SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 17 DOSAGE AND ADMINISTRATION 18 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 23 DOSAGE FORMS, COMPOSITION AND PACKAGING 23

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 26 MICROBIOLOGY 30 TOXICOLOGY 32 REFERENCES 38

PART III: CONSUMER INFORMATION

ABOUT THIS MEDICATION 40 WARNINGS AND PRECAUTIONS 40 INTERACTIONS WITH THIS MEDICATION 41 PROPER USE OF THIS MEDICATION 41 SIDE EFFECTS AND WHAT TO DO ABOUT THEM 41 HOW TO STORE IT 42 MORE INFORMATION 43

ZERIT

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

ZERIT (stavudine) is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions Lactic Acidosis/Severe Hepatomegaly with Steatosis/Hepatic Failure

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 antiretroviral agents. 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 WARNINGS AND PRECAUTIONS - Pregnancy). Particular caution should be exercised when administering ZERIT 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 sudden unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms (including motor weakness, see Neurologic Symptoms) might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome. Symptoms associated with hyperlactatemia may continue or worsen following discontinuation of antiretroviral therapy. Treatment with ZERIT should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). An increased risk of hepatotoxicity may occur in patients treated with ZERIT in combination with didanosine and hydroxyurea compared to when ZERIT is used alone. Deaths attributed to hepatotoxicity have occurred in patients receiving this combination. Patients treated with this combination should be closely monitored for signs of liver toxicity.

Neurologic

Motor weakness (which was fatal in some cases) has been reported rarely in patients receiving combination antiretroviral therapy including ZERIT. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barre syndrome (including respiratory failure). If motor weakness develops in a patient receiving ZERIT, the drug should be discontinued. 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 ZERIT therapy. Peripheral neuropathy, which is dose related, has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine (see ADVERSE REACTIONS). Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine with or without stavudine.

Pancreatic

Fatal and nonfatal pancreatitis have occurred during therapy when ZERIT was part of a combination regimen that included didanosine or didanosine and hydroxyurea, in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. This combination of ZERIT and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of ZERIT after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring. The new regimen should contain neither didanosine nor hydroxyurea.

General

Patients receiving ZERIT (stavudine) or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection and, therefore, should remain under close clinical observation by physicians experienced in the treatment of patients with HIV disease and associated complications.

Renal

In HIV-infected patients with renal impairment, renal clearance and apparent oral clearance of stavudine was decreased. The terminal elimination half-life (t1/2) was prolonged up to 8 hours. Cmax and Tmax were not significantly affected by reduced renal function. Based on these preliminary observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance (# 50 mL/min) (see DOSAGE AND ADMINISTRATION).

Immune

Immune Reconstitution Syndrome: During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Hepatic

Hepatitis or liver failure, which was fatal in some cases, have been reported with ZERIT. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with antiretroviral agents in combination with hydroxyurea. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. The safety and efficacy of ZERIT have not been established in patients with significant underlying liver disorders. 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.

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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

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 :g/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 :g/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 Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

Special Populations

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 not known if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS AND PRECAUTIONS - Lactic Acidosis / Severe Hepatomegaly with Steatosis / Hepatic Failure). 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. Health care providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) 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 or impaired fertility. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. 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. 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. Stavudine has been shown to cross the human placenta in an ex vivo term model. Animal reproduction studies are not always predictive of human response.

Studies in which lactating rats were administered a single dose (5 or 100 mg/kg) of stavudine demonstrated that stavudine is readily excreted into breast milk. Although it is not known whether ZERIT 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 ZERIT.

The safety and effectiveness of ZERIT have been established in pediatric patients supported by evidence from adequate and well-controlled studies of stavudine in adults with additional data concerning safety and pharmacokinetics in pediatric patients. Patients should be monitored for clinically significant elevations of hepatic transaminases. If these elevations develop on treatment, ZERIT therapy should be interrupted. If the hepatic transaminase values return to pretherapy levels, resumption of treatment may be considered using a dosage schedule of 1 mg/kg/day, not to exceed the recommended adult dose of 20 mg twice daily. One open-label, phase I trial enrolled 38 subjects aged 5 weeks to 15 years; 9 had received no prior antiretroviral therapy and 29 had received zidovudine for a median duration of 104 weeks. Patients in this trial received ZERIT in initial doses ranging from 0.125 to 4.0 mg/kg/day with an average dose of 1.7 mg/kg/day for a median duration of 84 weeks (range 8 - 140 weeks). A second open-label trial, initiated to provide stavudine for children who had failed or were intolerant of alternative antiretroviral therapy, enrolled 51 subjects aged 8 months to 18 years who had received prolonged zidovudine and didanosine. These patients were treated with ZERIT at a dose of 2 mg/kg/day, for a median duration of 33 weeks (range 2 days - 82 weeks). A multi-centre, randomized, double-blind trial (Study ACTG 240) evaluated ZERIT [d4t] (2 mg/kg/day) versus zidovudine [ZDV] (200 mg QID) in the treatment of HIV-infected pediatric patients who had received #6 weeks of prior antiretroviral therapy. Two hundred and sixteen subjects, with a median baseline CD4 cell count of 1000 cells/mm3, were enrolled. CD4 cell counts were better maintained on ZERIT treatment as compared with ZDV (p<0.05). Patients on ZDV experienced more neutropenia (19%) versus patients on ZERIT (7%) (p<0.01). No differences were observed in any other laboratory parameters, signs or symptoms.

Clinical studies of ZERIT 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 ZERIT cannot be ruled out. In a monotherapy Expanded Access Program for patients with advanced HIV infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg BID and 8 of 51 (16%) elderly patients receiving 20 mg BID. 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 BID and 25% of patients receiving 20 mg BID. 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 - Dosage Adjustment).

The constituted powder for oral solution contains 50 mg sucrose per mL of constituted solution.

Zerit capsules contain lactose (120 and 240 mg depending on capsule strength). This amount is probably insufficient to induce specific symptoms of intolerance.

Monitoring and Laboratory Tests

Complete blood counts and clinical laboratory tests should be performed prior to initiating ZERIT therapy and at appropriate intervals thereafter. Moderate elevations of mean corpuscular volume may be observed in patients taking ZERIT and may provide an indication of treatment compliance.

Information for Patients

The importance of early recognition of symptoms of lactic acidosis, which include abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of ZERIT therapy may be required.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

They may continue to develop opportunistic infections and other complications of HIV infection and, therefore, should remain under the care of a physician experienced in treating HIV-associated diseases.

An important toxicity of ZERIT 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 counselled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV disease, a history of peripheral neuropathy and in patients who are taking concurrent neurotoxic drug therapy, including didanosine; and that dose modification and/or discontinuation of ZERIT may be required if toxicity develops.

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

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. Patients treated with ZERIT in combination with didanosine, may be at increased risk for pancreatitis, which may be fatal. These patients should be followed closely for symptoms of pancreatitis. Patients treated with ZERIT in combination with didanosine and hydroxyurea may be at increased risk for lactic acidosis and hepatotoxicity, which may be fatal. These patients should be closely monitored for signs of liver toxicity.

ADVERSE REACTIONS

Adult Patients

Adverse Drug Event Overview

A total of 202 patients in two clinical studies were treated with combination therapy that included stavudine in the regimen. The most clinically relevant serious adverse events, regardless of relationship to study treatment in these two clinical studies, included lactic acidosis, pancreatitis, hepatic dysfunction and peripheral neuropathy. The most common adverse events in the stavudine-containing regimens of the combination therapy clinical studies, regardless of grade or relationship to study treatment, included asthenia, diarrhea, dry skin, headache, increased cough, nausea, pharyngitis, rash and vomiting. In total, 31 out of the 202 patients in the stavudine-containing regimens from these two clinical studies, discontinued study medication due to adverse events.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Many of the serious clinical adverse events reported from patients receiving stavudine in clinical trials were consistent with the course of HIV infection. Concurrent therapy with other medications was permitted in these trials. Therefore, it is difficult to distinguish which events were related to stavudine, the disease itself, or other therapies. 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. Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with ZERIT in combination with didanosine and hydroxyurea (see WARNINGS and PRECAUTIONS).

Lactic Acidosis

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.

Peripheral Neuropathy

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 neurotoxic drug therapy, 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 of ZERIT, permanent discontinuation of ZERIT should be considered.

Pancreatitis

Pancreatitis resulting in death was observed in patients treated with ZERIT plus didanosine, with or without hydroxyurea, in controlled clinical studies and in postmarketing reports. Pancreatitis was generally attributed to advanced disease or to prior or concurrent treatment with medications known to be associated with pancreatitis. The occurrences were not dose-related, and were occasionally fatal. Patients with a history of pancreatitis appear to be at increased risk for recurrence (see WARNINGS AND PRECAUTIONS).

Clinical Adverse Eventsa in START 1b Studies

with a frequency of > 5% in at least one treatment group (Combination Therapy)

Adverse Events	Percent of Patients
	START 1
	ZERIT + lamivudine + indinavir n = 100 c	zidovudine + lamivudine + indinavir n = 102
Digestive System
Nausea	43	63
Diarrhea	34	16
Vomiting	18	33
Pain Abdomen	21	14
Dyspepsia	5	8
Anorexia	12	9
Disorder Gastrointestinal	3	9
Body as a Whole
Asthenia	25	26
Headache	25	26
Pain Back	23	20
Infection	17	16
Fever	14	11
Pain	15	9
Flu Syndrome	8	6
Accidental Injury	6	6
Infection Fungal	7	5
Chills	7	1
Respiratory System
Pharyngitis	28	24
Cough Increased	21	16
Rhinitis	18	6
Sinusitis	13	7
Bronchitis	6	7
Skin/Appendages
Rash	18	13
Dry Skin	11	12
Acne	5	6
Nervous System
Adverse Events	Percent of Patients
	START 1
	ZERIT + lamivudine + indinavir n = 100 c	zidovudine + lamivudine + indinavir n = 102
Peripheral Neurologic Symptoms/Neuropathy	8	7
Depression	8	12
Insomnia	6	9
Dizziness	5	7
Metabolic/Nutritional System
Bilirubinemia	9	4
Weight Decreased	4	8
Urogenital System
Dysuria	9	6
Hematuria	10	4
Calculus Kidney	7	5
Special Senses
Taste Perversion	6	10
Conjunctivitis	6	4
Musculoskeletal System
Arthralgia	7	5
Myalgia	7	2

Any severity, regardless of relationship to study regimen.

START 1 compared triple combination regimens in 202 treatment-naive patients. Patients received either ZERIT (40 mg BID) plus lamivudine plus indinavir or zidovudine plus lamivudine plus indinavir.

Duration of stavudine therapy = 48 weeks.

Clinical Adverse Eventsa in START 2b Studies

with a frequency of > 5% in at least one treatment group (Combination Therapy)

Adverse Events	Percent of Patients
	START 2
	ZERIT + didanosine + indinavir n = 102 c	zidovudine + lamivudine + indinavir n = 103
Digestive System
Nausea	53	67
Diarrhea	45	39
Vomiting	30	35
Pain Abdomen	20	24
Flatulence	14	14
Dyspepsia	10	11
Anorexia	7	12
Dry Mouth	8	6
Eructation	4	8
Constipation	4	7
Ulcer Mouth	6	4
Body as a Whole
Asthenia	32	38
Headache	46	37
Pain Back	11	13
Infection	23	18
Fever	20	8
Pain	17	24
Flu Syndrome	10	8
Accidental Injury	6	8
Infection Fungal	6	5
Chills	7	5
Lesion	3	6
Respiratory System
Pharyngitis	37	28
Cough Increased	27	20
Rhinitis	22	16
Sinusitis	17	7
Respiratory System (con't)
Adverse Events	Percent of Patients
	START 2
	ZERIT + didanosine + indinavir n = 102 c	zidovudine + lamivudine + indinavir n = 103
Bronchitis	3	6
Disorder Lung	6	0
Skin/Appendages
Rash	30	18
Dry Skin	33	23
Acne	6	2
Pruritus	13	11
Sweating	9	6
Nervous System
Peripheral Neurologic Symptoms/Neuropathy	21	10
Depression	12	12
Insomnia	7	4
Dizziness	11	9
Metabolic/Nutritional System
Bilirubinemia	7	3
Urogenital System
Dysuria	2	6
Hematuria	7	8
Infection Urinary Tract	4	7
Special Senses
Taste Perversion	12	21
Musculoskeletal System
Arthralgia	9	12
Myalgia	10	6

Any severity, regardless of relationship to study regimen.
START 2 compared two triple-combination regimens in 205 treatment-naive patients. Patients received either ZERIT (40 mg BID) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir.
Duration of stavudine therapy = 48 weeks.

Laboratory Abnormalities

Selected laboratory abnormalities reported in two controlled combination studies are provided in the following tables.

Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3-4)

Parameter	Percent of Patients
	START 1		START 2
	ZERIT + lamivudine + indinavir n = 100	zidovudine + lamivudine + indinavir n = 102	ZERIT + 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

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

Parameter	Percent of Patients
	START 1		START 2
	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

Post-Market Adverse Drug Reactions

The following events have been identified during post-approval use of ZERIT. 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 reactions, chills/fever, redistribution/accumulation of body fat (see WARNINGS AND PRECAUTIONS, Fat Redistribution). Digestive Disorders: anorexia. Exocrine Gland Disorders: pancreatitis [including fatal cases (see WARNINGS AND PRECAUTIONS)]. Hematologic Disorders: anemia, leukopenia, macrocytosis, and thrombocytopenia. Liver lactic acidosis and hepatic steatosis [including fatal cases (see WARNINGS AND PRECAUTIONS )], hepatitis and liver failure [including fatal cases (see WARNINGS AND PRECAUTIONS)]. Metabolic Disorders: diabetes mellitus, hyperglycemia. Musculoskeletal: myalgia. Nervous system: insomnia, severe motor weakness (most often reported in the setting of symptomatic hyperlactatemia or lactic acidosis, including fatal cases, see WARNINGS AND PRECAUTIONS).

Pediatric Patients

Adverse reactions and serious laboratory abnormalities in pediatric patients were similar in type and frequency to those seen in adult patients.

DRUG INTERACTIONS

Drug-Drug Interactions

Zidovudine may competitively inhibit the intracellular phosphorylation of stavudine (see ACTIONS and CLINICAL PHARMACOLOGY). Therefore, use of zidovudine in combination with ZERIT is not recommended. In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin; therefore coadministration of stavudine with either doxorubicin or ribavirin should be undertaken with caution. No pharmacokinetic interactions were observed between ZERIT and didanosine, lamivudine (3TC), or nelfinavir when co-administered in clinical trials. 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.

Drug-Food Interactions

ZERIT (stavudine) may be taken without regard to meals. Absorption of stavudine was assesesed in a study of 16 asymptomatic HIV-infected patients. Each patient received a 70 mg oral dose of ZERIT in the fasting state, 1 hour before a standardized meal, and immediately after a standardized meal. The results indicate that systemic exposure to stavudine is not reduced when ZERIT is taken with food. Although the rate of absorption decreased, the extent of absorption was not significantly (p = 0.27) affected by the presence of food when ZERIT was taken immediately after a meal. Mean (+- SD) CMAX of stavudine was reduced from 1.44 (+- 0.49) :g/mL in the fasting state to 0.75 (+- 0.16) :g/mL after a meal, and the median time to achieve CMAX was prolonged from 0.6 to 1.5 hours. However, mean (+- SD) AUC06-4 values were 2.50 (+- 0.71) :g @hr/mL and 2.31 (+- 0.55) :g @hr/mL in the fasting state and after a meal, respectively, indicating that systemic exposure was similar with or without the presence of food.

Drug-Herb Interactions

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The interval between oral doses should be 12 hours. ZERIT (stavudine) may be taken with or without food. The recommended doses are based on body weight, as outlined in the following table:

Adult dosing

The interval between doses of ZERIT (stavudine) Oral Solution should be 12 hours and doses may be taken without regard to meals. The recommended dose for pediatric patients is 2 mg/kg/day, not to exceed the recommended adult dose of 40 mg twice daily. The systemic exposure to stavudine is the same following administration as capsules or solution. There is no clinical experience with ZERIT in children under the age of 3 months.

Dosage Adjustment

The following dose adjustments are recommended in adult patients with renal impairment.

For patients undergoing hemodialysis, the daily dose of ZERIT should be administered after the completion of a scheduled hemodialysis session. On nondialysis days, ZERIT should be administered at the same time of day as it is on dialysis days.

Although there are insufficient data to recommend a specific dosage adjustment for children with renal impairment, a reduction in dose and/or increase in the interval between doses should be considered in this patient population.

Dosing adjustment is not necessary in subjects with stable hepatic impairment. In the event of rapidly elevating aminotransferase levels, treatment with ZERIT should be suspended.

Patients should be monitored for clinically significant elevations of hepatic transaminases. If these elevations develop on treatment, ZERIT therapy should be interrupted. If the hepatic transaminase values return to pretherapy levels, resumption of treatment may be considered using a dosage schedule of 1 mg/kg/day, not to exceed the recommended adult dose of 20 mg twice daily.

Clinical symptoms of peripheral neuropathy which is usually characterized by numbness, tingling or pain in the feet or hands should prompt interruption of ZERIT treatment and evaluation of the patient. These symptoms may be difficult to detect in children (see WARNINGS AND PRECAUTIONS ). If symptoms develop, ZERIT should be interrupted. Symptoms may resolve if therapy is withdrawn promptly. Some patients may experience a temporary worsening of symptoms following discontinuation of therapy. If symptoms resolve completely, resumption of treatment may be considered. If a reduced dose is warranted, use one-half the recommended dose.

Administration

OVERDOSAGE

There is no known antidote for ZERIT (stavudine) overdosage. Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Patients may benefit from administration of activated charcoal. Stavudine can be removed by hemodialysis, the mean +- SD hemodialysis clearance of stavudine is 120 +- 18 mL/min. It is not known whether stavudine is eliminated by peritoneal dialysis.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ZERIT (stavudine), also known as d4T, is a synthetic thymidine nucleoside analogue active against the Human Immunodeficiency Virus (HIV).

studies demonstrate that stavudine is converted to the triphosphate by cellular kinases. The 5'-triphosphate is the active form of the drug. In cell culture studies with two different cell lines, stavudine triphosphate had an intracellular half-life of 3.5 hours. Stavudine triphosphate has been shown to be a potent competitive inhibitor of HIV reverse transcriptase (ki = 0.0083 to

0.032 uM). In addition, both stavudine triphosphate and the natural substrate, thymidine triphosphate, are used by HIV reverse transcriptase in vitro for incorporation into the nascent DNA chain. Stavudine lacks the 3'-hydroxyl group necessary for DNA elongation and once incorporated into DNA, functions as a DNA chain terminator in vitro. Both the inhibition of binding of thymidine triphosphate to reverse transcriptase and DNA chain termination may be partially responsible for inhibition of HIV replication in vitro. In addition to the inhibitory effect on HIV reverse transcriptase, stavudine triphosphate exhibits some inhibitory effect on DNA polymerase beta and gamma, and markedly reduces the syntheses of mitochondrial DNA. Clinically, ZERIT has been studied in various combinations with other classes of anti-retroviral drugs, including didanosine, lamivudine (3TC), ritonavir, nelfinavir, saquinavir, indinavir, and hydroxyurea (see PHARMACOLOGY - Clinical Studies). However, zidovudine in combination with ZERIT is not recommended (see WARNINGS AND PRECAUTIONS - Drug Interactions). Both drugs are phosphorylated by the same cellular enzyme (thymidine kinase), which may preferentially phosphorylate zidovudine, thereby decreasing the phosphorylation of stavudine to its active triphosphate form. Based on in vitro testing, the activation of stavudine has also been shown to be inhibited by other drugs. Among the several drugs tested, the only ones that may interfere with stavudine phosphorylation at relevent concentrations are doxorubicin and ribavirin, but not other drugs used in the therapy of HIV infection which are similarly phosphorylated. The clinical significance of this is unknown. Clinical trials supporting the use of ZERIT in appropriate antiretroviral regimens for the treatment of HIV-infected patients, demonstrated, overall, greatest inhibition of HIV RNA levels and greatest increase in CD4 cell counts with triple-combination regimens (see PHARMACOLOGY - Clinical Studies).

HIV isolates with reduced susceptibility to stavudine have been selected in vitro and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV isolates from stavudine-treated patients revealed, in 3 of 20 paired isolates, a 4- to 12-fold decrease in susceptibility to stavudine in vitro. The genetic basis for these susceptibility changes has not been identified. The clinical relevance of changes in stavudine susceptibility has not been established.

Five of 11 stavudine post-treatment isolates developed moderate resistance to zidovudine (9- to 176-fold) and 3 of those 11 isolates developed moderate resistance to didanosine (7- to 29-fold). The clinical relevance of these findings is unknown.

Pharmacokinetics in Adults

The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (refer to table below). Peak plasma concentrations (Cmax) 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.

Mean +- SD Pharmacokinetic Parameters of Stavudine in Adult and Pediatric HIV-Infected Patient

Absorption

Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution.

Distribution

Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 :g/mL. Stavudine distributes equally between red blood cells and plasma.

Metabolism

Excretion

Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

STORAGE AND STABILITY

ZERIT capsules should be stored at room temperature (15o to 30oC) and protected from excessive moisture. Keep bottles tightly closed. ZERIT for Oral Solution should be protected from excessive moisture and stored in tightly closed containers at room temperature (15deg - 30degC). After constitution, store tightly closed containers of ZERIT for Oral Solution in a refrigerator (2deg - 8degC). Discard any unused portion after 30 days. The solution may also be stored at room temperature for up to 3 days.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Capsules

15 mg of stavudine - light yellow and dark red capsule imprinted with "BMS 1964" and "15";

30 mg of stavudine - light orange and dark orange capsule imprinted with "BMS 1966" and "30"

ZERIT capsules are available in bottles of 60, in packages of 100 individually foil-wrapped capsules and in unit dose blister strips of 4 X 14 capsules.

ZERIT for Oral Solution

ZERIT for Oral Solution is a dye-free, fruit-flavored powder that provides 1 mg of stavudine per mL of solution upon constitution with water. Directions for solution preparation are included in the "DOSAGE AND ADMINISTRATION" section. ZERIT for Oral Solution is available in high-density polyethylene (HDPE) bottles, with child-resistant closures, that provide 200 mL of solution after constitution with water.

Composition

ZERIT (stavudine) capsules are available for oral administration in strengths of 5, 15, 20, 30 and 40 mg of stavudine. Non medicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate. Capsule shell: gelatin, black iron oxide (20 mg only), printing ink, silicon dioxyde, sodium lauryl sulphate, titanium dioxide and yellow and red iron oxides. ZERIT for Oral Solution is supplied as a dye-free, fruit-flavored powder in bottles with child- resistant closures providing 200 mL of a 1 mg/mL stavudine solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming (simethicone, polyethylene glycol monostearate, glyceryl monostearate, sorbic acid, water) and flavoring agents.

Route of Administration	Dosage Form / Strength	Nonmedicinal Ingredients
Oral	Capsules 5, 15, 20, 30 and 40 mg	Lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate. Capsule shell : gelatin, black iron oxide (20 mg only), printing ink, silicon dioxyde, sodium lauryl sulphate, titanium dioxide and yellow and red iron oxides.
Oral	Powder for Oral Solution 1 mg/mL	Methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming (simethicone, polyethylene glycol monostearate, glyceryl monostearate, sorbic acid, water) and flavoring agents

Patient weight	ZERIT Dosage
< 60 kg	30 mg bid
$ 60 kg	40 mg bid

Recommended ZERIT Dosing Modifications for Subjects with Renal Impairment
Creatinine Clearance (mL/min)	Recommended ZERIT Dose by Patient Weight
Creatinine Clearance (mL/min)	$ 60 kg	< 60 kg
> 50 *	40 mg every 12 hours *	30 mg every 12 hours *
26 - 50	20 mg every 12 hours	15 mg every 12 hours
<25 +	20 mg every 24 hours	15 mg every 24 hours

Parameter	Adult Patients	n	Pediatric Patients	n
Oral bioavailability (F)	86.4 +- 18.2%	25	76.9 +- 31.7%	20
Volume of distribution a (VD)	58 +- 21 L	44	18.5 +- 9.2 L/m 2	21
Apparent oral volume of distribution b (VD/F)	66 +- 22 L	71	not determined	!
Ratio of CSF: plasma concentrations (as %) c	not determined	!	59 +- 35%	8
Total body clearance a (CL)	8.2 +- 2.3 mL/min/kg	44	247 +- 94 mL/min/m 2	21
Apparent oral clearance b (CL/F)	8.0 +- 2.6 mL/min/kg	113	333 +- 87 mL/min/m 2	20
a	1.15 +- 0.35 h	44	1.11 +- 0.28 h	21
b	1.44 +- 0.30 h	115	0.96 +- 0.26 h	20
Urinary recovery of stavudine (% of dose)	39 +- 23%	88	34 +- 16%	19