy were stopped, and serum lactate level returned to normal within 4 weeks (Roy et al, 1999).
    D) EXPERIMENTAL THERAPY
    1) THYMIDINE
    a) Because zidovudine reduces intracellular pools of thymidine triphosphate in vitro, and thymidine competes with the antiviral activity of zidovudine in vitro, it has been suggested that thymidine administration may rescue cells from hematologic toxicity.
    b) There are no studies documenting the efficacy of thymidine therapy (Richman et al, 1987).
    c) When used in low doses (< 1 gram/square meter/day) as a rescue therapy for other anti-thymidine chemotherapy agents like methotrexate, thymidine produced a 20 percent incidence of myelosuppression. Higher doses were markedly myelosuppressive (Howell et al, 1979).
    2) VITAMIN B12
    a) Deficiencies of serum vitamin B12 levels have been noted in patients receiving zidovudine, and administration of vitamin B12 has been suggested as a possibility to prevent hematologic toxicity.
    b) This therapy has not been evaluated clinically (Richman et al, 1987).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Both hemodialysis and peritoneal dialysis have only a negligible effect on the removal of zidovudine; however, elimination of its metabolite, GZDV, is enhanced (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010).
    2) Hemodialysis did not appreciably reduce zidovudine or its glucuronide metabolites (GZDV) in one adult tested (Tartaglione et al, 1990)
    3) Another patient showed a mild change in zidovudine and especially GZDV levels after a 4 hour treatment (Garraffo et al, 1989).
    4) Four hours of hemodialysis did little to hasten elimination of zidovudine but did enhance elimination of GZDV (Singlas et al, 1989).

Abstracts

Case Reports

    A) ADULT
    1) ANEMIA: Ingestion of 20,000 mg of zidovudine (200 capsules) by a 28-year-old man with AIDS resulted in lethargy and fatigue 24 hours after the overdose.
    a) Worsening of his underlying anemia occurred, requiring no specific therapy. The nadir white count occurred at 48 hours postingestion (WBC 2300, hemoglobin 8.7 g/dL, hematocrit 26.6, platelets 127,000) (Pickus, 1988).
    2) MULTIPLE AGENT INGESTION: A 26-year-old man with AIDS ingested 10 to 20 grams (110 to 220 mg/kg) of zidovudine in addition to an unknown amount of phenobarbital and triazolam.
    a) Initial symptoms included headache, nausea, nystagmus, and ataxia 8 hours postingestion. No hematologic adverse effects were noted during hospitalization or at a 6 week follow-up.
    b) Neurological signs normalized within 48 hours (Spear et al, 1988).
    3) ZIDOVUDINE-TEMAZEPAM: A 34-year-old man with AIDS ingested 20 g of zidovudine along with temazepam. At 6 hours postingestion drowsiness was noted.
    a) A slight fall in hemoglobin from 14.2 g/dL to 12.5 g/dL 3 days postingestion was the only hematologic effect observed (Hargreaves et al, 1988).
    B) PEDIATRIC
    1) CASE REPORT: A 17-day-old healthy female born to a HIV-1-infected mother was admitted to the hospital with seizures, neutropenia, anemia and sepsis. It was noted on admission that patient had received a 10-fold incorrect dose (received 20 mg/kg every 6 hours for 17 days instead of 0.2 mL/kg every 6 hours) of zidovudine. Her hospital course was complicated by severe Streptococcus agalactiae meningo-encephalitis with the development of severe cerebral palsy, salt wasting syndrome, and hypothermia. It was presumed that ZDV-induced neutropenia facilitated the patient's development of bacterial sepsis. Following long term care, the patient died at 8 months of age of ab ingestis pneumonia (Manini et al, 2007). Of note, 3 other infants were also given inadvertent overdose of zidovudine (similar 10-fold error) for 6 to 20 days and developed only mild to moderate symptoms, but all fully recovered. The authors suggested that inter-individual differences (eg, thymidine kinase levels and the activity of some transmembrane drug transporters (genetically determined)) might explain the various outcomes in these infants.
    2) CASE REPORT: A 27-month-old boy with congenital infection with the human immunodeficiency virus accidently ingested 120 mg of zidovudine in addition to his regular 10 mg dose. Syrup of ipecac was administered 75 minutes after the ingestion to induce emesis; no other treatment was given. The child never developed any symptoms or any evidence of neurologic or hematologic toxicity (Moore et al, 1990).

Range Of Toxicity

Summary

    A) TOXICITY: Limited overdose data. Acute overdoses of up to 50 g have been survived by both adults and children with only adverse effects of fatigue, headache and vomiting reported.
    B) THERAPEUTIC DOSE: ADULT: 200 mg orally 3 times daily OR 300 mg orally twice daily; 1 mg/kg/dose IV 5 or 6 times daily. PEDIATRIC (at least 4-weeks-old): 4 kg to less than 9 kg: 12 mg/kg orally twice daily OR 8 mg/kg orally 3 times daily; 9 kg to less than 30 kg: 9 mg/kg orally twice daily OR 6 mg/kg orally 3 times daily; 30 kg or more: 300 mg orally twice daily OR 200 mg orally 3 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) HIV-1 INFECTION
    1) ORAL: 300 mg orally twice daily (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    2) IV: 1 mg/kg IV over 1 hour every 4 hours daily (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    B) PROPHYLAXIS OF PERINATAL HIV-1 TRANSMISSION, MATERNAL
    1) ORAL: 100 mg orally 5 times daily until the start of labor (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    2) IV: Intrapartum, 2 mg/kg (total body weight) over 1 hour, followed by 1 mg/kg (total body weight)/hr IV during labor and until umbilical cord clamping (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014; Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    7.2.2) PEDIATRIC
    A) HIV INFECTION
    1) ORAL, 4 WEEKS AND OLDER, WEIGHT BASED DOSING
    a) 4 KG TO LESS THAN 9 KG
    1) 12 mg/kg orally twice daily or 8 mg/kg orally 3 times daily (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    b) 9 KG TO LESS THAN 30 KG
    1) 9 mg/kg orally twice daily or 6 mg/kg orally 3 times daily (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    c) 30 KG OR GREATER
    1) 300 mg orally twice daily or 200 mg orally 3 times daily (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    d) ORAL, 4 WEEKS OF AGE AND OLDER, BSA-BASED DOSING
    1) 240 mg/m(2) twice daily or 160 mg/m(2) 3 times daily, not to exceed adult dosage of 600 mg/day (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    e) ORAL, 6 WEEKS AND OLDER, AND ADOLESCENT, BSA-BASED, GUIDELINE DOSING
    1) 180 to 240 mg/m(2) twice daily or 160 mg/m(2) every 8 hours (Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2011).
    f) ORAL, FULL-TERM NEONATES/INFANTS LESS THAN 6 WEEKS, BSA-BASED, GUIDELINE DOSING
    1) 4 mg/kg twice daily (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    g) INTRAVENOUS (UNABLE TO TAKE ORAL), FULL-TERM NEONATES/INFANTS LESS THAN 6 WEEKS OF AGE
    1) 1.5 mg/kg IV (infused over 30 minutes) every 6 hours (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    h) ORAL, PRETERM NEONATES LESS THAN 35 WEEKS GESTATIONAL AGE
    1) 2 mg/kg every 12 hours; advance to every 8 hours at 2 weeks of age (if 30 weeks gestation at birth or greater) or at 4 weeks of age (if less than 30 weeks gestation at birth) (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    i) INTRAVENOUS, PRETERM NEONATES LESS THAN 35 WEEKS GESTATIONAL AGE
    1) 1.5 mg/kg (infused over 30 minutes) every 12 hours; advance to every 8 hours at 2 weeks of age (if 30 weeks gestation at birth or greater) or at 4 weeks of age (if less than 30 weeks gestation at birth) (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    B) PROPHYLAXIS OF PERINATAL HIV TRANSMISSION, NEONATAL (THROUGH 6 WEEKS OF AGE)
    1) MANUFACTURER DOSING
    a) ORAL: 2 mg/kg every 6 hours (8 mg/kg/day) starting within 12 hours after birth (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    b) IV (UNABLE TO TAKE ORAL): 1.5 mg/kg IV infused over 30 minutes every 6 hours (6 mg/kg/day) starting within 12 hours after birth (Prod Info RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, 2014).
    2) GUIDELINE DOSING FOR FULL-TERM NEONATE
    a) ORAL: 4 mg/kg twice daily starting within 6 to 12 hours of birth (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    b) IV (UNABLE TO TAKE ORAL): 1.5 mg/kg (infused over 30 minutes) every 6 hours starting within 6 to 12 hours of birth (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    3) GUIDELINE DOSING FOR PRETERM NEONATE
    a) ORAL: 2 mg/kg every 12 hours starting within 6 to 12 hours of birth; advance to every 8 hours at 2 weeks of age (if 30 weeks gestation at birth or greater) or at 4 weeks of age (and if less than 30 weeks gestation at birth) (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).
    b) IV (UNABLE TO TAKE ORAL): 1.5 mg/kg every 12 hours starting within 6 to 12 hours of birth; advance to every 8 hours at 2 weeks of age (if 30 weeks gestation at birth or greater) or at 4 weeks of age (and if less than 30 weeks gestation at birth) (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2011).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) NO TOXICITY/MILD TOXICITY
    a) No toxicity was reported after an overdose of 3.6 g in a 37-year-old man with AIDS (Heard & Slovis, 1988).
    1) Ingestion of 3 g of zidovudine by a 25-year-old man resulted in lethargy, but no long-term toxicity was observed (Stern et al, 1992).
    b) No signs or symptoms of toxicity occurred in a 27-month-old boy who accidentally ingested 120 mg of zidovudine in addition to his regular 10 mg dose (Moore et al, 1990).
    c) Ingestion of 10 to 20 g (110 to 220 mg/kg) in a 26-year-old man resulted in mild toxicity with no bone marrow suppression (Spear et al, 1988).
    d) Acute overdoses of up to 50 g have been reported in both adults and pediatric patients, with NO fatalities. Spontaneous or induced nausea and vomiting was a consistent finding in all cases. Transient, non-severe hematologic changes were reported. Nonspecific CNS symptoms (headache, dizziness, drowsiness, lethargy, confusion) were reported in some patients. All patients recovered with no permanent sequelae (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010; Prod Info Retrovir(R) I.V. Infusion, zidovudine, 2001).
    2) SUBACUTE OVERDOSE
    a) INFANT: A healthy 4-day-old infant (3.3 kg at birth) born to an HIV-infected mother developed mild acidosis, elevated serum lactate, and persistent borderline neutropenia after he was administered 2 inadvertent 10-fold overdoses of oral zidovudine (AZT) totaling 134 mg (40.6 mg/kg). Neutropenia persisted for approximately 5 weeks during his 6-week course of AZT therapy (Livshits et al, 2011).
    b) INFANT: Three infants were also given inadvertent overdoses of zidovudine (similar 10-fold error) for 6 to 20 days and developed only mild to moderate symptoms, but all fully recovered (Manini et al, 2007). Another infant as admitted to the hospital with seizures, neutropenia, anemia and sepsis. It was noted on admission that patient had received a 10-fold overdose (received 20 mg/kg every 6 hours for 17 days instead of 0.2 mL/kg) of zidovudine. Her hospital course was complicated by severe Streptococcus agalactiae meningo-encephalitis with the development of severe cerebral palsy, salt wasting syndrome, and hypothermia. It was presumed that ZDV-induced neutropenia facilitated the patient's development of bacterial sepsis. The authors suggested that inter-individual differences (eg, thymidine kinase levels and the activity of some transmembrane drug transporters (genetically determined)) might explain the various outcomes in these infants.
    3) SEIZURES
    a) Ingestion of 36 g by a 35-year-old man resulted in a single grand mal seizure 3 hours postingestion. No other signs of toxicity were noted (Routy et al, 1989).
    4) BONE MARROW SUPPRESSION
    a) Ingestion of 20 g resulted in mild bone marrow suppression and lethargy in a 28-year-old man (Pickus, 1988).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) THERAPEUTIC
    1) The peak therapeutic serum level after a single 200 milligram dose is approximately 0.9 microgram/milliliter (Spear et al, 1988).
    b) OVERDOSE
    1) The serum level obtained 7.75 hours after ingestion of 10 to 20 grams (110 to 220 milligrams/kilogram) was 23.82 micrograms/milliliter in one overdose case and 49.4 micrograms/milliliter 12 hours after ingestion of 20 grams in another case (Hargreaves et al, 1988).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 3062 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 3084 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Zidovudine, a synthetic nucleoside analogue of thymidine, interferes with retroviral DNA polymerase (reverse transcriptase) and inhibits viral replication (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2010).
    1) Zidovudine is converted intracellularly into zidovudine monophosphate. It is further converted to a diphosphate and a triphosphate form.
    2) Zidovudine triphosphate interferes with HIV reverse transcriptase both by competing for utilization with deoxythymidine 5'-triphosphate (dTTP), and by its incorporation into viral DNA, thus inhibiting viral replication. The azido group substitution makes phosphodiester linkages impossible and terminates chain synthesis of DNA.
    3) Human immunodeficiency virus (HIV) is 100 times more susceptible to inhibition by zidovudine than the DNA polymerase of mammalian cells.

Toxicologic Mechanism

    A) Zidovudine displays a dose dependent inhibitory effect on myeloid and erythroid progenitor cells in vitro.
    1) It was suggested that the increased conversion of AZT to the active triphosphate, or the presence of greater numbers of rapidly dividing cells in bone marrow, explains the preferential toxicity for these cell lines (Sommadossi & Carlisle, 1987).

Physicochemical

Physical Characteristics

    A) ZIDOVUDINE is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg/mL in water at 25 degrees C (Prod Info RETROVIR(R) intravenous infusion, 2011).

Ph

    A) Approximately 5.5 (Prod Info RETROVIR(R) intravenous infusion, 2011)

Molecular Weight

    A) 267.24 (Prod Info RETROVIR(R) intravenous infusion, 2011)

References

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    53) Product Information: COMBIVIR oral tablets, lamivudine zidovudine oral tablets. ViiV Healthcare (per FDA), Research Triangle Park, NC, 2015.
    54) Product Information: Combivir(R), lamivudine and zidovudine. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    55) Product Information: EPIVIR(R) oral tablets, solution, lamivudine oral tablets, solution. GlaxoSmithKline, Research Triangle Park, NC, 2008.
    56) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    57) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    58) Product Information: RETROVIR(R) IV infusion, zidovudine IV infusion. GlaxoSmithKline, Research Triangle Park, NC, 2006.
    59) Product Information: RETROVIR(R) intravenous infusion, zidovudine intravenous infusion. ViiV Healthcare (per FDA), Research Triangle Park, NC, 2011.
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    62) Product Information: RETROVIR(R) oral tablets, oral capsules, oral syrup, intravenous injection, zidovudine oral tablets, oral capsules, oral syrup, intravenous injection. ViiV Healthcare (per FDA), Research Triangle Park, NC, 2014.
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