Stavudine inhibits the replication of the HIV-1 virus by interfering with viral DNA dependent DNA polymerase and is used in combination with other antiviral medicines.

Stavudine Uses:

• HIV-1 infection:

  • Treatment of HIV-1 infection in combination with other antiretroviral drugs

Stavudine Dose in Adults

Stavudine Dose in the treatment of HIV-1 infection: 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.

Stavudine Dose in Children

Note:

• Gene mutation and antiretroviral (ARV) resistance patterns should be evaluated (refer to www.iasusa.org for more information) when necessary.

Stavudine Dose in the treatment of HIV-1 infection:

Note:

• Although FDA approved, stavudine is no longer recommended for use in pediatric patients due to higher rates of adverse effects than other nucleoside reverse transcriptase inhibitors.
• If used, it should be in combination with other ARV agents.

• Infants and Children <30 kg:

  • Oral: 1 mg/kg/dose every 12 hours; maximum dose: 30 mg/dose.

• Children and Adolescents weighing 30 to <60 kg:

  • Oral: 30 mg every 12 hours.

• Adolescents weighing ≥60 kg:

  • AIDS Info and WHO recommendation: Oral: 30 mg every 12 hours.
  • Note: The drug manufacturer's labeling (40 mg) is not recommended due to a greater incidence of adverse effects.

Pregnancy Risk Category: C

• Stavudine is highly transferable across the human placenta.
• According to the data from the antiretroviral pregnancy registry, there has not been an increase in overall birth defects after first-trimester stavudine exposure.
• Although maternal antiretroviral treatment (ART) may increase preterm birth rates, information is not available due to variability in maternal factors (disease severity and gestational age at the initiation of therapy),
• Some studies have shown an increased risk of stillbirth and low birth weight in infants under gestational age. However, not all studies have confirmed this.
• Maternal ART is a benefit that can be clearly demonstrated and should not be delayed due to concern for adverse neonatal outcomes.
• All infants who have been exposed to antiretroviral medication should be followed up for a long time. Children with significant organ system abnormalities (especially the heart or CNS) that are not of known etiology should be examined for possible mitochondrial dysfunction.
• [US Boxed Warning]Pregnant women who have used didanosine and stauvudine together with antiretroviral drugs have been known to develop fatal lactic acidosis. It is not recommended that you combine didanosine with didanosine.
• The use of nucleoside-reverse transcriptase inhibitors has been linked to cases of lactic acidosis, hepatic steatosis, and other complications related to mitochondrial toxicity.
• These adverse events are very similar to other life-threatening, rare syndromes that can occur during pregnancy (e.g. HELLP syndrome).
• Combining didanosine with stavudine can increase the risk for neurodevelopmental disabilities.
• Stavudine is not recommended for initial treatment in pregnant women who are antiretroviral-naive. Because of its toxic effects, it should not be used in conjunction with zidovudine or didanosine.
• The pharmacokinetics of stavudine are not affected by pregnancy. Dose adjustments are not necessary.
• A high risk of toxicities means that women who become pregnant while on therapy should stop taking stavudine. Instead, they should switch to a different regimen.
• To keep HIV-positive pregnant women under the control and to reduce the chance of perinatal transmission, it is generally recommended that ART be performed.
• Monitoring during pregnancy is more common than monitoring in adults who are not pregnant.
• All HIV-positive women should continue ART after birth. ART can also be modified once the baby is born.

Stavudine use during breastfeeding:

• Breast milk contains Stavudine; infants who breastfeed are not exposed to it.
• Postnatal HIV transmission can still be prevented by infant or maternal antiretroviral treatment. A multiclass-resistant virus was also detected in infants breastfeeding despite maternal therapy.
• In the United States, where formulas are affordable, safe, and durable, the risk of infant death due to diarrhea or respiratory infections is low and there is no need to breastfeed, women with HIV should stop breastfeeding in order to reduce the transmission of HIV (HHS [perinatal] 2018).

Stavudine Dose in Kidney Disease:

• 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

Stavudine Dose in Liver disease:

• There are no dosage adjustments provided in the DRUG manufacturer's labeling. Use with caution.

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

Common Side Effects of Stavudine:

• Central Nervous System:

  • Headache
  • Peripheral Neuropathy

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Increased Amylase
  • Increased Gamma-Glutamyl Transferase

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Vomiting
  • Increased Serum Lipase

• Hepatic:

  • Hyperbilirubinemia
  • Increased Serum AST
  • Increased Serum ALT

Contraindications to Stavudine:

• Allergy reactions to the active ingredient stavudine, or any component of formulation
• Coadministration with didanosine

Warnings and precautions

• Immune reconstitution syndrome:

  • Some patients may experience symptoms of immune reconstitution syndrome, which is an inflammatory response to an indolent, residual opportunistic HIV infection. This may occur during the initial days of HIV treatment. Patients may also develop autoimmune disorders such as Graves' disease or polymyositis later in therapy. Further evaluation and treatment may be necessary.

• Hepatomegaly and lactic acidosis: [US Boxed Warn]

  • With nucleoside analogues, severe hepatomegaly and lactic acidosis have been reported. This includes fatal cases. Co-administration of didanosine and stavudine is not recommended.
  • Patients at high risk for liver disease should be cautious (although acidosis has been reported in patients who have not been identified as having such risk factors), and patients who are pregnant, obese, or exposed to prolonged sunlight.
  • Withhold treatment for any patient who has clinical or laboratory findings that indicate lactic acidosis, liver toxicity or transaminase elevation (hepatomegaly or steatosis may not be accompanied).

• Lipoatrophy

  • Subcutaneous fat loss, particularly in the face, legs, and buttocks, may occur.
  • Cumulative exposure may increase the risk of lipoatrophy and make it more severe. However, this condition is possible to reverse.
  • Monitor patients for signs of lipoatrophy and consider switching to a non-stavudine-containing regimen if lipoatrophy occurs.

• Motor weakness

  • A severe motor weakness resembling Guillain Barre syndrome has been reported (including fatal cases), often in conjunction with lactic acidosis.
  • If motor weakness occurs (with or without the use of lactic acidosis), the drug manufacturer suggests discontinuation.

• Pancreatitis: [US Boxed Warning]

  • Combination therapy with didanosine has led to pancreatitis, some of which can be fatal.
  • It is not recommended to co-administrate didanosine and stavudine.
  • Patients with suspected pancreatitis should be advised to stop taking stavudine or any other toxic agents to their pancreas.
  • If you are diagnosed with pancreatitis, be cautious about re-initiating stavudine. Monitor closely and don't use didanosine.

• Peripheral neuropathy:

  • Peripheral neuropathy may be treatment-limiting, especially if the dose is higher.
  • Patients with advanced HIV or pre-existing peripheral neuropathy should be cautious.
  • If peripheral neuropathy develops, it is worth suspending therapy immediately. The effect could be reversed if the therapy is stopped immediately.
  • If therapy is stopped, symptoms may get worse.

• Suppression of bone marrow

  • Patients with bone marrow suppression should be cautious.

• Hepatic impairment

  • Patients with impaired liver function should be cautious. If the condition worsens, discontinue or suspend treatment.

• Renal impairment

  • Patients with a renal disorder should be cautious.
  • Recommendations for dosage adjustments

Stavudine: Drug Interaction

Monitoring parameters:

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

How to administer Stavudine?

• May be administered without regard to meals.
• The capsule may be opened and dispersed in a small amount of water; administer immediately.
• The oral solution should be shaken vigorously prior to use.

Mechanism of action of Stavudine:

• It is a thymidine analogue that interacts with HIV viral DNA dependent polymerase and causes stoppage of viral replication.

Absorption:

• Rapid

Distribution:

• Penetrates the CSF, achieving 16%-97% (mean: 59%%) of concomitant plasma levels; distributes to extravascular spaces and equally between RBCs & plasma

Protein binding:

• Negligible

Metabolism:

• Converted intracellularly to active triphosphate form;
• metabolism of stavudine plays a limited 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

Bioavailability:

• Capsule and solution are bioequivalent;
  • Children: 76.9%;
  • Adults: 86.4%

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

Time to peak, serum:

• 1 hour

Excretion:

• Urine 95% (74% in form of the unchanged drug);
• feces 3% (62% as unchanged drug)

International Brands of Stavudine:

• Zerit
• Zerit XR
• Landstav
• Ranstar
• Stag-30
• Stavir
• Stavirex
• Stavmat
• Tonavir
• Virostav

Stavudine Brand Names in Pakistan: