Stavudine

Pronunciation: STAV-ue-deen
Class: Nucleoside reverse transcriptase inhibitor

Trade Names

Zerit
- Capsules, oral 15 mg
- Capsules, oral 20 mg
- Capsules, oral 30 mg
- Capsules, oral 40 mg
- Powder for solution, oral 1 mg/mL after reconstitution

Pharmacology

Inhibits replication of HIV.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Stavudine is rapidly absorbed. C max and AUC range from 0.03 to 4 mg/kg. T max occurs 1 h after dosing.

Distribution

Stavudine distributes equally between RBCs and plasma. V d is approximately 46 L. Protein binding was negligible over the concentration range of 0.01 to 11.4 mcg/mL.

Metabolism

Limited role in the Cl of stavudine. Unchanged stavudine is the major drug-related component in plasma, while metabolites constitute minor components.

Elimination

Renal elimination accounts for approximately 40% of overall Cl regardless of the route of administration. Stavudine undergoes active tubular secretion as well as glomerular filtration. Approximately 95% excreted in the urine and 3% in the feces. Terminal elimination half-life is 2.3 h.

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.

Hepatic Function Impairment

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

Elderly

Pharmacokinetics have not been studied.

Gender

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

Race

No clinically important pharmacokinetic differences were associated with race.

Indications and Usage

For the treatment of HIV-1 infection in combination with other antiretroviral agents.

Contraindications

Hypersensitivity to stavudine or any components of the product.

Dosage and Administration

Adults

PO 40 mg every 12 h for patients weighing at least 60 kg; 30 mg every 12 h for patients weighing less than 60 kg.

Children 14 days of age and older

PO 1 mg/kg/dose every 12 h for patients weighing less than 30 kg; give those weighing at least 30 kg the adult dosage.

Children birth to 13 days of age

PO 0.5 mg/kg every 12 h.

Renal Function Impairment

Use drug cautiously in patients with renal impairment. Dosage adjustment based on renal function may be required.

Renal Function Impairment Dosage in Adults CrCl (mL/min) ≥ 60 kg < 60 kg > 50 40 mg every 12 h 30 mg every 12 h 26 to 50 20 mg every 12 h 15 mg every 12 h 10 to 25 20 mg every 24 h 15 mg every 24 h Hemodialysis

20 mg every 24 h for patients weighing at least 60 kg, or 15 mg every 24 h for patients weighing less than 60 kg, administered after the completion of hemodialysis on dialysis days and at the same time of the day on nondialysis days.

General Advice

  • May be taken without regard to food.
  • To reconstitute powder for oral solution, add 202 mL of purified water to the container. Shake vigorously until the powder dissolves completely. This results in 200 mL of a 1 mg/mL solution, which may appear slightly hazy.
  • Shake solution well prior to each dose.

Storage/Stability

Store capsules and powder for oral solution between 59° and 86°F in a tightly closed container protected from moisture. Store reconstituted solution in a refrigerator between 36° and 46°F. Keep the bottle tightly closed. Discard any unused solution after 30 days.

Drug Interactions

Didanosine

Lactic acidosis, hepatotoxicity, pancreatitis, or peripheral neuropathy has occurred when didanosine is given in combination with stavudine (with or without hydroxyurea). Combined administration of stavudine and hydroxyurea with or without didanosine should be avoided. Coadministration of stavudine and didanosine should be used with caution during pregnancy.

Doxorubicin, ribavirin

Phosphorylation of stavudine may be inhibited by doxorubicin and ribavirin. Coadministration should be undertaken with caution. Closely monitor for treatment-associated toxicities, especially hepatic decompensation.

Hydroxyurea

Coadministration may increase the risk for lactic acidosis, hepatotoxicity, pancreatitis, or peripheral neuropathy. Avoid combined administration of stavudine and hydroxyurea, with or without didanosine.

Methadone

Stavudine AUC and C max may be decreased. Close clinical and laboratory monitoring is warranted when methadone is started or stopped. Adjust the stavudine dose as needed.

Zidovudine

May competitively inhibit the phosphorylation of stavudine; this combination is not recommended.

Adverse Reactions

CNS

Headache (54%); peripheral neurologic symptoms/neuropathy (52%); insomnia, severe motor weakness, most often in the setting of lactic acidosis (postmarketing).

Dermatologic

Rash (40%).

GI

Diarrhea (50%); nausea/vomiting (39%); abdominal pain, anorexia, pancreatitis, including fatal cases (postmarketing).

Hematologic

Anemia, leukopenia, macrocytosis, neutropenia, thrombocytopenia (postmarketing).

Hepatic

Symptomatic hyperlactemia/lactic acidosis and hepatic steatosis, hepatitis and liver failure (postmarketing).

Lab Tests

Amylase at least 1.4 times the ULN (14%); ALT greater than 5 times ULN (13%); AST greater than 5 times the ULN (11%).

Metabolic

Diabetes mellitus, hyperglycemia, lipoatrophy, lipodystrophy (postmarketing).

Miscellaneous

Allergic reaction, chills/fever, myalgia, redistribution/accumulation of body fat (postmarketing).

Precautions

Warnings

Pancreatitis

Fatal and nonfatal cases have occurred in combination with didanosine in both treatment-naive and treatment-experienced patients.

Lactic acidosis and hepatomegaly

Reported with steatosis (including fatal cases) with the use of nucleoside analogues alone or in combination. Fatal lactic acidosis has been reported in pregnant women who have received didanosine and stavudine with other antiretroviral agents. Use the combination with caution in pregnant women and only if the benefit clearly outweighs the risk.


Monitor

Monitor patients for development of lactic acidosis and/or severe hepatomegaly with steatosis, pancreatitis, infection, and for the development of peripheral neuropathy. Monitor patients with preexisting liver dysfunction for liver function abnormalities according to standard practice.


Pregnancy

Category C . Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine.

Lactation

Undetermined. HIV-infected mothers should not breast-feed their infants.

Elderly

Stavudine is known to be substantially excreted by the kidneys. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

Renal Function

Dosage adjustment is recommended.

Hepatic Function

Safety and efficacy not established in HIV-infected patients with significant underlying liver disease.

Fat redistribution

Accumulation/redistribution of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have occurred in patients receiving antiretroviral therapy.

Hepatic effects

Patients with preexisting liver dysfunction have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events. Hepatotoxicity and hepatic failure resulting in death have been reported.

Immune reconstitution syndrome

During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections.

Peripheral neuropathy

Has been reported and is dose-related. Occurs more frequently in patients with advanced HIV disease or a history of peripheral neuropathy, or those receiving other drugs that have been associated with neuropathy (eg, didanosine). If peripheral neuropathy develops, consider permanent discontinuation of stavudine.

Overdosage

Symptoms

Hepatic toxicity; peripheral neuropathy.

Patient Information

  • Advise patients to take drug twice daily every 12 h without regard to meals.
  • Remind patients using solution to use measuring cup provided with drug and to shake bottle vigorously before measuring each dose.
  • Inform patients that drug does not completely eliminate HIV virus and therefore does not reduce risk of transmitting HIV. Appropriate precautions must be followed.
  • Advise patient that drug is not a cure for HIV infection and that the patient may continue to acquire illnesses associated with HIV infection, including opportunistic infections, and to remain under a health care provider's care.
  • Inform patients of the importance of early recognition of symptoms of symptomatic hyperlactemia or lactic acidosis, including unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness, and to seek immediate medical attention if these occur.
  • Inform patients that peripheral neuropathy has occurred with stavudine use and symptoms include numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their health care provider.
  • Inform patients that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine.
  • Inform patients that an increased risk of hepatoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea.
  • Advise patients with diabetes that oral solution contains sucrose 50 mg/mL.
  • Inform patients that redistribution/accumulation of body fat may occur in patients receiving antiretroviral therapy, including stavudine.
  • Instruct patients to avoid alcohol while taking stavudine.

Copyright © 2009 Wolters Kluwer Health.

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