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 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 Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly.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.
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 AI455-019a (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 2b 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 NeurologicSymptoms/ Neuropathy |
8 |
7 |
21 |
10 |
Pancreatitis resulting in death was observed in patients treated with ZERIT 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 AI455-019a,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.
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 is used alone. Thus, patients treated with ZERIT 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 ZERIT 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).
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