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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. [DSC] = Discontinued product

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 [DSC])

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

Absorption

Rapid

Distribution

Penetrates into the CSF achieving 16% to 97% (mean: 59%) of concomitant plasma concentrations; distributes into extravascular spaces and equally between RBCs and plasma

Vd: Children: 0.73 ± 0.32 L/kg; Adults: 46 ± 21 L

Metabolism

Converted intracellularly to active triphosphate form; metabolism of stavudine plays minimal role in its clearance; minor metabolites include oxidized stavudine and its glucuronide conjugate, glucuronide conjugate of stavudine, N-acetylcysteine conjugate of the ribose after glycosidic cleavage

Excretion

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

Time to Peak

Serum: 1 hour

Half-Life Elimination

Note: Half-life is prolonged with renal dysfunction

Newborns (at birth): 5.3 ± 2 hours

Neonates 14 to 28 days old: 1.6 ± 0.3 hours

Children 5 weeks to 15 years: 0.9 ± 0.3 hours

Adults: 1.6 ± 0.2 hours

Intracellular: Adults: 3.5 to 7 hours

Protein Binding

Negligible

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.

Use: Labeled Indications

HIV-1: Treatment of HIV-1 infection in combination with other antiretroviral agents

Contraindications

Hypersensitivity to stavudine or any component of the formulation; coadministration with didanosine

Dosing: Adult

HIV-1 infection, treatment: Oral:

<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 regardless of body weight (HHS [adult] 2016).

Dosing: Geriatric

Older patients should be closely monitored for signs and symptoms of peripheral neuropathy. Dosage should be carefully adjusted to renal function.

Dosing: Pediatric

HIV-1 infection, treatment: Oral:

Neonates postnatal age (PNA) 0 to 13 days: 0.5 mg/kg every 12 hours

Neonates PNA ≥14 days: 1 mg/kg/dose every 12 hours

Infants and Children weighing <30 kg: 1 mg/kg/dose every 12 hours; maximum dose: 30 mg/dose

Children and Adolescents weighing 30 to <60 kg: 30 mg every 12 hours

Adolescents ≥60 kg: 30 mg every 12 hours (HHS [pediatric] 2016). Note: Manufacturer's labeling not recommended (40 mg) due to a greater incidence of adverse effects; pharmacokinetic data suggest toxicity may occur at this higher dose (HHS [pediatric] 2016).

Dosing: Renal Impairment

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

<60 kg: 15 mg every 24 hours

≥60 kg: 20 mg every 24 hours

Hemodialysis: Dialyzable (30%); Administer dose after hemodialysis on day of dialysis

<60 kg: 15 mg every 24 hours

≥60 kg: 20 mg every 24 hours

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

Dosing: 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. Capsule may be opened and dispersed in a small amount of water; administer immediately (HHS [pediatric] 2016). 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. The risk of lactic acidosis (possibly fatal), hepatomegaly, and pancreatitis may be increased with this combination. Avoid combination

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

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

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

Orlistat: May decrease the serum concentration of Antiretroviral Agents. 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%), peripheral neuropathy (8% to 21%)

Dermatologic: Skin rash (18% to 30%)

Endocrine & metabolic: Increased amylase (21% to 31%; grades 3/4: 4% to 8%), increased gamma-glutamyl transferase (15% to 28%; grades 3/4: 2% to 5%)

Gastrointestinal: Nausea (43% to 53%), diarrhea (34% to 45%), vomiting (18% to 30%), increased serum lipase (27%; grades 3/4: 5% to 6%)

Hepatic: Hyperbilirubinemia (65% to 68%; grades 3/4: 7% to 16%), increased serum AST (42% to 53%; grades 3/4: 5% to 7%), increased serum ALT (40% to 50%; grades 3/4: 6% to 8%)

<1%, postmarketing, and/or case reports: Abdominal pain, anemia, anorexia, chills, diabetes mellitus, fever, hepatic failure, hepatitis, hepatomegaly with steatosis (some fatal), hyperglycemia, hyperlipidemia, hypersensitivity reaction, immune reconstitution syndrome, insomnia, insulin resistance, lactic acidosis (some fatal), leukopenia, lipoatrophy, lipotrophy, macrocytosis, myalgia, neutropenia, pancreatitis (some fatal), redistribution of body fat, severe weakness (severe neuromuscular weakness resembling Guillain-Barré), 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. Coadministration of stavudine and didanosine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

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; coadministration with didanosine is contraindicated. 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. Coadministration with didanosine is contraindicated. Suspend stavudine and any agents toxic to the pancreas in patients with suspected pancreatitis. If pancreatitis diagnosis is 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. 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; lactic acidosis may also occur with concomitant didanosine administration. Use with hydroxyurea should be avoided; coadministration with didanosine is contraindicated.

• 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

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 to stavudine alone according to data collected by the antiretroviral pregnancy registry. Maternal antiretroviral therapy (ART) may increase the risk of preterm delivery, although available information is conflicting possibly due to variability of maternal factors (disease severity; gestational age at initiation of therapy); however, maternal antiretroviral medication should not be withheld due to concerns of preterm birth. Information related to stillbirth, low birth weight, and small for gestational age infants is limited. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

[US Boxed Warning]: Fatal lactic acidosis has been reported in pregnant women using didanosine and stavudine in combination with other antiretroviral agents; co-administration with didanosine is contraindicated. Cases of lactic acidosis and hepatic steatosis related to mitochondrial toxicity have been reported with use of nucleoside reverse transcriptase inhibitors (NRTIs). These adverse events are similar to other rare but life-threatening syndromes that occur during pregnancy (eg, HELLP syndrome). In general, NRTIs are well tolerated and the benefits of use generally outweigh potential risk. In addition to lactic acidosis, the combination of didanosine and stavudine has been shown to increase the risk of neurodevelopmental disability.

The Health and Human Services (HHS) Perinatal HIV Guidelines do not recommend stavudine for initial therapy in antiretroviral-naive pregnant females due to toxicity; do not use in combination with didanosine or zidovudine. Pharmacokinetics of stavudine are not significantly altered during pregnancy; dose adjustments are not needed. In addition, because of the high risk of toxicity, stavudine should be stopped in females who become pregnant during therapy and women should be switched to a preferred or alternative regimen.

In general, ART is recommended for all pregnant females with HIV to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. When HIV is diagnosed during pregnancy in a female who has never received antiretroviral therapy, ART should begin as soon as possible after diagnosis. Females who become pregnant on a stable ART regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated. Monitoring during pregnancy is more frequent than in nonpregnant adults; ART should be continued postpartum for all females living with HIV.

Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or http://www.APRegistry.com). Health care providers caring for HIV-infected females and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2017).

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, vomiting, or diarrhea. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of infection, muscle weakness, burning or numbness feeling, or change in body fat (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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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