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 (SEE WARNINGS AND PRECAUTIONS: PREGNANCY ) 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 (SEE WARNINGS )
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warnings
WARNINGS 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 PRECAUTIONS: Pregnancy ) . 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 3. Neurologic Symptoms ) 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). 2.Hepatic Impairment and 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. An increased risk of hepatotoxicity may occur in patients treated with stavudine in combination with didanosine and hydroxyurea compared to when stavudine is used alone. Deaths attributed to hepatotoxicity have occurred in patients receiving this combination. 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 (eg, loss of HIV/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions ), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV 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 (eg, Child-Pugh >6) (see the complete prescribing information for interferon and ribavirin). 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). Symptoms may continue or worsen following discontinuation of therapy. Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, with a history of neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine (see ADVERSE REACTIONS ). 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. The new regimen should not contain didanosine .
ADVERSE REACTIONS Adults Fatal lactic acidosis has occurred in patients treated with stavudine in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with stavudine . Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis. Stavudine therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, stavudine should be discontinued. Stavudine therapy has also been associated with peripheral sensory neuropathy, which can be severe, is dose related, and occurs more frequently in patients being treated with other drugs that have been associated with neuropathy (including didanosine), in patients with advanced HIV infection, or in patients who have previously experienced peripheral neuropathy. Patients should be monitored for the development of neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, patients may tolerate resumption of treatment at one-half the dose (see DOSAGE AND ADMINISTRATION ). If neuropathy recurs after resumption, permanent discontinuation of stavudine should be considered. Selected clinical adverse events that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 7. Table 7: Selected Clinical Adverse Events in study AI455-019 a (Monotherapy) Percent (%) Adverse Events Stavudine b ( 40 mg twice daily) (n=412) Zidovudine (200 mg 3 times daily) (n=402) Headache 54 49 Diarrhea 50 44 Peripheral Neurologic Symptoms/Neuropathy 52 39 Rash 40 35 Nausea and Vomiting 39 44 a Any severity, regardless of relationship to study drug. b Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks. Pancreatitis was observed in 3 of the 412 adult patients who received stavudine in a controlled monotherapy study. Selected clinical adverse events that occurred in antiretroviral- naive adult patients receiving stavudine from two controlled combination studies are provided in Table 8. Table 8 : Selected Clinical Adverse Events a in START 1 and START 2 b studies (Combination Therapy) Percent (%) START 1 START 2 b Adverse Events Stavudine + lamivudine + indinavir (n=100 c ) zidovudine + lamivudine + indinavir (n=102) Stavudine + didanosine + indinavir (n=102 c ) zidovudine + lamivudine + indinavir (n=103) Nausea 43 63 53 67 Diarrhea 34 16 45 39 Headache 25 26 46 37 Rash 18 13 30 18 Vomiting 18 33 30 35 Peripheral Neurologic Symptoms/Neuropathy 8 7 21 10 a Any severity, regardless of relationship to study regimen. b START 2 compared two triple-combination regimens in 205 treatment-naive patients. Patients received either stavudine(40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir. c Duration of stavudine therapy = 48 weeks. Pancreatitis resulting in death was observed in patients treated with stavudine plus didanosine, in controlled clinical studies and in postmarketing reports. Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 9. Table 9: Selected Adult Laboratory Abnormalities in Study AI455-019 a,b Percent (%) Parameter Stavudine (40 mg twice daily) (n=412) Zidovudine (200 mg 3 times daily) (n=402) AST (SGOT) (>5.0 x ULN) 11 10 ALT (SGPT) (>5.0 x ULN) 13 11 Amylase ( >1.4 x ULN) 14 13 a Data presented for patients for whom laboratory evaluations were performed. b Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks. ULN = upper limit of normal. Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 10 and 11. Table 10: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3-4) Percent (%) START 1 START 2 Parameter Stavudine + lamivudine + indinavir (n=100) Zidovudine + lamivudine + indinavir (n=102) Stavudine + didanosine + indinavir (n=102) zidovudine + lamivudine + indinavir (n=103) Bilirubin (>2.6 x ULN) 7 6 16 8 AST (SGOT) (>5 x ULN) 5 2 7 7 ALT (SGPT) (>5 x ULN) 6 2 8 5 GGT (>5 x ULN) 2 2 5 2 Lipase (>2 x ULN) 6 3 5 5 Amylase (>2 x ULN) 4 <1 8 2 ULN = upper limit of normal. Table 11: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades) Percent (%) START 1 START 2 Parameter Stavudine + lamivudine + indinavir (n=100) Zidovudine + lamivudine + indinavir (n=102) Stavudine + didanosine + indinavir (n=102) zidovudine + lamivudine + indinavir (n=103) Total Bilirubin 65 60 68 55 AST (SGOT) 42 20 53 20 ALT (SGPT) 40 20 50 18 GGT 15 8 28 12 Lipase 27 12 26 19 Amylase 21 19 31 17 Observed During Clinical Practice The following events have been identified during post-approval use of stavudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events 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 (see PRECAUTIONS: Fat Redistribution ). Digestive Disorders - anorexia. Exocrine Gland Disorders - pancreatitis [including fatal cases (see WARNINGS )]. Hematologic Disorders - anemia, leukopenia, thrombocytopenia, and macrocytosis. Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS ), hepatitis and liver failure. Metabolic Disorders —diabetes mellitus and hyperglycemia. Musculoskeletal - myalgia. Nervous System - insomnia, severe motor weakness (most often reported in the setting of lactic acidosis, see WARNINGS ). Use with Didanosine- and Hydroxyurea-Based Regimens When stavudine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when stavudine used alone. Thus, patients treated with stavudine in combination with didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of stavudine and hydroxyurea, with or without didanosine, should be avoided (see WARNINGS and PRECAUTIONS ). Pediatric Patients Adverse reactions and serious laboratory abnormalities in pediatric patients from birth through adolescence were similar in type and frequency to those seen in adult patients (see PRECAUTIONS: Pediatric Use ).