FDA Label for Stavudine

Warning: Lactic Acidosis And Hepatomegaly With Steatosis; Pancreatitis

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 (5.1)].

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 and Precautions (5.4)].

1 Indications And Usage

Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14)].

2 Dosage And Administration

The interval between doses of stavudine capsules should be 12 hours. Stavudine capsules may be taken with or without food.

2.1 Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:

• For patients weighing less than 60 kg: 30 mg every 12 hours.
• For patients weighing at least 60 kg: 40 mg every 12 hours.

2.2 Recommended Pediatric Dosage

• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
• For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
• For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

Adult Patients

Stavudine capsules may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.

Pediatric Patients

Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of stavudine capsules in this patient population.

3 Dosage Forms And Strengths

• The 15 mg capsules have a hard-shell gelatin capsule with an off-white opaque cap and a pink opaque body filled with a white to off-white powder. The capsule is axially printed with M 154 in black ink on both the cap and body.
• The 20 mg capsules have a hard-shell gelatin capsule with a pink opaque cap and a pink opaque body filled with a white to off-white powder. The capsule is axially printed with M 155 in black ink on both the cap and body.
• The 30 mg capsules have a hard-shell gelatin capsule with an off-white opaque cap and a light orange opaque body filled with a white to off-white powder. The capsule is axially printed with M 137 in black ink on both the cap and body.
• The 40 mg capsules have a hard-shell gelatin capsule with a light orange opaque cap and a light orange opaque body filled with a white to off-white powder. The capsule is axially printed with M 138 in black ink on both the cap and body.

4 Contraindications

Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

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 post-marketing 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.

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:

• lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning and Warnings and Precautions (5.1)]
• hepatic toxicity [see Warnings and Precautions (5.2)]
• neurologic symptoms and motor weakness [see Warnings and Precautions (5.3)]
• pancreatitis [see Boxed Warning and Warnings and Precautions (5.4)]
• lipoatrophy/lipodystrophy [see Warnings and Precautions (5.5)]

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.

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.

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

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

6.2 Clinical Trial Experience In Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients [see Use in Specific Populations (8.4)].

6.3 Post-Marketing Experience

The following adverse reactions have been identified during post-marketing use of stavudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions 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 Warnings and Precautions (5.5)].

Digestive Disorders: anorexia.

Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4)].

Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia and macrocytosis.

Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1)], hepatitis and liver failure.

Metabolic Disorders: lipoatrophy, lipodystrophy [see Warnings and Precautions (5.5)], diabetes mellitus and hyperglycemia.

Musculoskeletal: myalgia.

Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1, 5.3)].

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 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 [see Warnings and Precautions (5)]. The combination of stavudine and hydroxyurea, with or without didanosine, should be avoided.

7 Drug Interactions

Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.

Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. No pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10) or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.2)].

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits with exposures (based on C_max) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.

There are no adequate and well controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see Boxed Warning and Warnings and Precautions (5.1)].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. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to stavudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving stavudine.

8.4 Pediatric Use

Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients [see Dosage and Administration (2.2) and Adverse Reactions (6.2)].

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

Stavudine pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see Clinical Pharmacology (12.3, Table 9)].

8.5 Geriatric Use

Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].

8.6 Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

10 Overdosage

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.

11 Description

Stavudine (d4T) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine has the following structural formula:

Stavudine Structural Formula - 6f799e8d dd38 4787 8dce 517f4aec9ef0 01

Stavudine, USP is a white to off-white crystalline solid with the molecular formula C10H12N2O4 and a molecular weight of 224.21. The solubility of stavudine at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of stavudine at 23°C is 0.144.

Stavudine Capsules, USP are supplied for oral administration in strengths of 15 mg, 20 mg, 30 mg or 40 mg of stavudine, USP. Each capsule also contains inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The empty hard shell gelatin capsules contain gelatin and titanium dioxide. In addition, the 15 mg empty capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6; the 20 mg empty capsules contain D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40; the 30 mg empty capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40, FD&C Yellow No. 6; and the 40 mg empty capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Yellow No. 6.

The imprinting ink contains black iron oxide, potassium hydroxide, propylene glycol and shellac.

12.1 Mechanism Of Action

Stavudine is an antiviral drug [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours.

Absorption

Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within one hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of stavudine in HIV-1-infected adults are shown in Table 7.

Distribution

Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 mcg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8.

Metabolism

Metabolism plays a limited role in the clearance of stavudine. Unchanged stavudine was the major drug-related component circulating in plasma after an 80 mg dose of ¹⁴C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.

Elimination

Following an 80 mg dose of ¹⁴C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance.

In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Pediatric

Pharmacokinetic properties of stavudine in pediatric patients are presented in Table 9.

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 10). C_max and T_max were not significantly altered by renal impairment. The mean ± SD hemodialysis clearance value of stavudine was 120 ± 18 mL/min (n = 12); the mean ± SD percentage of the stavudine dose recovered in the dialysate, timed to occur between 2 to 6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3)].

Hepatic Impairment

Stavudine pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40 mg dose.

Geriatric

Stavudine pharmacokinetics have not been studied in patients > 65 years of age [see Use in Specific Populations (8.5)].

Gender

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males (n = 291) and females (n = 27).

Race

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n = 233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian and 4 other).

Drug Interaction Studies

Stavudine does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Because stavudine is not protein bound, it is not expected to affect the pharmacokinetics of protein bound drugs.

Tables 11 and 12 summarize the effects on AUC and C_max, with a 95% confidence interval (CI) when available, following coadministration of stavudine with didanosine, lamivudine and nelfinavir. No clinically significant pharmacokinetic interactions were observed.

Mechanism Of Action

Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (K_i = 0.0083 to 0.032 µM) and by causing DNA chain termination following its incorporation into viral DNA. Stavudine triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA.

Antiviral Activity In Cell Culture

The cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC₅₀) ranged from 0.009 to 4 µM against laboratory and clinical isolates of HIV-1. In cell culture, stavudine exhibited additive to antagonistic activity in combination with zidovudine. Stavudine in combination with either abacavir, didanosine, tenofovir or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9 to 45 µM concentrations tested, reduced the anti-HIV-1 activity of stavudine by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to stavudine and the inhibition of HIV-1 replication in humans has not been established.

Resistance

HIV-1 isolates with reduced susceptibility to stavudine have been selected in cell culture (strain-specific) and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6 to 29 months) stavudine monotherapy showed that post-therapy isolates from four patients exhibited EC₅₀ values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for stavudine susceptibility changes has not been identified.

Cross-Resistance

Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged stavudine treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to stavudine in cell culture. These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment. The clinical relevance of these findings suggests that stavudine should be avoided in the presence of thymidine analogue mutations.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

In 2-year carcinogenicity studies in mice and rats, stavudine was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose.

Stavudine was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavudine produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, stavudine elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 mcg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 mcg/mL, with and without metabolic activation). In the in vivo micronucleus assay, stavudine was clastogenic in bone marrow cells following oral stavudine administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days.

No evidence of impaired fertility was seen in rats with exposures (based on C_max) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

14 Clinical Studies

Combination Therapy

The combination use of stavudine is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing stavudine (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4⁺ cell counts through 48 weeks.

Monotherapy

The efficacy of stavudine was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992 to 1994) comparing stavudine with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.

16.1 Capsules

Stavudine Capsules, USP  are available containing 15 mg, 20 mg, 30 mg or 40 mg of stavudine, USP.

The 15 mg capsules have a hard-shell gelatin capsule with an off-white opaque cap and a pink opaque body filled with a white to off-white powder. The capsule is axially printed with M 154 in black ink on both the cap and body.

The 20 mg capsules have a hard-shell gelatin capsule with a pink opaque cap and a pink opaque body filled with a white to off-white powder. The capsule is axially printed with M 155 in black ink on both the cap and body.

The 30 mg capsules have a hard-shell gelatin capsule with an off-white opaque cap and a light orange opaque body filled with a white to off-white powder. The capsule is axially printed with M 137 in black ink on both the cap and body.

The 40 mg capsules have a hard-shell gelatin capsule with a light orange opaque cap and a light orange opaque body filled with a white to off-white powder. The capsule is axially printed with M 138 in black ink on both the cap and body.

They are supplied by State of Florida DOH Central Pharmacy as follows:

16.3 Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 Patient Counseling Information

See MEDICATION GUIDE.

17.1 General

Patients should be advised that stavudine capsules are not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using stavudine capsules and the importance of adherence to any antiretroviral regimen including those that contain stavudine capsules.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions or blood.
• Do not breast-feed. It is not known if stavudine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.

Patients should be informed that when stavudine capsules are used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine capsules are used alone.

Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule.

Patients should be instructed if they take too much stavudine capsules, they should contact a poison control center or emergency room right away.

Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.

17.2 Lactic Acidosis

Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine capsule therapy may be required.

17.3 Hepatic Toxicity

Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine capsules in combination with didanosine and hydroxyurea. This combination should be avoided.

17.4 Peripheral Neuropathy

Patients should be informed that an important toxicity of stavudine is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of stavudine capsules may be required if toxicity develops.

Caregivers of young children receiving stavudine capsule therapy should be instructed regarding detection and reporting of peripheral neuropathy.

17.5 Pancreatitis

Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine capsules and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.

The patient should be instructed to avoid alcohol while taking stavudine capsules. Alcohol may increase the patient’s risk of pancreatitis or liver damage.

17.6 Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including stavudine capsules. Patients receiving stavudine capsules should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.

Package Label

Label Image for 53808-0852
20mg

Label Image for 20mg - Stavudine