Zerit (Stavudine) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Adults

Fatal lactic acidosis has occurred in patients treated with ZERIT in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with ZERIT. Permanent discontinuation of ZERIT should be considered for patients with confirmed lactic acidosis.

ZERIT therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, ZERIT should be discontinued.

ZERIT (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 Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly.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 ZERIT should be considered.

When ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. Pancreatitis, peripheral neuropathy, and liver function abnormalities occur more frequently in patients treated with the combination of ZERIT and didanosine, with or without hydroxyurea. Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with ZERIT in combination with didanosine and hydroxyurea (see WARNINGS and PRECAUTIONS).

Selected clinical adverse events that occurred in adult patients receiving ZERIT (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	ZERITb (40 mg twice daily) (n=412)	zidovudine (200 mg 3 times daily) (n=402)
a Any severity, regardless of relationship to study drug.
b Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.
Headache	54	49
Diarrhea	50	44
Peripheral Neurologic    Symptoms/Neuropathy	52	39
Rash	40	35
Nausea and Vomiting	39	44

Pancreatitis was observed in 3 of the 412 adult patients who received ZERIT in a controlled monotherapy study.

Selected clinical adverse events that occurred in antiretroviral naive adult patients receiving ZERIT from two controlled combination studies are provided in Table 8.

Table 8: Selected Clinical Adverse Eventsa in START 1 and START 2^b Studies (Combination Therapy)

	Percent (%)
	START 1		START 2b
Adverse Events	ZERIT + lamivudine + indinavir (n=100c)	zidovudine + lamivudine + indinavir (n=102)	ZERIT + didanosine + indinavir (n= 102c)	zidovudine + lamivudine + indinavir (n=103)
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 ZERIT (40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir.
c Duration of stavudine therapy = 48 weeks.
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

Pancreatitis resulting in death was observed in patients treated with ZERIT (stavudine) plus didanosine, with or without hydroxyurea, 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	ZERIT (40 mg twice daily) (n=412)	zidovudine (200 mg 3 times daily) (n=402)
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.
AST (SGOT) (>5.0 x ULN)	11	10
ALT (SGPT) (>5.0 x ULN)	13	11
Amylase (≥1.4 x ULN)	14	13

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	ZERIT + lamivudine + indinavir (n=100)	Zidovudine + lamivudine + indinavir (n=102)	ZERIT + didanosine + indinavir (n= 102)	zidovudine + lamivudine + indinavir (n=103)
ULN = upper limit of normal.
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

Table 11: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)

	Percent (%)
	START 1		START 2
Parameter	ZERIT + lamivudine + indinavir (n=100)	zidovudine + lamivudine + indinavir (n=102)	ZERIT + 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 ZERIT (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 ZERIT, 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.
  
  
•   Musculoskeletal —myalgia.
  
  
•   Nervous System —insomnia, severe motor weakness (most often reported in the setting of lactic acidosis, see WARNINGS).