Usage
- Stavudine is an antiviral medication used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. It is not a cure for HIV or AIDS, but helps to slow the progression of the disease.
- Pharmacological Classification: Nucleoside reverse transcriptase inhibitor (NRTI).
- Mechanism of Action: Stavudine is a thymidine nucleoside analog. After intracellular phosphorylation to its active triphosphate form, stavudine inhibits HIV-1 reverse transcriptase by competing with the natural substrate, thymidine triphosphate. Additionally, it incorporates into viral DNA, causing chain termination and inhibiting viral DNA synthesis.
Alternate Names
- d4T
- 2’,3’-didehydro-3’-deoxythymidine
- Brand Name: Zerit, Zerit XR
How It Works
- Pharmacodynamics: Stavudine reduces HIV viral load by inhibiting reverse transcriptase and disrupting viral DNA synthesis. This helps to preserve immune function and delay the onset of AIDS-related complications.
- Pharmacokinetics:
- Absorption: Stavudine is rapidly absorbed after oral administration with high bioavailability (82-99%). Food may delay absorption but does not significantly affect overall exposure.
- Metabolism: Stavudine is phosphorylated intracellularly to its active triphosphate metabolite. It does not undergo extensive hepatic metabolism by CYP450 enzymes.
- Elimination: Primarily renal excretion (approximately 40% as unchanged drug). Dose adjustment is necessary in patients with renal impairment.
Dosage
Standard Dosage
Adults:
- 30 mg orally every 12 hours, regardless of body weight.
Children:
- Neonates (birth to 13 days old): 0.5 mg/kg orally every 12 hours.
- Infants and Children (14 days old and older, weighing less than 30 kg): 1 mg/kg orally every 12 hours.
- Adolescents (weighing 30 kg or more): 30 mg orally every 12 hours.
- Pediatric Safety Considerations: Close monitoring for adverse effects, particularly mitochondrial toxicity and peripheral neuropathy, is essential in pediatric patients.
Special Cases:
- Elderly Patients: Age-related renal impairment may necessitate dose adjustments.
- Patients with Renal Impairment: Dose reduction is necessary based on creatinine clearance (CrCl):
- CrCl ≤ 50 mL/min: 15-20 mg every 12 hours depending on body weight.
- Patients with Hepatic Dysfunction: Close monitoring is advised, although specific dose adjustments are not typically required.
- Patients with Comorbid Conditions: Caution is advised for patients with liver disease, pancreatitis, peripheral neuropathy, or bone marrow suppression.
Clinical Use Cases
Stavudine is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indication is chronic HIV infection management.
Dosage Adjustments
Dose adjustments are primarily based on renal function. Genetic polymorphisms affecting drug metabolism have not been extensively studied.
Side Effects
Common Side Effects:
- Peripheral neuropathy (numbness, tingling, burning pain in hands or feet)
- Nausea, vomiting, diarrhea
- Headache
- Rash
- Fatigue
Rare but Serious Side Effects:
- Lactic acidosis
- Hepatomegaly with steatosis (fatty liver)
- Pancreatitis
- Lipoatrophy (loss of body fat, especially in face, arms, and legs)
Long-Term Effects:
- Lipoatrophy
- Peripheral neuropathy
- Mitochondrial toxicity
Adverse Drug Reactions (ADR):
- Lactic acidosis
- Severe hepatomegaly with steatosis
- Pancreatitis
Contraindications
- Hypersensitivity to stavudine
- Coadministration with didanosine
Drug Interactions
- Didanosine: Contraindicated due to increased risk of pancreatitis, lactic acidosis, peripheral neuropathy, and hepatic dysfunction.
- Zidovudine: May decrease stavudine phosphorylation and activation.
- Hydroxyurea: Increased risk of hepatic toxicity.
- Doxorubicin, Ribavirin: May inhibit stavudine activation.
- Drugs causing peripheral neuropathy (e.g., isoniazid, vincristine): Increased risk of additive neurotoxicity.
- Numerous other drug interactions exist; consultation with a drug interaction checker is recommended.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C. Use only if the potential benefit outweighs the risk. A pregnancy exposure registry is available.
- Fetal Risks: Potential for mitochondrial dysfunction, although no definitive evidence of teratogenicity.
- Breastfeeding: Stavudine is excreted in breast milk. Mothers with HIV should not breastfeed to avoid HIV transmission and potential neonatal side effects.
Drug Profile Summary
- Mechanism of Action: Nucleoside reverse transcriptase inhibitor; inhibits viral replication by competing with natural substrate and causing DNA chain termination.
- Side Effects: Peripheral neuropathy, nausea, vomiting, diarrhea, headache, rash, lactic acidosis, hepatomegaly, pancreatitis, lipoatrophy.
- Contraindications: Hypersensitivity, coadministration with didanosine.
- Drug Interactions: Didanosine, zidovudine, hydroxyurea, doxorubicin, ribavirin, and others.
- Pregnancy & Breastfeeding: Category C; not recommended for breastfeeding.
- Dosage: 30 mg twice daily. Dosage adjustments for renal impairment.
- Monitoring Parameters: HIV viral load, CD4 cell count, liver function tests, renal function, signs of peripheral neuropathy, pancreatitis, and lactic acidosis.
Popular Combinations
Stavudine is no longer commonly used in combination regimens due to its toxicity profile. Contemporary HIV treatment guidelines recommend alternative NRTIs with better safety profiles.
Precautions
- Pre-screening for renal and hepatic function, history of peripheral neuropathy, and pancreatitis is essential.
- Monitor for signs of lactic acidosis, hepatic dysfunction, and peripheral neuropathy throughout treatment.
- Alcohol should be avoided due to the risk of pancreatitis and peripheral neuropathy.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Stavudine?
A: The standard dosage is 30 mg orally every 12 hours for adults and adolescents weighing 30 kg or more. Dosage adjustments are required for renal impairment and pediatric patients.
Q2: What are the most common side effects of Stavudine?
A: The most common side effects are peripheral neuropathy, nausea, vomiting, diarrhea, headache, and rash.
A: Lactic acidosis, severe hepatomegaly with steatosis, and pancreatitis are serious side effects requiring immediate medical attention.
Q4: Is Stavudine safe to use during pregnancy?
A: Stavudine is Pregnancy Category C and should be used only if the potential benefit outweighs the risk. Consultation with an expert is essential.
Q5: Can Stavudine be used with Didanosine?
A: No, Stavudine is contraindicated with Didanosine due to increased risk of serious side effects.
Q6: What should be monitored in patients receiving Stavudine?
A: HIV viral load, CD4 count, liver and renal function, and signs of peripheral neuropathy, lactic acidosis and pancreatitis should be monitored regularly.
Q7: Why is Stavudine no longer recommended as first-line therapy for HIV?
A: Due to its higher risk of mitochondrial toxicity and long-term side effects such as lipoatrophy and peripheral neuropathy compared to newer NRTIs with better safety profiles.
Q8: What is the mechanism by which Stavudine can cause peripheral neuropathy?
A: Stavudine’s mitochondrial toxicity is thought to play a significant role in the development of peripheral neuropathy. The drug can interfere with mitochondrial DNA polymerase gamma, leading to mitochondrial dysfunction in peripheral nerves.
Q9: How does renal impairment affect Stavudine dosage?
A: Patients with renal impairment require dose reductions. Specific recommendations are based on creatinine clearance levels and should be consulted.
