Stavudine: Difference between revisions

Jump to navigation Jump to search
No edit summary
No edit summary
Line 9: Line 9:
|adverseReactions=headache, diarrhea, neuropathy, rash, nausea, and vomiting
|adverseReactions=headache, diarrhea, neuropathy, rash, nausea, and vomiting
|blackBoxWarningTitle=WARNING: LACTIC ACIDOSIS AND HEPATOMEGALY WITH STEATOSIS; PANCREATITIS
|blackBoxWarningTitle=WARNING: LACTIC ACIDOSIS AND HEPATOMEGALY WITH STEATOSIS; PANCREATITIS
|blackBoxWarningBody=Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.  
|blackBoxWarningBody=Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal [[lactic acidosis]] has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.  


Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.
Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.
Line 27: Line 27:
|contraindications=Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.
|contraindications=Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.
|warnings======Lactic Acidosis/Severe Hepatomegaly with Steatosis=====
|warnings======Lactic Acidosis/Severe Hepatomegaly with Steatosis=====
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.
Lactic acidosis and severe [[hepatomegaly]] with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.


Particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.
Particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.
Line 44: Line 44:
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.


Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine.
Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. [[Peripheral neuropathy]], which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of [[peripheral neuropathy]], or in patients receiving other drugs that have been associated with neuropathy, including didanosine.


Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.
Patients should be monitored for the development of [[peripheral neuropathy]]. Stavudine-related [[peripheral neuropathy]] may resolve if therapy is withdrawn promptly. If [[peripheral neuropathy]] develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.


=====Pancreatitis=====
=====Pancreatitis=====
Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.
Fatal and nonfatal [[pancreatitis]] have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected [[pancreatitis]]. Reinstitution of stavudine after a confirmed diagnosis of [[pancreatitis]] should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.


=====Fat Redistribution=====
=====Fat Redistribution=====
Line 65: Line 65:
* Exocrine Gland Disorders: pancreatitis, including fatal cases.  
* Exocrine Gland Disorders: pancreatitis, including fatal cases.  
* Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.  
* Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.  
* Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis, hepatitis and liver failure.  
* Liver: symptomatic hyperlactatemia/[[lactic acidosis]] and hepatic steatosis, hepatitis and liver failure.  
* Metabolic Disorders: lipoatrophy, lipodystrophy, diabetes mellitus and hyperglycemia.  
* Metabolic Disorders: lipoatrophy, lipodystrophy, diabetes mellitus and hyperglycemia.  
* Musculoskeletal: myalgia.  
* Musculoskeletal: myalgia.  
* Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis)
* Nervous System: insomnia, severe motor weakness (most often reported in the setting of [[lactic acidosis]])
|drugInteractions=Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.  
|drugInteractions=Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.  
* Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.  
* Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.  
Line 80: Line 80:
There are no adequate and well-controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk.
There are no adequate and well-controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk.


Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Fatal [[lactic acidosis]] has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of [[lactic acidosis]]/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of [[lactic acidosis]]/hepatic steatosis syndrome.
|useInNursing=The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving stavudine.
|useInNursing=The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving stavudine.
|useInPed=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.
|useInPed=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.
Line 89: Line 89:
|useInGeri=Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.
|useInGeri=Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.


In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.
In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, [[peripheral neuropathy]] or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, [[peripheral neuropathy]] or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of [[peripheral neuropathy]].


Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment.
Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment.
|useInRenalImpair=Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis.
|useInRenalImpair=Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis.
|administration=Oral
|administration=Oral
|overdose=Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.
|overdose=Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include [[peripheral neuropathy]] and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.
|clinicalStudies======Combination Therapy=====
|clinicalStudies======Combination Therapy=====
The combination use of stavudine is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.
The combination use of stavudine is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.
Line 135: Line 135:


=====Lactic Acidosis=====
=====Lactic Acidosis=====
Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine therapy may be required.
Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or [[lactic acidosis]] syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine therapy may be required.


=====Hepatic Toxicity=====
=====Hepatic Toxicity=====
Line 141: Line 141:


=====Peripheral Neuropathy=====  
=====Peripheral Neuropathy=====  
Patients should be informed that an important toxicity of stavudine is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of stavudine may be required if toxicity develops.
Patients should be informed that an important toxicity of stavudine is [[peripheral neuropathy]]. Patients should be aware that [[peripheral neuropathy]] is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that [[peripheral neuropathy]] occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of [[peripheral neuropathy]], and discontinuation of stavudine may be required if toxicity develops.


Caregivers of young children receiving stavudine therapy should be instructed regarding detection and reporting of peripheral neuropathy.
Caregivers of young children receiving stavudine therapy should be instructed regarding detection and reporting of [[peripheral neuropathy]].


=====Pancreatitis=====
=====Pancreatitis=====
Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.
Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.


The patient should be instructed to avoid alcohol while taking stavudine. Alcohol may increase the patient’s risk of pancreatitis or liver damage.
The patient should be instructed to avoid alcohol while taking stavudine. Alcohol may increase the patient’s risk of [[pancreatitis]] or liver damage.


=====Fat Redistribution=====  
=====Fat Redistribution=====  
Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including stavudine. Patients receiving stavudine should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.
Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including stavudine. Patients receiving stavudine should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.
|alcohol=Alcohol-Stavudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Stavudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Zerit
}}
}}
__NOTOC__
__NOTOC__

Revision as of 13:33, 11 February 2015

Stavudine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING: LACTIC ACIDOSIS AND HEPATOMEGALY WITH STEATOSIS; PANCREATITIS
See full prescribing information for complete Boxed Warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.

Overview

Stavudine is a nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV)-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, neuropathy, rash, nausea, and vomiting.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.

  • Dosage:
  • For patients weighing less than 60 kg: 30 mg every 12 hours.
  • For patients weighing at least 60 kg: 40 mg every 12 hours.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Stavudine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Stavudine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.

  • Dosage:
  • For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
  • For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
  • For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Stavudine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Stavudine in pediatric patients.

Contraindications

Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

Warnings

WARNING: LACTIC ACIDOSIS AND HEPATOMEGALY WITH STEATOSIS; PANCREATITIS
See full prescribing information for complete Boxed Warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.
Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.

Particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.

Treatment with stavudine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis.

Hepatic Toxicity

The safety and efficacy of stavudine have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.

Use with Interferon and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine. Although no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6) (see the full prescribing information for interferon and ribavirin).

Neurologic Symptoms

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine.

Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

Pancreatitis

Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.

Fat Redistribution

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

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using stavudine including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Stavudine Clinical Trials Experience in the drug label.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of stavudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors.

  • Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat.
  • Digestive Disorders: anorexia.
  • Exocrine Gland Disorders: pancreatitis, including fatal cases.
  • Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.
  • Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis, hepatitis and liver failure.
  • Metabolic Disorders: lipoatrophy, lipodystrophy, diabetes mellitus and hyperglycemia.
  • Musculoskeletal: myalgia.
  • Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis)

Drug Interactions

Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

  • Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.
  • Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution.
  • Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. No pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.

There are no adequate and well-controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Stavudine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Stavudine during labor and delivery.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving stavudine.

Pediatric Use

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.

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

Stavudine pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens.

Geriatic Use

Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment.

Gender

There is no FDA guidance on the use of Stavudine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Stavudine with respect to specific racial populations.

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis.

Hepatic Impairment

There is no FDA guidance on the use of Stavudine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Stavudine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Stavudine in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

There is limited information regarding Stavudine Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Stavudine and IV administrations.

Overdosage

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.

Pharmacology

There is limited information regarding Stavudine Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Stavudine Mechanism of Action in the drug label.

Structure

There is limited information regarding Stavudine Structure in the drug label.

Pharmacodynamics

There is limited information regarding Stavudine Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Stavudine Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Stavudine Nonclinical Toxicology in the drug label.

Clinical Studies

Combination Therapy

The combination use of stavudine is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing stavudine (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4+cell counts through 48 weeks.

Monotherapy

The efficacy of stavudine was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992 to 1994) comparing stavudine with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.

How Supplied

  • Stavudine Capsules 15 mg
  • Bottle of 60 Capsules
  • NDC 65862-111-60
  • Stavudine Capsules 20 mg
  • Bottle of 60 Capsules
  • NDC 65862-112-60
  • Stavudine Capsules 30 mg
  • Bottle of 60 Capsules
  • NDC 65862-046-60
  • Stavudine Capsules 40 mg
  • Bottle of 60 Capsules
  • NDC 65862-047-60

Storage

Store at 20° to 25°C (68° to 77°F)

Images

Drug Images

{{#ask: Page Name::Stavudine |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Stavudine |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

Patients should be advised that stavudine is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using stavudine and the importance of adherence to any antiretroviral regimen including those that contain stavudine.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not breastfeed. It is not known if stavudine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.

Patients should be informed that when stavudine is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine is used alone.

Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule.

Patients should be instructed if they take too much stavudine, they should contact a poison control center or emergency room right away.

Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.

Lactic Acidosis

Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine therapy may be required.

Hepatic Toxicity

Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea. This combination should be avoided.

Peripheral Neuropathy

Patients should be informed that an important toxicity of stavudine is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of stavudine may be required if toxicity develops.

Caregivers of young children receiving stavudine therapy should be instructed regarding detection and reporting of peripheral neuropathy.

Pancreatitis

Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.

The patient should be instructed to avoid alcohol while taking stavudine. Alcohol may increase the patient’s risk of pancreatitis or liver damage.

Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including stavudine. Patients receiving stavudine should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.

Precautions with Alcohol

Alcohol-Stavudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Zerit

Look-Alike Drug Names

There is limited information regarding Stavudine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


Stavudine
Zerit® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Clinical Studies
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

Category

US Brand Names

Zerit®

FDA Package Insert

Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages

Mechanism of Action

References