Boxed Warning

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: PREGNANCY).

FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WHEN ZERIT WAS PART OF A COMBINATION REGIMEN THAT INCLUDED DIDANOSINE IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION (SEE WARNINGS).

Indications and Usage

ZERIT (stavudine), in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection (see Clinical Studies).

CLINICAL STUDIES

Combination Therapy

The combination use of ZERIT is based on the results of clinical studies in HIV-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 ZERIT (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 RNA levels and increases in CD4 cell counts through 48 weeks.

Monotherapy

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

Dosage and Administration

The interval between doses of ZERIT (stavudine) should be 12 hours. ZERIT may be taken with or without food.

Adults: The recommended dose based on body weight is as follows:

40 mg twice daily for patients ≥60 kg.

30 mg twice daily for patients <60 kg.

Pediatrics: The recommended dose for newborns from birth to 13 days old is 0.5 mg/kg/dose given every 12 hours (see CLINICAL PHARMACOLOGY ). The recommended dose for pediatric patients at least 14 days old and weighing less than 30 kg is 1 mg/kg/dose, given every 12 hours. Pediatric patients weighing 30 kg or greater should receive the recommended adult dosage.

Dosage Adjustment

Patients should be monitored for the development of peripheral neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. These symptoms may be difficult to detect in young children (see WARNINGS ). If these symptoms develop during treatment, stavudine therapy should be interrupted. Symptoms 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 recommended dose:

20 mg twice daily for patients ≥60 kg.

15 mg twice daily for patients <60 kg.

If peripheral neuropathy recurs after resumption of ZERIT, permanent discontinuation should be considered.

Renal Impairment

ZERIT may be administered to adult patients with impaired renal function with adjustment in dose as shown in Table 12.

Table 12: Recommended Dosage Adjustment for 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
10-25	20 mg every 24 hours	15 mg every 24 hours

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. Although there are insufficient data to recommend a specific dose adjustment of ZERIT in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.

Hemodialysis Patients

The recommended dose is 20 mg every 24 hours (≥60 kg) or 15 mg every 24 hours (<60 kg), administered after the completion of hemodialysis and at the same time of day on non-dialysis days.

Method of Preparation

ZERIT (stavudine) for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg stavudine per mL of solution, as follows:

Add 202 mL of purified water to the container.
Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL stavudine solution. The solution may appear slightly hazy.
Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2° C to 8° C (36° F to 46° F). Discard any unused portion after 30 days.

Contraindications

ZERIT is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

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 AI455-019^a (Monotherapy)
Percent (%)
Adverse Events	ZERIT^b (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 Events^a in START 1 and START 2^b Studies (Combination Therapy)
START 1		START 2^b
Percent (%)
Adverse Events	ZERIT + lamivudine + indinavir (n=100^c)	zidovudine + lamivudine + indinavir (n=102)	ZERIT + didanosine + indinavir (n=102^c)	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 AI455-019^a,b
Percent (%)
Parameter	ZERIT (40 mg twice daily) (n=412)	zidovudine (200 mg 3 times daily) (n=402)
^a Data presented for patients for whom laboratory evaluations were performed.
^b Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.
ULN = upper limit of normal.
AST (SGOT) (>5.0 x ULN)	11	10
ALT (SGPT) (>5.0 x ULN)	13	11
Amylase (≥1.4 x ULN)	14	13

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 10 and 11.

Table 10: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3–4)
START 1		START 2
Percent (%)
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)
START 1		START 2
Percent (%)
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 ).

Drug Interactions

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

In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution. (See WARNINGS .)

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.

Description

ZERIT^® is the brand name for stavudine (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV).

ZERIT (stavudine) Capsules are supplied for oral administration in strengths of 15, 20, 30, and 40 mg of stavudine. Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate. The hard gelatin shell consists of gelatin, titanium dioxide, and iron oxides. The capsules are printed with edible inks.

ZERIT (stavudine) 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 and flavoring agents.

The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine has the following structural formula:

Stavudine is a white to off-white crystalline solid with the molecular formula C₁₀H₁₂N₂O₄ and a molecular weight of 224.2. 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 structural formula

Clinical Pharmacology

Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Tables 1-3). 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 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of ZERIT (stavudine) in HIV-infected adults are shown in Table 1.

Table 1: Steady-State Pharmacokinetic Parameters of ZERIT in HIV-Infected Adults
Parameter	ZERIT 40 mg BID Mean ± SD (n=8)
^a from 0 to 24 hours.
AUC = area under the curve over 24 hours.
C_max = maximum plasma concentration.
C_min = trough or minimum plasma concentration.
AUC (ng•h/mL)^a	2568 ± 454
C_max (ng/mL)	536 ± 146
C_min (ng/mL)	8 ± 9

Distribution

Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 2.

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 62.0%, 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-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 2). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Table 2: Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults: Bioavailability, Distribution, and Clearance
Parameter	Mean ± SD	n
^a following 1-hour IV infusion.
^b following single oral dose.
^c assuming a body weight of 70 kg.
^d over 12-24 hours.
Oral bioavailability (%)	86.4 ± 18.2	25
Volume of distribution (L)^a	46 ± 21	44
Total body clearance (mL/min)^a	594 ± 164	44
Apparent oral clearance (mL/min)^b	560 ± 182^c	113
Renal clearance (mL/min)^a	237 ± 98	39
Elimination half-life, IV dose (h)^a	1.15 ± 0.35	44
Elimination half-life, oral dose (h)^b	1.6 ± 0.23	8
Urinary recovery of stavudine (% of dose)^a,d	42 ± 14	39

Special Populations

Pediatric

For pharmacokinetic properties of stavudine in pediatric patients see Table 3.

Table 3: Pharmacokinetic Parameters (Mean ± SD) of Stavudine in HIV-Exposed or -Infected Pediatric Patients
Parameter	Ages 5 weeks to 15 years	n	Ages 14 to 28 days	n	Day of Birth	n
^a following 1-hour IV infusion.
^b at median time of 2.5 hours (range 2-3 hours) following multiple oral doses.
^c following single oral dose.
^d over 8 hours.
ND = not determined.
Oral bioavailability (%)	76.9 ± 31.7	20	ND	ND
Volume of distribution (L/kg)^a	0.73 ± 0.32	21	ND	ND
Ratio of CSF: plasma concentrations (as %)^b	59 ± 35	8	ND	ND
Total body clearance (mL/min/kg)^a	9.75 ± 3.76	21	ND	ND
Apparent oral clearance (mL/min/kg)^c	13.75 ± 4.29	20	11.52 ± 5.93	30	5.08 ± 2.80	17
Elimination half-life, IV dose (h)^a	1.11 ± 0.28	21	ND	ND
Elimination half-life, oral dose (h)^c	0.96 ± 0.26	20	1.59 ± 0.29	30	5.27 ± 2.01	17
Urinary recovery of stavudine (% of dose)^c,d	34 ± 16	19	ND	ND

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 4). 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 2-6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that ZERIT (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION ).

Table 4: Mean ± SD Pharmacokinetic Parameter Values of ZERIT^a in Adults with Varying Degrees of Renal Function
Creatinine Clearance			Hemodialysis Patients^b (n=11)
>50 mL/min (n=10)	26-50 mL/min (n=5)	9-25 mL/min (n=5)	Hemodialysis Patients^b (n=11)
^a Single 40-mg oral dose.
^b Determined while patients were off dialysis.
T_½ = terminal elimination half-life.
NA = not applicable.
Creatinine clearance (mL/min)	104 ± 28	41 ± 5	17 ± 3	NA
Apparent oral clearance (mL/min)	335 ± 57	191 ± 39	116 ± 25	105 ± 17
Renal clearance (mL/min)	167 ± 65	73 ± 18	17 ± 3	NA
T_½ (h)	1.7 ± 0.4	3.5 ± 2.5	4.6 ± 0.9	5.4 ± 1.4

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 PRECAUTIONS: Geriatric Use .)

Gender

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

Drug Interactions (see PRECAUTIONS: Drug Interactions)

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

Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of HIV/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/HCV co-infected patients (see WARNINGS ).

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 5 and 6 summarize the effects on AUC and C_max, with a 95% confidence interval (CI) when available, following coadministration of ZERIT with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.

Table 5: Results of Drug Interaction Studies with ZERIT: Effects of Coadministered Drug on Stavudine Plasma AUC and C_max Values
Drug	Stavudine Dosage	n^a	AUC of Stavudine (95% CI)	C_max of Stavudine (95% CI)
↑ indicates increase.
↔ indicates no change, or mean increase or decrease of <10%.
^a HIV-infected patients.
Didanosine, 100 mg q12h for 4 days	40 mg q12h for 4 days	10	↔	↑ 17%
Lamivudine, 150 mg single dose	40 mg single dose	18	↔ (92.7-100.6%)	↑12% (100.3-126.1%)
Nelfinavir, 750 mg q8h for 56 days	30-40 mg q12h for 56 days	8	↔	↔

Table 6: Results of Drug Interaction Studies with ZERIT: Effects of Stavudine on Coadministered Drug Plasma AUC and C_max Values
Drug	Stavudine Dosage	n^a	AUC of Coadministered Drug (95% CI)	C_max of Coadministered Drug (95% CI)
↔ indicates no change, or mean increase or decrease of <10%.
^a HIV-infected patients.
Didanosine, 100 mg q12h for 4 days	40 mg q12h for 4 days	10	↔	↔
Lamivudine, 150 mg single dose	40 mg single dose	18	↔ (90.5-107.6%)	↔ (87.1-110.6%)
Nelfinavir, 750 mg q8h for 56 days	30-40 mg q12h for 56 days	8	↔	↔

Clinical Studies

How Supplied / Storage and Handling

ZERIT^® (stavudine) Capsules are supplied by State of Florida DOH Central Pharmacy as follows:

NDC	Strength	Quantity/Form	Color	Source Prod. Code
53808-0656-1	20 mg	30 Capsules in a Blister Pack	light brown	0003-1965
53808-0657-1	30 mg	30 Capsules in a Blister Pack	light orange & dark orange	0003-1966
53808-0795-1	40 mg	30 Capsules in a Blister Pack	dark orange	0003-1967

Storage

ZERIT Capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° C and 30° C (59° F and 86° F) are permitted (see USP Controlled Room Temperature).

ZERIT for Oral Solution should be protected from excessive moisture and stored in tightly closed containers at 25° C (77° F). Excursions between 15° C and 30° C (59° F and 86° F) are permitted (see USP Controlled Room Temperature). After constitution, store tightly closed containers of ZERIT for Oral Solution in a refrigerator, 2° C to 8° C (36° F to 46° F). Discard any unused portion after 30 days.

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

Patient Counseling Information

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 ZERIT therapy may be required.

Patients should be informed that an important toxicity of ZERIT (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 disease or a history of peripheral neuropathy, 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.

Patients should be informed that 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. An increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of ZERIT and didanosine. Patients treated with this combination should be closely monitored for symptoms of pancreatitis. An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with ZERIT in combination with didanosine and hydroxyurea. This combination should be avoided.

Patients should be informed that ZERIT (stavudine) is not a cure for HIV infection, and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using ZERIT. They should be advised that ZERIT therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of ZERIT are unknown at this time.

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.

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

Patients should be advised of the importance of adherence to any antiretroviral regimen, including those that contain ZERIT.

Professional Information — Stavudine C 37