Stavudine (Page 2 of 9)

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 Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly.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.

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 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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.

6.1 Clinical Trial Experience in Adults

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Selected adverse reactions that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

Table 2: Selected Adverse Reactions in Study AI455-019* (Monotherapy)
*
The incidences reported included all severity grades and all reactions regardless of causality.
Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks

Adverse Reaction

Percent (%)

Stavudine

(40 mg twice daily)

Zidovudine

(200 mg 3 times daily)

Headache 54 49
Diarrhea 50 44

Peripheral Neurologic

52 39
Rash 40 35
Nausea and Vomiting 39 44

Pancreatitis was observed in three of the 412 adult patients who received stavudine in study AI455-019.

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in Table 3.

Table 3: Selected Adverse Reactions * in START 1 and START 2 Studies (Combination Therapy)
*
The incidences reported included all severity grades and all reactions regardless of causality.
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.
Duration of stavudine therapy = 48 weeks
Adverse Reaction Percent (%)
START 1 START 2

Stavudine +

Lamivudine + Indinavir

)

Zidovudine +

Lamivudine + Indinavir

Stavudine +

Didanosine + Indinavir

)

Zidovudine + Lamivudine + Indinavir

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

8 7 21 10

Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

Table 4: Selected Laboratory Abnormalities in Study AI455-019*
ULN = upper limit of normal
*
Data presented for patients for whom laboratory evaluations were performed.
Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks
Parameter Percent (%)

Stavudine

(40 mg twice daily)

Zidovudine

(200 mg 3 times daily)

AST (SGOT) (> 5 x ULN) 11 10
ALT (SGPT) (> 5 x ULN) 13 11
Amylase (≥ 1.4 x ULN) 14 13

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.

Table 5: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3 to 4)
ULN = upper limit of normal.
Parameter Percent (%)
START 1 START 2

Stavudine +Lamivudine + Indinavir

Zidovudine +

Lamivudine + Indinavir

Stavudine +

Didanosine + Indinavir

Zidovudine + Lamivudine +

Indinavir

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 6: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)
Parameter Percent (%)
START 1 START 2

Stavudine +

Lamivudine + Indinavir

Zidovudine +

Lamivudine + Indinavir

Stavudine +

Didanosine + Indinavir

Zidovudine +

Lamivudine + Indinavir

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

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