VA Class:AM800
Stavudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).1, 2, 4, 6, 7, 11, 12, 20, 21, 23, 24, 200
Stavudine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients.1
Stavudine usually has been used in multiple-drug regimens that include another HIV nucleoside reverse transcriptase inhibitor (NRTI) (dual NRTIs) and either an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) or HIV protease inhibitor (PI) (NNRTI- or PI-based regimens).1, 200, 201
The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the individual patient.200, 201, 202 For information on general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, see the Antiretroviral Agents General Statement 8:18.08.
Antiretroviral-naive Adults and Adolescents
The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that stavudine is not recommended for initial treatment regimens in antiretroviral-naive adults or adolescents.200
A dual NRTI option of stavudine and lamivudine is not recommended as a component in initial treatment regimens in antiretroviral-naive adults or adolescents because of reported toxicities (e.g., lipoatrophy, peripheral neuropathy, hyperlactatemia including lactic acidosis, hepatic steatosis, pancreatitis).200
A dual NRTI option of stavudine and didanosine should not be used at any time because of a high incidence of toxicities (e.g., peripheral neuropathy, pancreatitis, lactic acidosis).200, 202 (See HIV Nucleoside Reverse Transcriptase Inhibitors [NRTIs] under Drug Interactions: Antiretroviral Agents and see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
A dual NRTI option of stavudine and zidovudine should not be used at any time because of antagonistic antiretroviral effects.200, 202 (See HIV Nucleoside Reverse Transcriptase Inhibitors [NRTIs] under Drug Interactions: Antiretroviral Agents.)
Safety and efficacy of stavudine in treatment-naive (have not previously received antiretroviral therapy) adults have been evaluated in several randomized, open-label studies.1 In one study (Start 1), a PI-based regimen of indinavir given with stavudine and lamivudine was compared with a regimen of indinavir given with zidovudine and lamivudine.1 In another study (Start 2), a PI-based regimen of indinavir, stavudine, and didanosine was compared with a regimen of indinavir, zidovudine, and lamivudine.18 At 48 weeks, a regimen of stavudine and either lamivudine or didanosine used in conjunction with indinavir resulted in decreases in plasma HIV-1 RNA levels and increases in CD4+ T-cell counts that were comparable or superior to those associated with a regimen of zidovudine, lamivudine, and indinavir.1, 18
Antiretroviral-experienced Adults and Adolescents
Although monotherapy is no longer recommended for the treatment of HIV infection,200 efficacy of stavudine in previously-treated patients was demonstrated in a randomized, double-blind study (study AI455-019) in 822 HIV-infected adults who had been receiving zidovudine monotherapy for a median duration of about 88 weeks (range: 11-356 weeks) and had median baseline CD4+ T-cell counts of about 235/mm3 (range: 10-735/mm3).1, 47 In terms of progression of HIV-1 disease and death, outcomes were similar for both drugs.1
Stavudine is used in conjunction with other antiretroviral agents for the treatment of HIV infection in pediatric patients who were treatment-naive or previously received antiretroviral therapy.1, 13, 14, 15, 39, 48, 55, 62
For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or NNRTI in conjunction with 2 NRTIs (dual NRTIs).201 These experts state that a dual NRTI option of stavudine and either lamivudine or emtricitabine may be used in children of any age, but should be considered only in special circumstances.201
The dual NRTI option of stavudine and didanosine has been associated with a high incidence of toxicities (e.g., lactic acidosis, peripheral neuropathy, pancreatitis) and is not recommended for use in initial treatment regimens in antiretroviral-naive children.201
A dual NRTI option of stavudine and zidovudine should not be used at any time because of antagonistic antiretroviral effects.201
Use of stavudine in pediatric patients for the treatment of HIV infection is supported by evidence from adequate and controlled studies in adults and additional safety and pharmacokinetic data in pediatric patients.1 Safety and efficacy of 3- or 4-drug regimens that include stavudine have been evaluated in treatment-naive HIV-infected children13, 48, 62 and previously treated children.14, 15, 55
For further information on treatment of HIV infection in pediatric patients, see Guidelines for Use of Antiretroviral Agents: Antiretroviral Therapy in Pediatric Patients, in the Antiretroviral Agents General Statement 8:18.08.
Postexposure Prophylaxis following Occupational Exposure to HIV
Stavudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199
The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada®).199 These experts state that stavudine is one of several alternative agents that may be used in conjunction with other antiretrovirals in PEP regimens, but should be used only with expert consultation.199 Because of the risk of toxicity (e.g., peripheral neuropathy, pancreatitis, lactic acidosis), a dual NRTI option of stavudine and didanosine should not be used in PEP regimens.199
Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199
For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP, see Guidelines for Use of Antiretroviral Agents: Antiretrovirals for Postexposure Prophylaxis following Occupational Exposure to HIV (PEP), in the Antiretroviral Agents General Statement 8:18.08.
Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Stavudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.198
For additional information on nonoccupational exposure to HIV and recommendations regarding nPEP, see Guidelines for Use of Antiretroviral Agents: Antiretrovirals for Postexposure Prophylaxis following Sexual, Injection Drug Use, or other Nonoccupational Exposures to HIV (nPEP), in the Antiretroviral Agents General Statement 8:18.08.
Stavudine is administered orally every 12 hours without regard to meals.1
Stavudine powder for oral solution should be reconstituted prior to administration by adding the amount of purified water specified to provide a solution containing 1 mg/mL.1 The container should be shaken vigorously until the powder dissolves completely; the solution may appear slightly hazy1 Reconstituted stavudine solutions should be shaken well prior to measuring a dose; unused solution should be discarded after 30 days when stored as directed.1
Dosage of stavudine is based on patient weight.1
For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, the usual dosage of stavudine is 40 mg every 12 hours in those weighing 60 kg or more and 30 mg every 12 hours in those weighing less than 60 kg.1
Postexposure Prophylaxis following Occupational Exposure to HIV
For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the recommended dosage of stavudine is 40 mg twice daily in adults weighing more than 60 kg or 30 mg twice daily in adults weighing less than 60 kg.199 Stavudine is used in conjunction with other antiretrovirals.199 (See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)
The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199
Postexposure Prophylaxis following Nonoccupational Exposure to HIV
For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP), the usual dosage of stavudine is 40 mg twice daily in adults weighing 60 kg or more or 30 mg twice daily in adults weighing less than 60 kg.198 Stavudine is used in conjunction with other antiretrovirals.198 (See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.)
The nPEP regimen should be initiated as soon as possible following nonoccupational exposure to HIV (preferably within 72 hours) and continued for 28 days.198
For the treatment of HIV-1 infection, the recommended dosage of stavudine for neonates from birth to 13 days of age is 0.5 mg/kg every 12 hours.1 For pediatric patients at least 14 days of age who weigh less than 30 kg, the recommended dosage of stavudine is 1 mg/kg every 12 hours.1
Pediatric patients weighing 30 kg or more may receive the recommended adult dosage.1
Because elimination of stavudine may be reduced in patients with renal impairment, dosage of the drug should be reduced in adults with a creatinine clearance of 50 mL/minute or less and in those undergoing hemodialysis.1 (See Table 1.)
Clcr (mL/minute) | Weight <60 kg | Weight ≥60 kg |
|---|---|---|
26-50 | 15 mg every 12 hours | 20 mg every 12 hours |
10-25 | 15 mg every 24 hours | 20 mg every 24 hours |
Hemodialysis patients | 15 mg every 24 hours given after completion of dialysis on dialysis days and at same time of day on nondialysis days | 20 mg every 24 hours given after completion of dialysis on dialysis days and at same time of day on nondialysis days |
Although stavudine clearance may be altered in pediatric patients with renal impairment,1 data are insufficient to recommend specific dosage adjustments in such children.1
Hepatic Effects and Lactic Acidosis
Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving stavudine and also have been reported in patients receiving other human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitors (NRTIs).1 Although relative rates of lactic acidosis have not been assessed in prospective well-controlled studies, longitudinal cohort and retrospective studies suggest that this adverse effect may occur more often with antiretroviral regimens that include stavudine.1 Female gender, obesity, and long-term therapy with NRTIs also may be risk factors.1 Fatal lactic acidosis has been reported in pregnant women who received antiretroviral regimens that included both stavudine and didanosine.1, 49, 202 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.) In addition, deaths attributed to hepatotoxicity have occurred in patients who received antiretroviral regimens that included stavudine, didanosine, and hydroxyurea.1 For further information on lactic acidosis and hepatomegaly in patients receiving NRTIs, see Cautions: Hepatic Effects and Lactic Acidosis, in Zidovudine 8:18.08.20.
Increased serum concentrations of AST (SGOT),1 ALT (SGPT),1γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP),1 and bilirubin1 have been reported in patients receiving stavudine. In early clinical studies evaluating stavudine, increased serum concentrations of AST or ALT (more than 5 times the upper limit of normal) were reported in 11-13% of patients receiving stavudine alone.1 In more recent clinical studies evaluating use of stavudine in conjunction with other antiretroviral agents (indinavir and either didanosine or lamivudine), the overall incidence of increased serum concentrations of GGT was 15-28% and the overall incidence of increased serum concentrations of AST, ALT, or bilirubin was 40-68%; AST, ALT, or GGT concentrations were more than 5 times the upper limit of normal in 2-8% of patients.1
Hepatitis and liver failure have been reported in patients receiving stavudine during postmarketing experience.1
Liver function abnormalities, including severe and potentially fatal hepatic events, have occurred in patients with preexisting hepatic dysfunction (e.g., chronic active hepatitis) receiving multiple-drug antiretroviral regimens.1 Hepatotoxicity has been reported more frequently in patients receiving stavudine, didanosine, and hydroxyurea than in those receiving stavudine alone; death attributed to hepatotoxicity has occurred in patients receiving stavudine, didanosine, and hydroxyurea.1 Hepatic decompensation, sometimes fatal, has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with interferon alfa (or peginterferon alfa) and ribavirin.1, 80
Potentially severe peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in about 52% of patients receiving stavudine alone and in 8-21% of patients receiving stavudine in conjunction with other antiretroviral agents (indinavir and either lamivudine or didanosine).1 Stavudine-associated peripheral neuropathy appears to be dose-related, and has been reported most frequently in patients with advanced HIV, patients with a history of peripheral neuropathy, or patients receiving other neurotoxic drugs (e.g., didanosine).1
Stavudine-associated peripheral neuropathy may resolve if the drug is promptly discontinued; however, symptoms may worsen temporarily in some patients following discontinuance of the drug.1 Permanent discontinuance of stavudine should be considered in patients who develop peripheral neuropathy.1 (See Cautions: Precautions and Contraindications.)
In clinical studies evaluating stavudine, headache was reported in 54% of patients receiving stavudine alone and in 25-46% of those receiving stavudine in conjunction with other antiretroviral agents (indinavir and either didanosine or lamivudine).1 During postmarketing experience, insomnia has been reported.1
Rapidly ascending neuromuscular weakness, which has been fatal in some cases, has been reported rarely in patients receiving stavudine in conjunction with other antiretroviral agents.1, 75 Most reported cases of motor weakness occurred in the setting of lactic acidosis or symptomatic elevations of serum lactate concentrations. 1, 75 (See Cautions: Hepatic Effects and Lactic Acidosis.) The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure).1 If motor weakness develops in a patient receiving stavudine, the drug should be discontinued.1 Symptoms may continue or worsen following discontinuance.1
Pancreatitis, which has been fatal in some cases, has occurred in patients receiving stavudine in conjunction with didanosine and has been reported in both treatment-naive and previously-treated patients, regardless of degree of immunosuppression.1 In an early clinical study evaluating stavudine, pancreatitis was observed in less than 1% of adult patients receiving stavudine monotherapy.1 Patients receiving didanosine in conjunction with stavudine (with or without hydroxyurea) may be at increased risk of pancreatitis.1 Stavudine, didanosine, and any other agent toxic to the pancreas should be discontinued in any patient who develops suspected pancreatitis.1 (See Cautions: Precautions and Contraindications.)
Increased serum concentrations of amylase1 or lipase1 have been reported in 21-31% of patients receiving stavudine in conjunction with other antiretroviral agents (indinavir and either didanosine or lamivudine); 4-8% of patients had amylase or lipase concentrations more than 2 times the upper limit of normal.1
Diarrhea, nausea, and vomiting have been reported in patients receiving stavudine.1 In early clinical studies evaluating stavudine, diarrhea was reported in 50% and nausea and vomiting were reported in 39% of patients receiving stavudine alone.1 In more recent clinical studies evaluating stavudine used in conjunction with other antiretroviral agents (indinavir and either didanosine or lamivudine), diarrhea was reported in 34-45%, nausea in 43-53%, and vomiting in 18-30% of patients.1
Abdominal pain and anorexia have been reported in patients receiving stavudine during postmarketing surveillance.1
Dermatologic and Sensitivity Reactions
Rash has been reported in 40% of patients receiving stavudine alone and in 18-30% of those receiving stavudine in conjunction with other antiretroviral agents (indinavir and either didanosine or lamivudine) in clinical studies.1
Allergic reaction has been reported in patients receiving stavudine during postmarketing surveillance.1
Unlike zidovudine, stavudine does not appear to be myelosuppressive.51 However, anemia, leukopenia, and thrombocytopenia have been reported in some patients receiving stavudine during postmarketing surveillance.1
Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents, including stavudine.1, 50 The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown.1 A causal relationship has not been established.1
In clinical trials in treatment-naive patients, a higher incidence of clinical lipoatrophy or lipodystrophy occurred in patients receiving stavudine than in patients receiving other NRTIs (e.g., abacavir, tenofovir, zidovudine).1 The incidence and severity of lipoatrophy or lipodystrophy with stavudine-containing regimens are cumulative over time.1 In clinical trials, switching from stavudine to other NRTIs (abacavir, tenofovir) resulted in increases in limb fat with modest to no improvement in clinical lipoatrophy.1 (See Cautions: Precautions and Contraindications.)
Immune Reconstitution Syndrome
During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1
Other adverse effects that have been reported in patients receiving stavudine during postmarketing experience include chills,1 fever,1 myalgia,1 hyperglycemia,1 and diabetes mellitus.1
Precautions and Contraindications
Stavudine is contraindicated in patients hypersensitive to the drug or to any ingredient in the respective formulation.1
In 2010, the US Food and Drug Administration (FDA) required and approved a Risk Evaluation and Mitigation Strategy (REMS) for stavudine that required that a medication guide be provided to the patient each time the drug was dispensed and required the manufacturer to periodically submit REMS assessments to the FDA.81 In May 2011, the FDA rescinded the REMS requirement for stavudine; however, the medication guide remains part of stavudine approved product labeling.82
Use of stavudine or other NRTIs has been associated with potentially fatal lactic acidosis and severe hepatomegaly with steatosis.1 (See Cautions: Hepatic Effects and Lactic Acidosis.) Stavudine should be discontinued in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1 Permanent discontinuance of stavudine should be considered in patients with confirmed lactic acidosis.1 Stavudine should be used with caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.1 Patients should be advised that generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, sudden unexplained weight loss), respiratory symptoms (tachypnea, dyspnea), or neurologic symptoms (including motor weakness) might be indicative of symptomatic hyperlactatemia or lactic acidosis syndrome and that they should contact their clinician immediately if these symptoms occur.1
Safety and efficacy of stavudine have not been established in HIV-infected patients with substantial underlying liver disease.1 Because hepatic toxicity has been reported in patients with underlying hepatic dysfunction (including chronic active hepatitis) receiving multiple-drug antiretroviral regimens, such patients should be closely monitored.1 If worsening of liver disease occurs, interruption or discontinuance of therapy should be considered.1 Because an increased risk of potentially fatal hepatotoxicity may occur in patients receiving stavudine in conjunction with didanosine and hydroxyurea, concomitant use of didanosine, stavudine, and hydroxyurea should be avoided.1 Patients receiving stavudine with interferon alfa (or peginterferon alfa) with or without ribavirin should be closely monitored for toxicity, especially hepatic decompensation.1, 80 Discontinuance of stavudine should be considered as appropriate.1 If treatment-associated toxicity, including hepatic decompensation (e.g., Child-Pugh score greater than 6) occurs, dosage adjustment or discontinuance of interferon alfa (or peginterferon alfa) and/or ribavirin should be considered.1, 80
Patients receiving stavudine should be monitored for the development of peripheral neuropathy.1 Patients and caregivers of young children should be advised that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during stavudine therapy and usually occurs in patients with advanced HIV infection or a history of peripheral neuropathy.1 If peripheral neuropathy occurs in a patient receiving stavudine, permanent discontinuance of the drug should be considered.1
Fatal and nonfatal pancreatitis has been reported in patients receiving stavudine in conjunction with didanosine.1 Stavudine, didanosine, and any other agent toxic to the pancreas should be discontinued in any patient who develops suspected pancreatitis.1 Reinitiation of stavudine following a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring.1 If stavudine is reinitiated in these patients, didanosine should not be included in the regimen.1
Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and queried about body changes related to these effects.1 Patients should be advised that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are as yet unknown.1 (See Cautions: Adipogenic Effects.)
Because of potential risks associated with stavudine (including clinical lipoatrophy or lipodystrophy), clinicians should assess the benefits versus risks of the drug for each patient and should consider alternative antiretrovirals.1
Stavudine in conjunction with other antiretroviral agents is not a cure for HIV infection, and patients receiving the drugs may continue to develop opportunistic infections and other complications associated with HIV disease.1 Patients should be informed of the critical nature of compliance with HIV therapy and the importance of remaining under the care of a clinician.1 Patients should be advised to take their antiretroviral regimen exactly as prescribed and to not alter or discontinue the regimen without consulting a clinician.1
Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Patients should continue to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.1, 200
Patients with diabetes mellitus should be advised that stavudine oral solution contains 50 mg of sucrose per mL.1
Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients.1
Safety of stavudine in pediatric patients was initially evaluated in 3 clinical studies: study ACTG 240, in which 105 pediatric patients ages 3 months to 6 years received stavudine (2 mg/kg daily) for a median of 6.4 months; a controlled clinical study in which 185 neonates received stavudine (2 mg/kg daily) alone or in conjunction with didanosine from birth through 6 weeks of a and a clinical study in which 8 neonates received stavudine (2 mg/kg daily) in conjunction with didanosine and nelfinavir from birth through 4 weeks of age.1 Adverse effects and laboratory abnormalities reported in these pediatric clinical studies generally were similar to those reported in adult studies.1
Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and older to determine whether geriatric patients respond differently than younger patients.1 However, greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.1
In a monotherapy Expanded Access Program (EAP) for patients with advanced HIV infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 16 or 38% of geriatric patients receiving stavudine in a dosage of 20 or 40 mg twice daily, respectively, compared with 25 or 30% of the approximately 12,000 patients enrolled in the EAP who developed such symptoms after the same stavudine dosages.1 Therefore, the manufacturer states that geriatric patients should be closely monitored for signs and symptoms of peripheral neuropathy.1 In addition, stavudine is known to be substantially excreted by the kidney and the risk of stavudine-induced toxicity may be increased in patients with renal impairment.1 Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.1 Dosage adjustment is recommended for patients with renal impairment. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)1
Mutagenicity and Carcinogenicity
Stavudine was not mutagenic in the Ames, Escherichia coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation.1 However, stavudine produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test.1 In the in vitro assays, stavudine elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25-250 mcg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25-2500 mcg/mL, with and without metabolic activation).1 In the in vivo micronucleus assay in mice, stavudine was clastogenic in bone marrow cells at dosages of 600-2000 mg/kg daily for 3 days.1
There was no evidence of carcinogenicity in 2-year studies in mice or rats using dosages that produced exposures (based on area under the plasma concentration-time curve [AUC]) that were 39 or 168 times, respectively, the expected human exposure at recommended dosages.1 Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure that were 250 or 732 times, respectively, the expected human exposure at recommended dosages.1
Pregnancy, Fertility, and Lactation
Stavudine crosses the placenta in rats, and concentrations of the drug in rat fetal tissue are approximately 50% of those present in maternal plasma.1 Reproduction studies in rats and rabbits using stavudine exposures (based on peak plasma concentrations) up to 399 and 183 times, respectively, the expected human exposure associated with a dosage of 1 mg/kg daily have not revealed evidence of teratogenicity.1 There was an increased incidence of rat fetuses with a common skeletal variation (unossified or incomplete ossification of sternebra) with stavudine exposures that were 399 times the usual human exposure; no effect was observed at exposures 216 times the usual human exposure.1 In addition, a slight postimplantation loss was noted at exposure 216 times the usual human exposure, but no effect with exposures approximately 135 times the usual human exposure.1 An increase in early rat neonatal mortality (birth to 4 days of age) also occurred at stavudine exposures 399 times the usual human exposure, while survival of neonates was unaffected at approximately 135 times the usual human exposure.1 However, it should be noted that animal reproduction studies are not always predictive of human response.1
There are no adequate and controlled studies to date using stavudine in pregnant women, and the drug should be used during pregnancy only if potential benefits justify potential risks.1
The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that stavudine is not recommended for initial treatment regimens in antiretroviral-naive pregnant women because of reported toxicities.202 If stavudine is used during pregnancy, these experts state that it should not be used in a dual NRTI option that includes didanosine or zidovudine.202 (See HIV Nucleoside Reverse Transcriptase Inhibitors [NRTIs] under Drug Interactions: Antiretroviral Agents.)
Fatal lactic acidosis and hepatic failure have been reported in pregnant women who received antiretroviral regimens that included both stavudine and didanosine.1, 49, 202 In 3 reported cases of fatal lactic acidosis, the women were either pregnant or postpartum and had received both stavudine and didanosine throughout gestation; in 2 of these cases, pancreatitis also occurred.49 The infants of 2 of these pregnancy-related cases of fatal lactic acidosis also died: one in utero at 32 weeks of gestation and one after emergency caesarian section at 36 weeks of gestation.49 Several cases of nonfatal pancreatitis, with and without lactic acidosis or hepatic failure, also have been reported in pregnant women receiving regimens that included both stavudine and didanosine.49 Women receiving NRTIs appear to be at increased risk of lactic acidosis and severe hepatomegaly with steatosis, and it is unclear whether pregnancy potentiates this risk.1, 49 A regimen that includes both stavudine and didanosine should be used with caution in pregnant women and only if no other alternatives are available.1 In addition, clinicians caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis and hepatitis steatosis syndrome.1
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including stavudine, an antiretroviral pregnancy registry has been established; clinicians are encouraged to contact the registry at 800-258-4263 or [Web] to report cases of prenatal exposure to antiretroviral agents.1, 202
No evidence of impaired fertility has been observed in rats with stavudine exposures (based on peak plasma concentrations) up to 216 times the expected human exposure associated with a dosage of 1 mg/kg daily.1
Stavudine is distributed into human breast milk.202 (See Pharmacokinetics: Distribution.)
Because of the risk of transmission of HIV to an uninfected infant through breast milk, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy.1, 202 Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from stavudine in nursing infants, women should be instructed not to breast-feed while they are receiving stavudine.1
In one limited study in human immunodeficiency virus (HIV)-infected adults, concomitant use of fluconazole (200 mg once daily) and stavudine (30 or 40 mg twice daily) for 7 days resulted in an 11% decrease in peak plasma concentrations of stavudine but did not affect the area under the plasma concentration-time curve (AUC) of the drug.38
In one limited study in HIV-infected adults, concomitant use of rifabutin (300 mg once daily) and stavudine (30 or 40 mg twice daily) for 7 days resulted in an 16% decrease in the AUC and a 31% decrease in peak plasma concentrations of stavudine.38
HIV Entry and Fusion Inhibitors
There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and stavudine.224
HIV Integrase Inhibitors (INSTIs)
There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and stavudine.236
In vitro studies indicate that additive to synergistic antiretroviral effects can occur between raltegravir and stavudine.225
HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
In vitro studies using some HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, nevirapine) indicate that the antiretroviral effects of stavudine and these drugs may be additive or synergistic against HIV-1.213, 215 There is no in vitro evidence of antagonistic antiretroviral effects between stavudine and etravirine214 or rilpivirine.226
Concomitant use of stavudine (30-40 mg twice daily) and nevirapine (200 mg once daily for 14 days, then 200 mg twice daily for 14 days) does not have a clinically important effect on peak plasma concentrations or AUC of stavudine.215
Pharmacokinetic interactions are not expected if rilpivirine is used concomitantly with stavudine.226
HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Results of in vitro studies indicate that the antiretroviral effects of stavudine and other HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, didanosine, emtricitabine, lamivudine, tenofovir) may be additive to synergistic against HIV-1.1, 28, 29, 218, 219, 221 However, antagonism has been reported when stavudine was used with zidovudine.26, 28, 29, 200
Concomitant use of stavudine and didanosine (with or without hydroxyurea) is associated with an increased risk of pancreatitis, peripheral neuropathy, and lactic acidosis.1, 200 Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with stavudine used in conjunction with didanosine and hydroxyurea.1
Although the manufacturers state that the dual NRTI option of stavudine and didanosine should be used with caution and is recommended during pregnancy only if potential benefits clearly outweigh potential risks,1, 217 experts state that stavudine and didanosine should not be used concomitantly at any time, including during pregnancy, because of a high incidence of toxicities.200, 202 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.) Concomitant use of stavudine, didanosine, and hydroxyurea should be avoided.1
There are no clinically important pharmacokinetic interactions between stavudine and emtricitabine.218
In a pharmacokinetic study evaluating concomitant use of a single dose of stavudine (40 mg) and lamivudine (150 mg) in HIV-infected individuals, peak plasma concentrations of stavudine were increased 12%, but the AUC of stavudine and the peak plasma concentration and AUC of lamivudine were not affected.1 This pharmacokinetic interaction is not considered clinically important.1
Zidovudine and stavudine should not be used concomitantly at any time because of in vitro and in vivo evidence of antagonistic antiretroviral effects.1, 200, 201, 202 Antagonism may occur because zidovudine and stavudine compete for cellular thymidine kinase that is needed for monophosphorylation of both drugs.1, 29
Results of in vitro studies indicate that the antiretroviral effects of stavudine and some HIV protease inhibitors (PIs), including amprenavir (commercially available as fosamprenavir), nelfinavir, saquinavir, and tipranavir are additive or synergistic against HIV-1.28, 32, 205, 208, 210, 211 There is no in vitro evidence of antagonistic antiretroviral effects between stavudine and atazanavir203 or darunavir.204
Although specific data are not available, a pharmacokinetic interaction between stavudine and darunavir is unlikely.204
Concomitant use of indinavir (800 mg 3 times daily) and stavudine (40 mg twice daily) for 1 week in HIV-infected patients did not result in clinically important changes in indinavir plasma concentrations or AUC, but resulted in decreased peak plasma concentrations and increased AUC of stavudine.206
There are no clinically important drug interactions between stavudine and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir).207
Concomitant use of stavudine (30-40 mg every 12 hours) and nelfinavir (750 mg every 8 hours) for 56 days did not have a clinically important effect on peak plasma concentrations or AUCs of either drug.1
Concomitant use of stavudine and ritonavir-boosted tipranavir does not have any clinically important effects on stavudine pharmacokinetics.211
In one limited study in HIV-infected adults, concomitant use of clarithromycin (500 mg twice daily) and stavudine (30 or 40 mg twice daily) for 7 days resulted in an 8% decrease in the AUC and a 15% decrease in peak plasma concentrations of stavudine.38
Doxorubicin inhibits phosphorylation of stavudine in vitro.1 While the clinical importance of the interaction is unknown, concomitant use should be undertaken with caution.1
In multiple-dose studies in HIV-infected adults, concomitant use of ganciclovir (1000 mg every 8 hours) and stavudine (40 mg every 12 hours) did not affect the pharmacokinetics of either drug.54
Clinically important interactions are not expected with concomitant use of stavudine and simeprevir.187
When stavudine is used in conjunction with didanosine, with or without hydroxyurea, there is an increased risk of pancreatitis, peripheral neuropathy, and hepatotoxicity.1 Concomitant use of stavudine and hydroxyurea should be avoided.1 (See Didanosine under Drug Interactions: HIV Nucleoside Reverse Transcriptase Inhibitors [NRTIs].)
Concomitant use of methadone and stavudine decreases peak plasma concentrations and AUC of stavudine.31, 200 In a limited number of individuals, concomitant use of stavudine and methadone resulted in a 44% decrease in peak concentrations and a 25% decrease in the AUC of stavudine; trough concentrations of methadone did not appear to be affected.31 Some experts suggest that dosage adjustments are not necessary in patients receiving the drugs concomitantly.200
Although further study is needed, it has been suggested that concomitant use of ribavirin and NRTIs may increase the risk of mitochondrial dysfunction and associated toxicities (e.g., lactic acidosis) reported with this group of antiretroviral agents.65, 66, 68 There have been several reports of lactic acidosis or pancreatitis occurring in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with ribavirin and interferon alfa (or peginterferon alfa).65, 68 These patients had been receiving long-term therapy with antiretroviral regimens that included one or more NRTIs (abacavir, didanosine, stavudine, zidovudine) and were clinically stable until lactic acidosis or pancreatitis developed 4-6 months after a regimen of ribavirin and interferon alfa was initiated for the treatment of chronic HCV infection.65, 68 Because ribavirin also is a nucleoside analog, it has been suggested that concomitant use of ribavirin and NRTIs may result in an adverse additive effect on mitochondrial function; however, other clinicians suggest that ribavirin may have potentiated the effects of the NRTIs through some other mechanism or that the viral diseases themselves may have been partly responsible for mitochondrial dysfunction in these patients.65, 66, 67, 68
In vitro, ribavirin inhibits the phosphorylation of stavudine.1 No changes in stavudine pharmacokinetics (i.e., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or loss of virologic suppression of HIV or HCV were observed in HIV-infected patients coinfected with HCV receiving ribavirin and stavudine as part of a multiple-drug regimen.1
The manufacturer of ribavirin states that concomitant use of ribavirin and nucleoside analogs should be undertaken with caution and only if the potential benefits outweigh the potential risks.64
Limited information is available on the acute toxicity of stavudine.1 No acute toxicity was reported in adults who received stavudine in dosages 12-24 times the usually recommended dosage.1 Chronic overdosage may result in peripheral neuropathy and hepatic toxicity.1
If acute overdosage of stavudine occurs, supportive and symptomatic treatment should be initiated and the patient should be observed carefully. Stavudine can be removed by hemodialysis; it is not know whether the drug is removed by peritoneal dialysis.1
Following conversion to a pharmacologically active metabolite, stavudine apparently inhibits replication of retroviruses, including human immunodeficiency virus (HIV), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1, 2, 3, 4, 9, 12, 16, 17, 21, 23 The drug, therefore, exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor.1, 2, 3, 4, 9, 12, 16, 17, 21, 23
Like other nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, zidovudine), the antiviral activity of stavudine appears to depend on intracellular conversion of the drug to a 5'-triphosphate metabolite;2, 3, 4, 9, 12, 16, 17, 21 thus, dideoxydidehydrothymidine-5'-triphosphate (d4T-triphosphate) and not unchanged stavudine appears to be the pharmacologically active form of the drug.2, 3, 4, 16, 17, 21
Like zidovudine and didanosine, stavudine appears to enter cells by passive diffusion.2, 5, 9 Following entry into human cells, there are substantial differences in the rates at which cells phosphorylate the various nucleoside-analog antiviral agents and in the enzymatic pathways involved.2, 3, 4, 9, 16, 17, 21 Stavudine generally is phosphorylated about 180-fold less efficiently than zidovudine;2, 4, 11, 17 however, because of differences in their patterns of phosphorylation, equimolar amounts of the 2 compounds are metabolized to similar intracellular levels of active triphosphate metabolite.17 Consequently, stavudine, compared with zidovudine, has slightly less but comparable activity against HIV in vitro.2, 4, 6, 9, 11, 16, 17, 20, 21, 23
Enzymatic conversion of stavudine to d4T-triphosphate appears to be complex, involving several steps and enzymes.2, 8, 17, 21 Stavudine is first converted to dideoxydidehydrothymidine-5'-monophosphate (d4T-monophosphate) by thymidine kinase.2, 4, 8, 17, 22 Subsequently, d4T-monophosphate is converted to dideoxydidehydrothymidine-5'-diphosphate (d4T-diphosphate), and then to d4T-triphosphate, presumably by the same cellular kinases involved in the metabolism of zidovudine.2, 3, 8, 17 Phosphorylation of stavudine to d4T-monophosphate appears to be the rate-limiting reaction, and subsequent conversion to the diphosphate and triphosphate forms occurs readily; unlike zidovudine, no accumulation of the monophosphate form is observed.2, 4, 5, 6, 8, 11, 17 Because phosphorylation of stavudine depends on cellular rather than viral enzymes, conversion of the drug to the active triphosphate derivative occurs in both virus-infected and uninfected cells.7, 8
d4T-Triphosphate is a structural analog of thymidine triphosphate, the natural substrate for viral RNA-directed DNA polymerase.3, 4, 9, 12, 16 Although other mechanisms may be involved in the antiretroviral activity of the drug, d4T-triphosphate appears to compete with thymidine triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA.3, 4, 12, 16, 21 Following incorporation of d4T-triphosphate into the viral DNA chain instead of thymidine triphosphate, synthesis is terminated prematurely because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.3, 4, 8, 12 Like zalcitabine (no longer commercially available in the US), stavudine apparently does not interfere with formation of naturally occurring nucleoside triphosphates and has little or no effect on intracellular concentrations of thymidine triphosphate, the natural substrate for viral RNA-directed DNA polymerase.2, 3, 4, 9, 21, 22 This ability of stavudine to provide antiviral concentrations of the active metabolite (d4T-triphosphate) concomitantly with normal levels of thymidine triphosphate needed to support cellular DNA synthesis may contribute to the reduced cytotoxic effects of the drug;2, 21 however, further study is needed to elucidate the mechanism(s) of cytotoxicity.7
d4T-Triphosphate can bind to and inhibit some mammalian cellular DNA polymerases, particularly β- and γ-polymerases, in vitro,1, 3, 4, 11 and markedly reduce the synthesis of mitochondrial DNA.1, 11 Mammalian α-polymerase, a DNA enzyme essential for cell division and cellular DNA repair, is relatively resistant to inhibition by d4T-triphosphate;4, 12, 17γ-polymerase, an enzyme involved in mitochondrial DNA synthesis, is the polymerase most susceptible to inhibition.4, 11, 12 However, d4T-triphosphate and other dideoxynucleoside triphosphates appear to have much greater affinity for viral RNA-directed DNA polymerase than for mammalian DNA polymerases.3, 4, 12, 17 This differential sensitivity of mammalian and viral DNA polymerases to dideoxynucleoside triphosphates may account, in part, for some of the antiviral selectivity of these drugs in cells that can phosphorylate them.3, 4, 12, 16, 17 However, inhibition of β- and γ-polymerases by these drugs may account, to some extent, for the toxic effects associated with stavudine and other nucleosides in humans.3, 4, 12
Stavudine has virustatic activity against human immunodeficiency virus type 1 (HIV-1)1, 2, 3, 4, 9, 10, 11, 12, 16, 17, 20, 21, 23, 24, 27, 28 and type 2 (HIV-2).27
Results of some in vitro studies indicate that the antiretroviral activities of stavudine and some other nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, zidovudine) may be additive or synergistic against HIV-1.28, 29 Increased antiretroviral activity against zidovudine-susceptible HIV-1 also was evident in some in vitro studies using stavudine in conjunction with saquinavir (an HIV protease inhibitor) or with nevirapine (a nonnucleoside reverse transcriptase inhibitor), and there was evidence that stavudine with zidovudine and lamivudine, nevirapine, or saquinavir can be additive or synergistic against zidovudine-susceptible HIV-1 in vitro.28, 30 However, although the clinical importance is unclear, slight antagonism also occurred in vitro with some of these combinations, especially when zidovudine-resistant strains of HIV-1 were used.28, 29, 30
Strains of HIV-1 with reduced susceptibility to stavudine have been produced in vitro.1, 27 In addition, strains of HIV-1 with reduced susceptibility to stavudine have emerged during therapy with the drug.1, 27 Cross-resistance has been reported among the HIV nucleoside reverse transcriptase inhibitors (NRTIs).1, 41 HIV isolates resistant to zidovudine, didanosine, lamivudine, and stavudine have been isolated from patients who received zidovudine and didanosine for 1 year or longer.41 For information on genotypic assays used to detect specific HIV-1 genetic variants (mutations), phenotypic assays used to measure HIV-1 drug resistance and recommendations regarding these assays, see In Vitro Resistance Testing under Guidelines for Use of Antiretroviral Agents: Laboratory Monitoring, in the Antiretroviral Agents General Statement 8:18.08.08.
The pharmacokinetics of stavudine have been studied in human immunodeficiency virus (HIV)-infected adult patients and in HIV-exposed or HIV-infected pediatric patients.1 Population pharmacokinetic analysis from a controlled study in HIV-infected patients did not reveal any clinically important race- or gender-related differences in the pharmacokinetics of the drug.1 The pharmacokinetics of stavudine have not been studied to date in geriatric adults older than 65 years of age.1
Systemic exposure to stavudine is the same following administration of the commercially available capsules or reconstituted oral solution.1
Stavudine is rapidly absorbed following oral administration, and peak plasma concentrations of the drug are attained within 1 hour after the dose.1, 69 Oral bioavailability of stavudine is reported to be about 86% in adults and 77% in pediatric patients 5 weeks to 15 years of age.1
Results of a single-dose study in HIV-infected adults indicate that food may decrease peak plasma concentrations and time to peak concentrations of stavudine, but does not have an appreciable effect on the area under the concentration-time curve (AUC) of the drug69
Data from single- and multiple-dose studies indicate that peak plasma concentrations and AUC of stavudine increase in proportion to dose over the dosage range of 0.03-4 mg/kg; there is no evidence that accumulation occurs following multiple doses.1
Distribution of stavudine into body tissues and fluids has not been fully characterized. Following a single IV dose in HIV-infected individuals, the volume of distribution is 46 L in adults and 0.73 L/kg in pediatric patients 5 weeks to 15 years of age.1
Results of a study in HIV-infected men indicate that stavudine is distributed into semen in concentrations approximating those of concurrent plasma concentrations.78
Stavudine is distributed into CSF following oral administration.1, 70, 71 In a limited number of HIV-infected adults receiving oral stavudine in a dosage of 40 mg twice daily in conjunction with other antiretroviral agents, CSF concentrations of the drug averaged 71 ng/mL (range: 20-91 ng/mL) in samples taken 1 hour after a dose at 8 weeks of therapy; steady-state peak plasma concentrations at this time averaged 930 ng/mL (range: 551-1447 ng/mL).71 Similar CSF and plasma concentrations of stavudine were measured in these patients after almost 2 years of continuous therapy with the drug.71 In HIV-infected pediatric patients 5 weeks to 15 years of age who received multiple oral doses of stavudine, the mean ratio of CSF to plasma concentrations of the drug has been reported to be 59%.1
Ex vivo studies indicate that stavudine crosses the human placenta.202
Stavudine is distributed into human breast milk, and breast milk to maternal plasma concentration ratios of 1-1.76 have been reported.202
Binding of stavudine to serum proteins is negligible over the concentration range of 0.01-11.4 mcg/mL.1
Metabolism has only a limited role in clearance of stavudine.1 Unchanged stavudine is the major drug component circulating in plasma.1 Minor metabolites that have been identified in plasma include oxidized stavudine, glucuronide conjugates of the drug and the oxidized metabolite, and an N -acetylcysteine conjugate of the ribose after glycosidic cleavage (suggests thymine is also a metabolite).1 In healthy individuals, approximately 95% of a dose is eliminated in urine (73.7% as unchanged drug) and 3% is eliminated in feces (62% as unchanged drug).1
Intracellularly, in both virus-infected and uninfected cells, stavudine is converted to stavudine monophosphate by cellular thymidine kinase.2, 4, 8, 17, 22 The monophosphate is subsequently converted to stavudine diphosphate and then to stavudine triphosphate, presumably by the same cellular kinases involved in the metabolism of zidovudine.2, 8, 17 Intracellular (host cell) conversion of stavudine to the triphosphate derivative is necessary for the antiviral activity of the drug.2, 4, 17 (See Mechanism of Action: Antiviral Effects.)
The mean elimination half-life of stavudine following a single oral dose in HIV-infected adults is 1.6 hours .1 The mean terminal elimination half-life of the drug is 2.3 hours following a single oral dose in healthy individuals.1 The mean elimination half-life following a single oral dose in HIV-exposed or HIV-infected patients is 0.96 hours in those 5 weeks to 15 years of age, 1.59 hours in those 14-28 days of age, and 5.27 hours in those 1 day of age.1
The apparent oral clearance of stavudine following a single oral dose averages 560 mL/minute in HIV-infected adults; 13.75 mL/minute per kg in HIV-infected pediatric patients 5 weeks to 15 years of a 11.52 mL/minute per kg in HIV-exposed or HIV-infected pediatric patients 14-28 days of a and 5.08 mL/minute per kg in HIV-exposed or HIV-infected pediatric patients 1 day of age.1 Renal clearance of unchanged stavudine accounts for about 40% of the overall clearance of the drug over 12-24 hours, regardless of the route of administration.1 The mean renal clearance is about twice the average endogenous creatinine clearance, indicating that renal tubular secretion contributes to the elimination of stavudine in addition to glomerular filtration.1 Following a single dose of stavudine in HIV-infected adult or pediatric patients 5 weeks to 15 years of age, approximately 42 or 34%, respectively, of the dose is excreted in urine.1
The apparent oral clearance of stavudine decreases and the AUC and elimination half-life of the drug increase as creatinine clearance decreases.1, 73 Following a single 40-mg oral dose of stavudine, the elimination half-life of the drug was 1.7 hours in patients with creatinine clearances exceeding 50 mL/minute and 3.5 or 4.6 hours in those with creatinine clearances of 26-50 or 9-25 mL/minute, respectively.1 In hemodialysis patients, the mean half-life of the drug was 5.4 hours.1
In a limited study in adults not infected with HIV who had hepatic impairment secondary to cirrhosis (modified Child-Pugh grade B or C), hepatic impairment did not have a clinically important effect on the pharmacokinetics of a single 40-mg dose of stavudine.1
Stavudine is removed by hemodialysis.1, 73 The amount of drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). In one study, the mean hemodialysis clearance of stavudine was 120 mL/minute and approximately 31% of a single 40-mg stavudine dose was removed between 2-6 hours after the dose.1 It is not know whether stavudine is removed by peritoneal dialysis.1
Stavudine (dideoxydidehydrothymidine, 2',3'-dideoxythymidinene, 2',3'-didehydro-2',3'-dideoxythymidine), a synthetic antiretroviral agent,1, 2, 4, 6, 7, 11, 12, 20, 21, 23, 24, 200 is an HIV nucleoside reverse transcriptase inhibitor (NRTI).1, 9 The drug is a dideoxynucleoside reverse transcriptase inhibitor.1, 9 Stavudine is an analog of thymidine, a naturally occurring pyrimidine.1, 2, 3, 4, 6, 8, 9, 16 Stavudine differs from thymidine in the 2'-3' double bond on the deoxyribose moiety and the replacement of the 3'-hydroxyl group with a hydrogen atom.2, 3, 8, 9, 12, 20 The absence of the free 3'-hydroxyl group results in the inability of stavudine to form phosphodiester linkages at this position.1, 2, 3, 8, 9, 12
Stavudine occurs as a white to off-white crystalline solid.1 The aqueous solubility of stavudine at 23°C is approximately 83 mg/mL.1
Commercially available stavudine capsules should be stored in a tight container at 25°C, but may be exposed to temperatures ranging from 15-30°C.1
Stavudine powder for oral solution should be kept in a tight container and protected from excessive moisture.1 The powder should be stored at 25°C, but may be exposed to temperatures ranging from15-30°C.1 Following reconstitution, the oral solution should be stored in a tight container at 2-8°C.1 Any unused reconstituted oral solution should be discarded after 30 days.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 15 mg* | Stavudine Capsules | |
20 mg* | Stavudine Capsules | |||
Zerit® | Bristol-Myers Squibb | |||
30 mg* | Stavudine Capsules | |||
Zerit® | Bristol-Myers Squibb | |||
40 mg* | Stavudine Capsules | |||
Zerit® | Bristol-Myers Squibb | |||
For solution | 1 mg/mL* | Stavudine for Oral Solution | ||
Zerit® | Bristol-Myers Squibb |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Bristol-Myers Squibb. Zerit® (stavudine) capsules and powder for oral solution prescribing information. Princeton, NJ; 2012 Jan.
2. Ho HT. Cellular pharmacology of 2',3'-dideoxy-2', 3'-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob Agents Chemother . 1989; 33:844-9. [PubMed 2764535][PubMedCentral]
3. Yarchoan R, Mitsuya H. Clinical and basic advances in the antiretroviral therapy of human immunodeficiency virus infection. Am J Med . 1989; 87:191-200. [PubMed 2474251]
4. Hitchcock MJM. 2'3'-Didehydro-2',3'-dideoxythymidine (D4T), an anti-HIV agent. Antiviral Chem . 1991; 2:125-32.
5. August EM, Birks EM. 3'-Deoxythymidin-2'-ene permeation of human lymphocyte H9 cells by nonfacilitated diffusion. Mol Pharmacol . 1991; 39:246-9. [PubMed 1847498]
6. Martin JC, Hitchcock MJM, Fridland A et al. Comparative studies of 2'3'-didehydro-2',3'-dideoxythymidine (D4T) with other pyrimidine nucleoside analogues. Ann NY Acad Sci . 1990; 616:22-8. [PubMed 1964029]
7. Zhu Z, Hitchcock MJM. Metabolism and DNA interaction of 2'3'-didehydro-2',3'-dideoxythymidine in human bone marrow cells. Mol Pharmacol . 1991; 40:838-45. [PubMed 1658614]
8. August EM, Marongiu ME, Lin T-S et al. Initial studies on the cellular pharmacology of 3'-deoxythymidin-2'-ene (d4T): a potent and selective inhibitor of human immunodeficiency virus. Biochem Pharmacol . 1988; 37:4419-22. [PubMed 2849444]
9. Yarchoan R, Mitsuya H, Myers CE et al. Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med . 1989; 321:726-38. [PubMed 2671731]
10. Browne MJ, Mayer KH, Chafee SBD et al. 2',3'-Didehydro-3'-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. J Infect Dis . 1993; 167:21-9. [PubMed 8093363]
11. De Clercq E. HIV inhibitors targeted at reverse transcriptase. AIDS Res Hum Retroviruses . 1992; 8:119-34. [PubMed 1371690]
12. Yarchoan R. Anti-retroviral therapy of AIDS and related disorders: general principles and specific development of dideoxynucleosides. Pharmacol Ther . 1989; 40:329-48. [PubMed 2646649]
13. Funk MB, Linde R, Wintergerst U et al. Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children. AIDS . 1999; 13:1653-8. [PubMed 10509566]
14. Krogstad P, Lee S, Johnson G et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis . 2002; 34:991-1001. [PubMed 11880966]
15. Yogev R, Lee S, Wiznia A et al. Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect Dis J . 2002; 21:119-25. [PubMed 11840078]
16. Mansuri MM, Hitchcock MJM, Buroker RA et al. Comparison of in vitro biological properties and mouse toxicities of three thymidine analogs active against human immunodeficiency virus. Antimicrob Agents Chemother . 1990; 34:637-41. [PubMed 1693057][PubMedCentral]
17. Balzarini J, Herdewijn P. Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. J Biol Chem . 1989; 264:6127-33. [PubMed 2539371]
18. Eron JJ, Murphy RL, Peterson D et al. A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II). AIDS . 2000; 14:1601-10. [PubMed 10983647]
20. Hamamoto Y, Nakashima H, Matsui T et al. Inhibitory effect of 2',3'-didehydro-2',3'-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus. Antimicrob Agents Chemother . 1987; 31:907-10. [PubMed 3039911][PubMedCentral]
21. Mansuri MM, Starrett Jr JE, Ghazzouli I et al. 1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent. J Med Chem . 1989; 32:461-6. [PubMed 2536441]
22. Marongiu ME, August EM. Effect of 3'-deoxythymidin-2'-ene (d4T) on nucleoside metabolism in H9 cells. Biochem Pharmacol . 1990; 39:1523-8. [PubMed 2159760]
23. Lin TS, Schinazi RF. Potent and selective in vitro activity of 3'-deoxythymidin-2'-ene (3'-deoxy-2',3'-didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol . 1987; 36:2713-8. [PubMed 2443141]
24. Baba M, Pauwels R, Herdewijn P et al. Both 2',3'-dideoxythymidine and its 2',3'-unsaturated derivative (2',3'-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem Biophys Res Commun . 1987; 142:128-34. [PubMed 3028398]
26. Havlir DV, Tierney C, Friedland GH et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis . 2000; 182:321-5. [PubMed 10882616]
27. Lea AP. Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection. Drugs . 1996; 51:846-64. [PubMed 8861550]
28. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis . 1996; 173:355-64. [PubMed 8568296]
29. Deminie CA, Bechtold CM, Stock D et al. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother . 1996; 40:1346-51. [PubMed 8725999][PubMedCentral]
30. Zhu QY, Scarborough A, Polsky B et al. Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains. AIDS Res Hum Retroviruses . 1996; 12:507-17. [PubMed 8679306]
31. Rainey PM, Friedland G, McCance-Katz EF et al. Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr . 2000; 24:241-8. [PubMed 10969348]
32. Patick AK, Boritzki TJ, Bloom LA. Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. Antimicrob Agents Chemother . 1997; 41:2159-64. [PubMed 9333041][PubMedCentral]
38. Piscitelli SC, Kelly G, Walker RE et al. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother . 1999; 43:647-50. [PubMed 10049281][PubMedCentral]
39. Kline MW, Fletcher CV, Federici ME et al. Combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus infection: pharmacokinetic properties, safety, and immunologic and virologic effects. Pediatrics . 1996; 97:886-90. [PubMed 8657531]
41. Shafer RW, Iversen AKN, Winters MA et al. Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. J Infect Dis . 1995; 172:70-8. [PubMed 7541064]
47. Spruance SL, Pavia AT, Mellors JW et al. Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double-blind, controlled trial. Ann Intern Med . 1997; 126:355-63. [PubMed 9054279]
48. Kline MW, Fletcher CV. A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddI) in children infected with human immunodeficiency virus. J Pediatr . 1998; 132:543-6. [PubMed 9544920]
49. Smyth AC. Bristol-Myers Squibb. Dear healthcare provider letter regarding fatal lactic acidosis in pregnant women treated throughout gestation with the combination of stavudine and didanosine 2001 Jan 5. From FDA web site. [Web]
50. Chene G, Angelini E, Cotte L et al. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis . 2002; 34:649-57. [PubMed 11810598]
51. Hurst M, Noble S. Stavudine: an update of its use in the treatment of HIV infection. Drugs . 1999; 58:919-49. [PubMed 10595868]
54. Jung D, AbdelHameed MH, Teitelbaum P et al. The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients J Clin Pharmacol . 1999; 39:505-12.
55. Wintergerst U, Hoffmann F, Solder B et al. Comparison of two antiretroviral triple combinations including the protease inhibitor indinavir in children infected with human immunodeficiency virus. Pediatr Infect Dis J . 1998; 17:495-9. [PubMed 9655541]
62. Kline MW, Van Dyke RB, Lindsey JC et al. Combination therapy with stavudine (d4T) plus didanosine (ddI) in children with human immunodeficiency virus infection. Pediatrics . 1999; 103:e62. [PubMed 10224206][PubMedCentral]
64. Schering Corporation. Rebetron® combination therapy containing Rebetol® (ribavirin) capsules and Intron® (interferon alfa-2b, recombinant) injection prescribing information. Kenilworth, NJ; 2001 Aug.
65. Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet . 2001; 357:280-1. [PubMed 11214134]
66. Kakuda TN, Brinkman K. Mitochondrial toxic effects and ribavirin. Lancet . 2001; 357:1802-3. [PubMed 11407388]
67. Brinkman K, Kakuda TN. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy? Curr Opinion Infect Dis . 2000; 13:5-11.
68. Salmon-Ceron D, Chauvelot-Moachon L, Abad S et al. Mitochondrial toxic effects and ribavirin. Lancet . 2001; 357:1803-4. [PubMed 11407389]
69. Kaul S, Christofalo B, Raymond RH et al. Effect of food on the bioavailability of stavudine in subjects with human immunodeficiency virus infection. Antimicrob Agents Chemother . 1998; 42:2295-8. [PubMed 9736552][PubMedCentral]
70. Haworth SJ, Christofalo B, Anderson RD et al. A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults. J Acquir Immune Defic Syndr Hum Retrovirol . 1998; 17:235-8. [PubMed 9495223]
71. van Praag RME, van Weert ECM, van Heeswijk RPG et al. Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob Agents Chemother . 2002; 46:896-9. [PubMed 11850283][PubMedCentral]
72. Schaad HJ, Petty BG, Grasela DM et al. Pharmacokinetics and safety of a single dose of stavudine (d4T) in patients with severe hepatic impairment. Antimicrob Agents Chemother . 1997; 41:2793-6. [PubMed 9420063][PubMedCentral]
73. Grasela DM, Stoltz RR, Barry M et al. Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis. Antimicrob Agents Chemother . 2000; 44:2149-53. [PubMed 10898689][PubMedCentral]
75. Stevens MR. Bristol-Myers Squibb. Dear healthcare provider letter regarding rare occurrences of rapidly ascending neuromuscular weakness, mimicking the clinical presentation of Guillain-Barre syndrome, in patients receiving stavudine in combination with other antiretrovirals. Princeton, NJ; 2002 Feb. From FDA web site. [Web]
78. Taylor S, van Heeswijk RP, Hoetelmans RM et al. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS . 2000; 14:1979-84. [PubMed 10997403]
80. Genentech USA. Pegasys® (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2011 Sep.
81. Zerit® (stavudine) capsules and powder for oral solution risk evaluation and mitigation strategy (REMS). From FDA website. [Web]
82. Marcus KA. Supplemental approval release REMS requirement. Silver Spring, MD: US Food and Drug Administration; 2011 May 11. From FDA website. [Web]
187. Janssen Products LP. Olysio® (simeprevir) capsules prescribing information. Titusville, NJ; 2013 Nov.
198. Center for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep . 2005; 54(No. RR-2):1-19.
199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [PubMed 23917901]
200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 1, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 12, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
203. Bristol-Myers Squibb. Reyataz® (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.
204. Janssen. Prezista® (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Jun.
205. ViiV Healthcare. Lexiva® (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.
206. Merck Sharp & Dohme. Crixivan® (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.
207. Abbott Laboratories. Kaletra® (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.
208. ViiV Healthcare. Viracept® (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2012 Apr.
210. Genentech USA. Invirase® (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.
211. Boehringer Ingelheim. Aptivus® (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.
213. Bristol-Myers Squibb. Sustiva® (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2012 Jun.
214. Janssen. Intelence® (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.
215. Boehringer Ingelheim. Viramune® (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2011 Nov.
217. Bristol-Myers Squibb. Videx® EC (didanosine) delayed-release capsules enteric-coated beadlets prescribing information. Princeton, NJ; 2011 Nov.
218. Gilead Sciences. Emtriva® (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2012 Jul.
219. ViiV Healthcare. Epivir® (lamivudine) tablet, film coated and solution prescribing information. Research Triangle Park, NC; 2011 Nov.
221. Gilead Sciences. Viread® (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2012 Jan.
224. ViiV Healthcare. Selzentry® (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.
225. Merck Sharp & Dohme. Isentress® (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.
226. Tibotec Therapeutics. Edurant® (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.
236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2014 May.