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warnings and cautions
5 WARNINGS AND PRECAUTIONS Lactic Acidosis/Severe Hepatomegaly with Steatosis: Suspend treatment with stavudine in patients who develop clinical symptoms or signs with or without laboratory findings. (5.1) Hepatic Toxicity: May be severe, fatal. Consider interruption or discontinuation. Avoid use in combination with didanosine and hydroxyurea. Risk of hepatic decompensation exists when used in combination with interferon and ribavirin; closely monitor and consider discontinuation of stavudine. (5.2) Neurologic Symptoms: Motor weakness, most often seen in the setting of lactic acidosis, may mimic Guillain-Barré syndrome; discontinue treatment. Monitor for peripheral neuropathy, which can be severe; treatment discontinuation should be considered. (5.3) Pancreatitis: Suspend treatment, resume with particular caution and close monitoring and avoid use in combination with didanosine. (5.4) Patients may develop redistribution/accumulation of body fat, monitor for signs and symptoms of lipoatrophy/lipodystrophy. Alternative antiretrovirals should be considered. (5.5) Patients may develop immune reconstitution syndrome. (5.6) 5.1 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 [see Use in Specific Populations (8.1) ] . 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 [see Warnings and Precautions (5.3) ] 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. 5.2 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. [See Adverse Reactions (6) .] 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 [see Drug Interactions (7) ] , 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 ). 5.3 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 [see Adverse Reactions (6) ] . 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. 5.4 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. 5.5 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.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 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. 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. 5.6 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 infection, cytomegalovirus, pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) 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. 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.