STAVUDINE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be administered without regard to meals.
Oral Liquid Formulations
-Shake well prior to each administration.
-Measure dosage with the measuring cup provided.

Reconstitution:
-Review the manufacturer's reconstitution instructions for the particular product and package size; the amount of water to be used for reconstitution may vary between manufacturers.

-Shake vigorously until the powder dissolves completely; the solution may appear slightly hazy.
-Storage: Store reconstituted solution in the refrigerator; discard any unused portion after 30 days.

Stavudine therapy can be associated with symptomatic peripheral neuropathy (52% in adults), which is dose-related and occurs more frequently in patients being treated with neurotoxic drug therapy, patients with advanced HIV infection, or in those who have previously experienced peripheral neuropathy. Symptoms include numbness, tingling, or pain in the hands or feet. Prompt drug withdrawal may resolve the neuropathy. In some cases, symptoms can worsen following drug withdrawal. If symptoms resolve completely, patients may tolerate restarting stavudine therapy at one-half the dose. If neuropathy recurs after resumption of stavudine, permanent discontinuation of stavudine therapy should be considered. Treatment of patients with a history of peripheral neuropathy requires special caution and close monitoring.

Commonly reported adverse reactions with stavudine in adults include headache (54%) and rash (unspecified) (40%). Allergic reaction, fever, chills, and myalgia were all noted in post-marketing reports. Adverse reactions reported in pediatric patients during clinical trials was similar to those observed in adults.

Hematologic disorders reported during post-marketing use of stavudine includes anemia, leukopenia, macrocytosis, neutropenia, and thrombocytopenia. These disorders may indicate bone marrow depression during stavudine therapy. Patients most at risk are those with initially low blood counts.

Adverse GI events associated with stavudine therapy that were reported in adult trials include diarrhea (50%) and nausea/vomiting (39%). Adverse reactions reported in pediatric patients during clinical trials were similar to those observed in adults. Fatal and non-fatal pancreatitis has been reported during postmarketing surveillance when stavudine is given as part of combination therapy with didanosine in both treatment-naive and treatment-experienced patients, regardless of the degree of immunosuppression of the patient. The combination of stavudine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis; concurrent treatment of stavudine and didanosine is contraindicated. Hyperamylasemia was noted in 14% of adult patients during trials with stavudine as monotherapy. Anorexia and abdominal pain were also noted in postmarketing reports.

Adverse reactions reported in pediatric patients during clinical trials was similar to those observed in adults. Stavudine therapy is commonly associated with mildly to moderately elevated hepatic enzymes; significant increases in AST or ALT occur in roughly 11% and 13% of adult patients, respectively. Increases up to 53% have been noted in patients on combination therapy. Hyperbilirubinemia was noted in up to 68% of patients during combination antiretroviral therapy with stavudine. Enzyme concentrations generally return to baseline after discontinuation of therapy. Cases of lactic acidosis and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside reverse transcriptase inhibitors, including stavudine during postmarketing surveillance. A majority of these cases have occurred in women. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine. In addition, deaths attributed to hepatotoxicity have occurred in patients receiving the combination of stavudine, didanosine, and hydroxyurea. Early signs and symptoms associated with a serum high lactate level may be subtle and include generalized fatigue, digestive symptoms (abdominal pain and sudden unexplained weight loss), respiratory symptoms (tachypnea and dyspnea), or neurologic symptoms. Patients with these symptoms should promptly interrupt antiretroviral therapy, and a full medical work-up should be performed rapidly. Hepatitis and hepatic failure have also been reported in postmarketing surveillance. Treatment with stavudine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, cohort and longitudinal studies suggest that this infrequent adverse event may be more often associated with antiretroviral regimens containing stavudine.

Rare cases of rapidly ascending neuromuscular weakness, mimicking the clinical presentation of Guillain-Barre syndrome (including respiratory failure), have been reported in HIV patients receiving stavudine in combination with other antiretrovirals. Some cases were fatal. Most cases were reported in the setting of lactic acidosis or symptomatic hyperlactatemia and, in most, antiretroviral therapy had been continued in the presence of non-specific signs compatible with early symptomatic hyperlactatemia that proceeded the development of neuromuscular signs and symptoms. If motor weakness develops in a patient receiving stavudine, the drug should be discontinued.

Lipoatrophy has been reported in patients receiving stavudine. The incidence and severity of lipoatrophy are cumulative over time with stavudine-containing regimens; monitor drug recipients for symptoms or signs of lipodystrophy. In clinical trials, treatment-naive patients receiving stavudine were more likely to develop lipodystrophy than patients receiving other nucleosides (tenofovir or abacavir). Given the potential risk associated with stavudine therapy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.


Diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance of stavudine. Because these events have been identified during the post-approval use of stavudine from an unknown population size, an estimate of frequency is not available.

Insomnia has been noted in post-marketing reports with stavudine.

Unplanned stavudine therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis), or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1-2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Cases of fatal and nonfatal pancreatitis have occurred in patients treated with stavudine in combination with didanosine in both treatment-naive and treatment-experienced patients, regardless of the degree of immunosuppression. Due to the increased risk for toxicity, concurrent treatment with stavudine and didanosine is contraindicated. If pancreatitis is suspected, treatment with stavudine and any other medication that may be toxic to the pancreas should be suspended. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close monitoring.

Stavudine should be used with caution in patients with known risk factors for hepatic disease. Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of stavudine. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, cohort and longitudinal studies suggest that this infrequent adverse event may be more often associated with antiretroviral regimens containing stavudine. Adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk also applies to pediatric females. Clinicians need to be alert for early diagnosis of this syndrome. Alcoholism, obesity, and prolonged exposure to nucleosides may also be risk factors for hepatotoxicity. However, hepatotoxicity has been reported in patients with no risk factors. In addition, deaths attributed to hepatotoxicity have occurred in patients receiving the combination of stavudine, didanosine, and hydroxyurea. Due to increased risk for toxicity, concurrent treatment of stavudine and didanosine is contraindicated, and use of stavudine and hydroxyurea should be avoided. Patients should be closely monitored for signs of liver toxicity during stavudine therapy. Treatment with stavudine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked elevation of hepatic enzymes. Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis.

Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients >= 2 years receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Patients with preexisting peripheral neuropathy should receive stavudine cautiously as it may exacerbate symptoms. Patients with advanced HIV disease or who are receiving concurrent neurotoxic agents are at increased risk. Caregivers of infants or young children should be counseled regarding detection of peripheral neuropathies. Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of neuromuscular disease, such as Guillain-Barre syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy.

Stavudine's renal clearance is considerably prolonged in patients with renal impairment. Dosage adjustments are required in patients with a creatinine clearance <= 50 ml/min and in patients with renal failure or receiving dialysis.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when stavudine is used either alone or in combination with other agents. Monotherapy with stavudine is not recommended.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children < 3 years is not usually recommended; however, treatment should be considered for all children >= 3 years and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Description: Stavudine (d4T) is an oral antiretroviral nucleoside reverse transcriptase inhibitor (NRTI). It is a synthetic thymidine nucleoside analog used in combination with other agents to treat HIV-infected patients. Stavudine is indicated as part of combination therapy for the treatment of HIV infection; it is not recommended to be given as monotherapy. Concurrent administration of stavudine and didanosine is contraindicated due to the potential for toxicity; concurrent treatment with zidovudine should also be avoided because of the potential for virologic antagonism. Lactic acidosis and severe hepatomegaly have been reported at a higher incidence than with other NRTIs. Stavudine is FDA-approved in pediatric patients as young as neonates.

NOTE: The HIV guidelines recommend that stavudine should never be used in pediatric patients due to the toxicity associated with this drug and the availability of safer agents; concurrent use with didanosine is contraindicated (due to increased toxicity risk).

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Stavudine is not recommended as part of an antiretroviral regimen in any patient due to an increased risk of serious toxicity.
-Refer to the HIV treatment guidelines for specific preferred and alternative regimens.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage (immediate release capsules or oral solution):
Neonates 0 to 13 days: 0.5 mg/kg/dose PO every 12 hours.
Neonates 14 to 29 days: 1 mg/kg/dose PO every 12 hours.
Infants and Children weighing less than 30 kg: 1 mg/kg/dose PO every 12 hours.
Children and Adolescents weighing 30 to 59 kg: 30 mg PO every 12 hours.
Children and Adolescents weighing 60 kg or more: 30 mg PO every 12 hours is recommended by HIV/WHO guidelines. 40 mg PO every 12 hours is the FDA-approved dosage.

Maximum Dosage Limits:
-Neonates
Less than 14 days: 1 mg/kg/day PO.
Greater than or equal to 14 days: 2 mg/kg/day PO.
-Infants
2 mg/kg/day PO.
-Children
Less than 30 kg: 2 mg/kg/day PO.
30 kg to less than 60 kg: 60 mg/day PO.
Greater than or equal to 60 kg: 80 mg/day PO.
-Adolescents
Less than 30 kg: 2 mg/kg/day PO.
30 kg to less than 60 kg: 60 mg/day PO.
Greater than or equal to 60 kg: 80 mg/day PO.

Patients with Hepatic Impairment Dosing
No dosage adjustment is required.

Patients with Renal Impairment Dosing
Dosing recommendations in pediatric patients:
GFR greater than 50 mL/min/1.73m2: No dosage adjustment needed.
GFR 30 to 50 mL/min/1.73m2: Reduce recommended dose by 50% and give every 12 hours.
GFR less than or equal to 29 mL/min/1.73m2: Reduce recommended dose by 75% and give every 24 hours.

FDA-approved recommendations in adults:
CrCl greater than 50 mL/min: No dosage adjustment needed.
CrCl 26 to 50 mL/min: Reduce recommended dose by 50% and give every 12 hours.
CrCl 10 to 25 mL/min: Reduce recommended dose by 50% and extend dosing interval to every 24 hours.

Other recommendations in adults:
GFR greater than 50 mL/min: No dosage adjustment needed.
GFR 10 to 50 mL/min: Reduce recommended dose by 50% and give every 12 to 24 hours.
GFR less than 10 mL/min: Reduce recommended dose by 50% and give every 24 hours

Intermittent hemodialysis
For pediatric patients, reduce the recommended dose by 75% and give every 24 hours and administer after dialysis on dialysis days. For adults, the FDA-labeled recommendations are to reduce the dose by 50% and give every 24 hours, administering the dose after the completion of hemodialysis on dialysis days.

Peritoneal dialysis
For pediatric patients, reduce the recommended dose by 75% and give every 24 hours.

Continuous renal replacement therapy (CRRT)
For pediatric patients, reduce the recommended dose by 50% and give every 12 hours.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Stavudine inhibits the replication of retroviruses. In vitro studies show it inhibits replication of HIV in human cells. Antiretroviral activity is dependent on phosphorylation by cellular kinases to stavudine triphosphate. Once in the active form, stavudine inhibits HIV reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate and by its incorporation into viral DNA causing a termination of DNA elongation. Stavudine inhibits DNA elongation because it lacks an essential 3'-OH group. Stavudine triphosphate also inhibits cellular DNA polymerase beta and gamma and reduces the synthesis of mitochondrial DNA.

Pharmacokinetics: Stavudine is administered orally. It distributes equally between red blood cells and plasma. Stavudine crosses the blood-brain barrier and distributes into cerebrospinal fluid. Protein binding is negligible.

Metabolism plays a limited role in stavudine clearance. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine. Approximately 95% a radiolabeled dose was recovered in the urine, with 73.7% recovered as parent drug. Approximately 3% of the radiolabeled dose was recovered in the feces, with 62% recovered as parent drug. Body clearance of the drug is independent of dose, regardless of route of administration. Terminal half-life following oral administration is roughly 2.3 hours in adults after a single oral dose. Excretion is about 40% renal via active tubular secretion and glomerular filtration.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Stavudine is rapidly absorbed after oral administration. The systemic exposure is the same regardless of capsule or solution administration. Mean absolute bioavailability is 86.4% +/- 18.2. Bioavailability increases proportionally to dosage, with peak concentrations occurring within 1 hour.


-Special Populations
Pediatrics
Neonates
In newborns from birth to 14 days, the elimination half-life of stavudine is about 5.5 hours; in newborns 14-28 days old, the elimination half-life decreases to 1.59 +/- 0.29 h after an oral dose.

Infants, Children, and Adolescents
The oral bioavailability of stavudine in pediatric patients aged 5 weeks to 15 years is 76.9% +/- 31.7. The volume of distribution in this population is 0.73 +/- 0.32 with a ratio of CSF:plasma (as %) 59 +/- 35. The elimination half-life is 0.96 +/- 0.26h after an oral dose.

Hepatic Impairment
The pharmacokinetics of stavudine are not altered in adult patients (n = 5) with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C).

Renal Impairment
In pediatric patients, urinary excretion may be altered in children with renal impairment; however, specific data are unavailable. In adults, renal insufficiency prolongs the terminal elimination half-life; however, Cmax and Tmax are not significantly altered by renal impairment. In patients with CrCl > 50 ml/min, the renal clearance is 167 +/- 65 ml/min with a half-life of 1.7 h +/- 0.4. In patients with CrCl 25-50 ml/min, the renal clearance is 73 +/- 18 ml/min with a half-life of 3.5 h +/- 2.5. In patients with CrCl 9-25 ml/min, the renal clearance is 17 +/- 3 ml/min with a half-life of 4.6 h +/- 0.9. In hemodialysis patients, the half-life is 5.4 h +/- 1.4. Patients with reduced creatinine clearance require dosage modification.