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Stavudine

Pronunciation

(STAV yoo deen)

Index Terms

  • d4T

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Capsule, Oral:

Zerit: 15 mg, 20 mg, 30 mg, 40 mg

Generic: 15 mg, 20 mg, 30 mg, 40 mg

Solution Reconstituted, Oral:

Zerit: 1 mg/mL (200 mL) [dye free; fruit flavor]

Generic: 1 mg/mL (200 mL)

Brand Names: U.S.

  • Zerit

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HIV)

Pharmacology

Stavudine is a thymidine analog which interferes with HIV viral DNA dependent DNA polymerase resulting in inhibition of viral replication; nucleoside reverse transcriptase inhibitor

Distribution

Vd: 46 L

Metabolism

Undergoes intracellular phosphorylation to an active metabolite (stavudine triphosphate)

Excretion

Urine 95% (74% as unchanged drug); feces 3% (62% as unchanged drug)

Time to Peak

Serum: 1 hour

Half-Life Elimination

HIV-infected Children: 0.96 hours, HIV-infected Adults: 1.6 hours

Special Populations: Renal Function Impairment

Oral Cl decreases and terminal elimination half-life increases in patients with renal insufficiency. Adjust dosage in patients with reduced CrCl and patients receiving maintenance hemodialysis.

Special Populations: Hepatic Function Impairment

Pharmacokinetics were not altered in patients with Child-Pugh class B or C hepatic impairment.

Special Populations: Elderly

Pharmacokinetics have not been studied.

Special Populations: Gender

No clinically important differences in pharmacokinetics occurred between men and women.

Special Populations: Race

No clinically important pharmacokinetic differences were associated with race.

Use: Labeled Indications

Treatment of HIV infection in combination with other antiretroviral agents

Contraindications

Hypersensitivity to stavudine or any component of the formulation

Dosage

Oral:

Newborns (Birth to 13 days): 0.5 mg/kg every 12 hours

Children:

≥14 days and <30 kg: 1 mg/kg every 12 hours

≥30 kg: Refer to adult dosing

Adults:

<60 kg: 30 mg every 12 hours

≥60 kg: 40 mg every 12 hours

Note: According to the Department and Health and Human Services (HHS) HIV treatment guidelines, the World Health Organization recommends 30 mg every 12 hours in all adult and adolescent patients regardless of body weight (HHS [adult] 2015).

Elderly: Older patients should be closely monitored for signs and symptoms of peripheral neuropathy; dosage should be carefully adjusted to renal function

Dosage adjustment in renal impairment:

Children: Specific recommendations not available. Reduction in dose or increase in dosing interval should be considered.

Adults:

CrCl >50 mL/minute:

<60 kg: 30 mg every 12 hours

≥60 kg: 40 mg every 12 hours

CrCl 26-50 mL/minute:

<60 kg: 15 mg every 12 hours

≥60 kg: 20 mg every 12 hours

CrCl 10-25 mL/minute, hemodialysis (administer dose after hemodialysis on day of dialysis):

<60 kg: 15 mg every 24 hours

≥60 kg: 20 mg every 24 hours

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling. Use with caution.

Reconstitution

Reconstitute powder for oral suspension with 202 mL of purified water as specified on the bottle. Shake vigorously until suspended. Final suspension will be 1 mg/mL (200 mL).

Administration

May be administered without regard to meals. Oral solution should be shaken vigorously prior to use.

Dietary Considerations

May be taken without regard to meals. Some products may contain sucrose.

Storage

Capsules and powder for reconstitution may be stored at controlled room temperature of 25°C (77°F). Reconstituted oral solution should be stored in refrigerator at 2°C to 8°C (36°F to 46°F) and is stable for 30 days.

Drug Interactions

Didanosine: Stavudine may enhance the adverse/toxic effect of Didanosine. Lactic acidosis (possibly fatal) is of particular concern. Management: Use extreme caution and monitor for lactic acidosis with concomitant stavudine and didanosine therapy. Avoid use of stavudine and didanosine (in combination or alone) with hydroxyurea due to increased risk of serious toxicity. Consider therapy modification

DOXOrubicin (Conventional): May diminish the therapeutic effect of Stavudine. Consider therapy modification

DOXOrubicin (Liposomal): May diminish the therapeutic effect of Stavudine. Consider therapy modification

Hydroxyurea: May enhance the adverse/toxic effect of Stavudine. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Stavudine may enhance the adverse/toxic effect of Hydroxyurea. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Avoid combination

Ribavirin (Oral Inhalation): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Ribavirin (Systemic): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Zidovudine: May diminish the therapeutic effect of Stavudine. Avoid combination

Adverse Reactions

Adverse reactions reported below represent experience with combination therapy with other nucleoside analogues and protease inhibitors.

>10%:

Central nervous system: Headache (25% to 46%)

Dermatologic: Rash (18% to 30%)

Gastrointestinal: Nausea (43% to 53%; less than comparator group), vomiting (18% to 30%; less than comparator group), diarrhea (34% to 45%)

Hepatic: Hyperbilirubinemia (65% to 68%; grade 3/4: 7% to 16%), AST increased (42% to 53%; grade 3/4: 5% to 7%), ALT increased (40% to 50%; grade 3/4: 6% to 8%), GGT increased (15% to 28%; grade 3/4: 2% to 5%)

Neuromuscular & skeletal: Peripheral neuropathy (8% to 21%)

Miscellaneous: Amylase increased (21% to 31%; grade 3/4: 4% to 8%), lipase increased (~27%; grade 3/4: 5% to 6%)

Postmarketing and/or case reports: Abdominal pain, allergic reaction, anemia, anorexia, chills, diabetes mellitus, fever, hepatic failure, hepatitis, hepatomegaly (with steatosis; some fatal), hyperglycemia, hyperlactatemia (symptomatic), hyperlipidemia, immune reconstitution syndrome, insomnia, insulin resistance, lactic acidosis (some fatal), leukopenia, macrocytosis, myalgia, neuromuscular weakness (severe-resembling Guillain-Barré), neutropenia, pancreatitis (some fatal), redistribution/accumulation/atrophy of body fat, thrombocytopenia

ALERT: U.S. Boxed Warning

Lactic acidosis and hepatomegaly with steatosis:

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. Use the combination of stavudine and didanosine with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk.

Pancreatitis:

Fatal and nonfatal pancreatitis has occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Lactic acidosis/hepatomegaly: [US Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues, including fatal cases; combination therapy with didanosine may increase risk; use with caution in patients with risk factors for liver disease (although acidosis has occurred in patients without known risk factors, risk may be increased with female gender, obesity, pregnancy, or prolonged exposure). Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).

• Motor weakness: Severe motor weakness (resembling Guillain-Barré syndrome) has been reported (including fatal cases, usually in association with lactic acidosis); manufacturer recommends discontinuation if motor weakness develops (with or without lactic acidosis).

• Pancreatitis: [US Boxed Warning]: Pancreatitis (including some fatal cases) has occurred during combination therapy with didanosine. Suspend stavudine and didanosine combination therapy, and any other agents toxic to the pancreas, in patients with suspected pancreatitis. If pancreatitis diagnosis confirmed, use extreme caution if reinitiating stavudine; monitor closely and do not use didanosine in regimen.

• Peripheral neuropathy: May be treatment-limiting, especially with higher doses; use with caution in patients with pre-existing peripheral neuropathy, advanced HIV, and/or in combination with other medications known to cause neuropathy (eg, didanosine).Consider discontinuation of therapy if peripheral neuropathy develops; effect may be reversible if therapy discontinued immediately. Symptoms may worsen initially when therapy is discontinued.

Disease-related concerns:

• Bone marrow suppression: Use with caution in patients with pre-existing bone marrow suppression.

• Hepatic impairment: Use with caution in patients with hepatic impairment; discontinue or interrupt therapy if worsening liver function occurs.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.

Concurrent drug therapy issues:

• Combination with didanosine or hydroxyurea: May increase risk of hepatotoxicity/pancreatitis or severe peripheral neuropathy; avoid stavudine or hydroxyurea combination.

• Interferon alfa: Use with caution in combination with interferon alfa with or without ribavirin in HIV/HBV coinfected patients; monitor closely for hepatic decompensation, anemia, or neutropenia; dose reduction or discontinuation of interferon and/or ribavirin may be required if toxicity evident.

• Zidovudine: Should not use zidovudine in combination with stavudine.

Monitoring Parameters

Monitor liver function tests and renal function tests; signs and symptoms of peripheral neuropathy; monitor viral load and CD4 count

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Stavudine has a high level of transfer across the human placenta. No increased risk of overall birth defects has been observed following first trimester exposure according to data collected by the antiretroviral pregnancy registry. Pharmacokinetics of stavudine are not significantly altered during pregnancy; dose adjustments are not needed. Cases of lactic acidosis/hepatic steatosis syndrome related to mitochondrial toxicity have been reported in pregnant women with prolonged use of nucleoside analogues. It is not known if pregnancy itself potentiates this known side effect; however, women may be at increased risk of lactic acidosis and liver damage. In addition, these adverse events are similar to other rare but life-threatening syndromes that occur during pregnancy (eg, HELLP syndrome). Combination treatment with didanosine may also contribute to the risk of lactic acidosis and is not recommended. Hepatic enzymes and electrolytes should be monitored in women receiving nucleoside analogues and clinicians should watch for early signs of the syndrome. In addition, mitochondrial dysfunction may develop in infants following in utero exposure. The DHHS Perinatal HIV Guidelines recommend stavudine to be used only in special circumstances during pregnancy; do not use with didanosine or zidovudine; not recommended for initial therapy in antiretroviral-naive pregnant women due to toxicity (HHS [perinatal], 2014).

Regardless of CD4 count or HIV RNA copy number, all HIV-infected pregnant women should receive a combination antiretroviral (ARV) drug regimen. A combination of antepartum, intrapartum, and infant ARV prophylaxis is recommended. ARV therapy should be started as soon as possible in women with symptomatic infection. Although earlier initiation may be more effective in reducing the perinatal transmission of HIV, initiation may be delayed until after 12 weeks' gestation in women who do not require immediate treatment after careful consideration of maternal conditions (eg, nausea and vomiting) and the potential risks of first trimester fetal exposure for specific agents. A scheduled cesarean delivery at 38 weeks' gestation is recommended for all women with HIV RNA >1000 copies/mL or unknown concentrations near delivery in order to decrease transmission. If ARV therapy must be interrupted for <24 hours during the peripartum period, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to ARV medications. In couples who want to conceive, the HIV-infected partner should attain maximum viral suppression prior to conception.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal], 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, or diarrhea. Have patient report immediately to prescriber signs of lactic acidosis, paresthesia, lipodystrophy, signs of hepatic impairment, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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