HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ZERIT
`safely and effectively. See full prescribing information for ZERIT.
`ZERIT(cid:147) (stavudine) capsules, for oral use
`ZERIT(cid:147) (stavudine) for oral solution
`Initial U.S. Approval: 1994
`WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with
`STEATOSIS; PANCREATITIS
`See full prescribing information for complete boxed warning.
`
`(cid:120) Lactic acidosis and severe hepatomegaly with steatosis, including
`fatal cases. Fatal lactic acidosis has been reported in pregnant
`women who received the combination of ZERIT and didanosine.
`Coadministration of ZERIT with didanosine is contraindicated. (4,
`5.1)
`(cid:120) Fatal and nonfatal pancreatitis have occurred when ZERIT was
`part of a combination regimen that included didanosine.
`Coadministration of ZERIT with didanosine is contraindicated. (4,
`5.4)
`--------------------------RECENT MAJOR CHANGES----------------------------
`Boxed Warning
`12/2017
`Contraindications (4)
`12/2017
`Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)
`12/2017
`---------------------------INDICATIONS AND USAGE----------------------------
`ZERIT (stavudine) is a nucleoside reverse transcriptase inhibitor for use in
`combination with other antiretroviral agents for the treatment of human
`immunodeficiency virus (HIV)-1 infection. (1)
`------------------------DOSAGE AND ADMINISTRATION----------------------
`(cid:120) Recommended dosage for adults:
`(cid:120) less than 60 kg: 30 mg every 12 hours (2.1)
`(cid:120) at least 60 kg: 40 mg every 12 hours (2.1)
`(cid:120) Recommended dosage for pediatric patients:
`(cid:120) newborns from birth to 13 days old: 0.5 mg/kg every 12 hours (2.2)
`(cid:120) at least 14 days old and weighing less than 30 kg: 1 mg/kg every
`12 hours (2.2)
`(cid:120) weighing at least 30 kg: adult dose (2.2)
`(cid:120) Renal impairment: Dose adjustment is recommended for CrCl (cid:100)50 mL/min.
`(2.3)
`(cid:120) For oral solution: Requires preparation by a pharmacist. (2.4)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`(cid:120) Capsules: 15 mg, 20 mg, 30 mg, 40 mg (3, 16)
`
`(cid:120) For oral solution: 1 mg/mL following constitution (3, 16)
`------------------------------CONTRAINDICATIONS-------------------------------
`ZERIT
`is contraindicated
`in patients with clinically
`significant
`hypersensitivity to stavudine or to any of the components of this product. (4)
`Coadministration of ZERIT with didanosine is contraindicated. (4)
`
`--------------------------WARNINGS AND PRECAUTIONS----------------------
`(cid:120) Hepatic
`toxicity: May be severe,
`fatal. Consider
`interruption or
`discontinuation. Avoid
`use
`in
`combination with
`hydroxyurea.
`Coadministration of ZERIT with didanosine is contraindicated. Risk of
`hepatic decompensation exists when used in combination with interferon and
`ribavirin; closely monitor and consider discontinuation of stavudine. (4, 5.2,
`7)
`(cid:120) Neurologic symptoms: Motor weakness, most often seen in the setting of
`lactic acidosis, may mimic Guillain-Barré syndrome; discontinue treatment.
`Monitor for peripheral neuropathy, which can be severe;
`treatment
`discontinuation should be considered. (5.3)
`(cid:120) Patients may develop localized loss of body fat, monitor for signs and
`symptoms of lipoatrophy. Alternative antiretrovirals should be considered.
`(5.5)
`(cid:120) Patients may develop immune reconstitution syndrome. (5.6)
`-------------------------------ADVERSE REACTIONS------------------------------
`(cid:120) In adults, the most common adverse reactions are headache, diarrhea,
`neuropathy, rash, nausea, and vomiting. (6.1)
`(cid:120) Adverse reactions in pediatric patients were consistent with those seen in
`adults. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`--------------------------------DRUG INTERACTIONS-----------------------------
`(cid:120) The combination of ZERIT and hydroxyurea should be avoided. (7)
`(cid:120) Coadministration of ZERIT with zidovudine should be avoided. (7)
`(cid:120) Coadministration of ZERIT and doxorubicin or ribavirin should be
`undertaken with caution. (7)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`(cid:120) Pregnancy: Fatal lactic acidosis has been reported in pregnant women who
`received both didanosine and stavudine with other agents. (4, 8.1)
`(cid:120) Nursing mothers should be instructed not to breastfeed due to the potential
`for postnatal HIV transmission. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 12/2017
`
`3
`4
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS AND HEPATOMEGALY WITH
`STEATOSIS; PANCREATITIS
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Adult Dosage
`2.2
`Recommended Pediatric Dosage
`2.3
`Dosage Adjustment
`2.4
`Method of Preparation for Oral Solution
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Lactic Acidosis/Severe Hepatomegaly with Steatosis
`5.2
`Hepatic Toxicity
`5.3
`Neurologic Symptoms
`5.4
`Pancreatitis
`5.5
`Lipoatrophy
`5.6
`Immune Reconstitution Syndrome
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`
`6
`
`7
`
`8
`
`10
`11
`12
`
`13
`
`14
`16
`17
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`12.4 Microbiology
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`Reference ID: 4193815
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`MYLAN v. BMS
`IPR2018-00892
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`

`FULL PRESCRIBING INFORMATION
`
`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 ZERIT and didanosine with other antiretroviral agents.
`Coadministration of ZERIT and didanosine is contraindicated because of increased risk of
`serious and/or life-threatening events [see Warnings and Precautions (5.1)]. Suspend
`treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced
`hepatotoxicity occur.
`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 and
`Precautions (5.4)].
`
`1.
`
`INDICATIONS AND USAGE
`
`ZERIT(cid:147), in combination with other antiretroviral agents, is indicated for the treatment of human
`immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14)].
`2.
`DOSAGE AND ADMINISTRATION
`
`The interval between doses of ZERIT (stavudine) should be 12 hours. ZERIT 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.
`(cid:120)
`For patients weighing at least 60 kg: 40 mg every 12 hours.
`(cid:120)
`2.2 Recommended Pediatric Dosage
`
`(cid:120)
`
`For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
`
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`(cid:120)
`
`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.
`(cid:120)
`2.3 Dosage Adjustment
`Renal Impairment
`
`Adult Patients: ZERIT may be administered to adult patients with impaired renal function with
`an adjustment in dosage as shown in Table 1.
`
`Table 1: Recommended Dosage Adjustment for Adult Patients with Renal Impairment
`Creatinine
`Recommended ZERIT Dose
`by Patient Weight
`Clearance
`(mL/min)
`
`less than 60 kg
`
`at least 60 kg
`
`greater than 50
`
`26–50
`
`40 mg every 12 hours
`
`20 mg every 12 hours
`
`30 mg every 12 hours
`
`15 mg every 12 hours
`
`10–25
`
`15 mg every 24 hours
`20 mg every 24 hours
`15 mg every 24 hours*
`20 mg every 24 hours*
`* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis
`days.
`
`Hemodialysis
`
`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 ZERIT in this patient
`population.
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`2.4 Method of Preparation 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:
`1. Add 202 mL of purified water to the container.
`2. 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.
`3. 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.
`DOSAGE FORMS AND STRENGTHS
`
`3.
`
`(cid:120) ZERIT 15 mg capsules with dark red cap and light yellow body, printed with black ink
`“BMS 1964” on the cap and with black ink “15” on the body.
`(cid:120) ZERIT 20 mg capsules with light brown cap and light brown body, printed with black ink
`“BMS 1965” on the cap and with black ink “20” on the body.
`(cid:120) ZERIT 30 mg capsules with dark orange cap and light orange body, printed with black ink
`“BMS 1966” on the cap and with black ink “30” on the body.
`(cid:120) ZERIT 40 mg capsules with dark orange cap and dark orange body, printed with black ink
`“BMS 1967” on the cap and with black ink “40” on the body.
`(cid:120) ZERIT for oral solution is a dye-free, fruit-flavored powder that provides 1 mg of stavudine
`per milliliter solution after constitution.
`CONTRAINDICATIONS
`
`4.
`
`ZERIT is contraindicated in patients with clinically significant hypersensitivity to stavudine or to
`any of the components contained in the formulation.
`Co-administration of ZERIT with didanosine is contraindicated due to the potential for serious
`and/or life-threatening events notably lactic acidosis, hepatotoxicity, peripheral neuropathy, and
`pancreatitis [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].
`
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`

`5. WARNINGS AND PRECAUTIONS
`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. Coadministration of ZERIT and didanosine is
`contraindicated [see Contraindications (4) and Use in Specific Populations (8.1)].
`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 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 ZERIT 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 ZERIT should be considered for patients
`with confirmed lactic acidosis.
`5.2 Hepatic Toxicity
`
`The safety and efficacy of ZERIT 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 postmarketing
`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. Coadministration of ZERIT and didanosine is
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`contraindicated; and the combination of ZERIT and hydroxyurea should be avoided [see
`Contraindications (4) and Drug Interactions (7)].
`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
`(eg, 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 (eg, 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 ZERIT. 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, ZERIT 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 ZERIT 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 [see Drug Interactions (7)].
`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 ZERIT should be considered. In some cases, symptoms
`may worsen temporarily following discontinuation of therapy.
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`5.4 Pancreatitis
`
`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. The combination of ZERIT
`and any other agents that are toxic to the pancreas should be suspended in patients with
`suspected pancreatitis. Coadministration of ZERIT and didanosine is contraindicated [see
`Contraindications (4)]. Reinstitution of ZERIT after a confirmed diagnosis of pancreatitis should
`be undertaken with particular caution and close patient monitoring.
`5.5 Lipoatrophy
`
`In randomized controlled trials of treatment-naive patients, clinical lipoatrophy 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 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 ZERIT should be monitored for symptoms or signs of lipoatrophy and
`questioned about body changes related to lipoatrophy. Given the potential risks of using ZERIT
`including lipoatrophy, 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 ZERIT. 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.
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`

`6.
`
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`
`(cid:120)
`
`(cid:120)
`(cid:120)
`(cid:120)
`(cid:120)
`
`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 [see Warnings and Precautions (5.5)]
`
`When ZERIT 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 Trials Experience
`
`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.
`Clinical Trials Experience in Adults
`
`Selected adverse reactions that occurred in adult patients receiving ZERIT in a controlled
`monotherapy study (Study AI455-019) are provided in Table 2.
`
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`

`Table 2: Selected Adverse Reactions in Study AI455-019a (Monotherapy)
`
`
`
`Percent (%)
`
`Adverse Reaction
`Headache
`
`Diarrhea
`
`ZERITb
`(40 mg twice daily)
`(n=412)
`54
`
`50
`
`zidovudine
`(200 mg 3 times daily)
`(n=402)
`49
`
`44
`
`52
`
`Peripheral Neurologic Symptoms/
` Neuropathy
`40
`Rash
`39
`Nausea and Vomiting
`a The incidences reported included all severity grades and all reactions regardless of causality.
`b Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.
`
`39
`
`35
`44
`
`Pancreatitis was observed in 3 of the 412 adult patients who received ZERIT in study
`AI455-019.
`Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving ZERIT
`from two controlled combination studies are provided in Table 3.
`
`Table 3: Selected Adverse Reactionsa in START 1 and START 2b Studies
`(Combination Therapy)
`
`Adverse Reaction
`Nausea
`
`Diarrhea
`
`Headache
`Rash
`Vomiting
`Peripheral Neurologic Symptoms/
` Neuropathy
`
`Percent (%)
`
`START 1
`ZERIT +
`lamivudine +
`indinavir
`(n=100c)
`43
`
`zidovudine +
`lamivudine +
`indinavir
`(n=102)
`63
`
`START 2b
`ZERIT +
`didanosine +
`indinavir
`(n=102c)
`53
`
`zidovudine +
`lamivudine +
`indinavir
`(n=103)
`67
`
`34
`
`25
`18
`18
`
`8
`
`16
`
`26
`13
`33
`
`7
`
`Page 9 of 27
`
`45
`
`46
`30
`30
`
`21
`
`39
`
`37
`18
`35
`
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`

`Table 3: Selected Adverse Reactionsa in START 1 and START 2b Studies
`(Combination Therapy)
`
`Percent (%)
`
`START 2b
`START 1
`ZERIT +
`ZERIT +
`zidovudine +
`lamivudine +
`didanosine +
`lamivudine +
`indinavir
`indinavir
`indinavir
`(n=102c)
`(n=100c)
`(n=102)
`Adverse Reaction
`a The incidences reported included all severity grades and all reactions regardless of causality.
`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.
`
`zidovudine +
`lamivudine +
`indinavir
`(n=103)
`
`Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019)
`are provided in Table 4.
`
`Table 4: Selected Laboratory Abnormalities in Study AI455-019a,b
`
`
`
`Percent (%)
`
`ZERIT
`(40 mg twice daily)
`(n=412)
`
`zidovudine
`(200 mg 3 times daily)
`(n=402)
`
`Parameter
`AST (SGOT)
` (>5.0 x ULN)
`ALT (SGPT)
` (>5.0 x ULN)
`Amylase
`((cid:116)1.4 x ULN)
`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.
`
`11
`
`13
`
`14
`
`10
`
`11
`
`13
`
`Selected laboratory abnormalities reported in two controlled combination studies are provided in
`Tables 5 and 6.
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`

`Table 5: Selected Laboratory Abnormalities in START 1 and START 2 Studies
`(Grades 3–4)
`
`Percent (%)
`
`ZERIT +
`lamivudine +
`indinavir
`(n=100)
`
`START 1
`zidovudine +
`lamivudine +
`indinavir
`(n=102)
`
`ZERIT +
`didanosine +
`indinavir
`(n=102)
`
`START 2
`zidovudine +
`lamivudine +
`indinavir
`(n=103)
`
`7
`
`5
`
`6
`
`2
`
`6
`
`4
`
`6
`
`2
`
`2
`
`2
`
`3
`
`<1
`
`16
`
`7
`
`8
`
`5
`
`5
`
`8
`
`8
`
`7
`
`5
`
`2
`
`5
`
`2
`
`Parameter
`Bilirubin
` (>2.6 x ULN)
`AST (SGOT)
` (>5 x ULN)
`ALT (SGPT)
` (>5 x ULN)
`GGT
` (>5 x ULN)
`Lipase
` (>2 x ULN)
`Amylase
` (>2 x ULN)
`ULN = upper limit of normal.
`
`Table 6: Selected Laboratory Abnormalities in START 1 and START 2 Studies
`(All Grades)
`
`Percent (%)
`
`ZERIT +
`lamivudine +
`indinavir
`(n=100)
`65
`
`START 1
`zidovudine +
`lamivudine +
`indinavir
`(n=102)
`60
`
`ZERIT +
`didanosine +
`indinavir
`(n=102)
`68
`
`START 2
`zidovudine +
`lamivudine +
`indinavir
`(n=103)
`55
`
`53
`
`50
`
`28
`
`26
`
`31
`
`20
`
`18
`
`12
`
`19
`
`17
`
`42
`
`40
`
`15
`
`27
`
`21
`
`20
`
`20
`
`8
`
`12
`
`19
`
`Page 11 of 27
`
`Parameter
`Total Bilirubin
`
`AST (SGOT)
`
`ALT (SGPT)
`
`GGT
`
`Lipase
`
`Amylase
`
`Reference ID: 4193815
`
`11
`
`

`

`Clinical Trials 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)].
`6.2 Postmarketing Experience
`
`The following adverse reactions have been identified during postmarketing use of ZERIT.
`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 ZERIT, or a combination of these factors.
`
`Body as a Whole: abdominal pain, allergic reaction, chills/fever.
`
`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 [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)].
`
`7
`
`DRUG INTERACTIONS
`
`ZERIT is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.
`
`Page 12 of 27
`
`Reference ID: 4193815
`
`12
`
`

`

`Hydroxyurea: 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 hydroxyurea, may be at increased risk for pancreatitis
`and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and
`Precautions (5.2)]. The combination of ZERIT and hydroxyurea should be avoided.
`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. 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 (eg, plasma concentrations or intracellular triphosphorylated active metabolite
`concentrations) or pharmacodynamic (eg, 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)].
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Pregnancy Category C
`
`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. 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.
`
`Page 13 of 27
`
`Reference ID: 4193815
`
`13
`
`

`

`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 is contraindicated [see Contraindications (4)].
`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
`breastfeed 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 breastfeed if they are receiving
`ZERIT.
`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
`(6.1)].
`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 ZERIT
`2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received
`ZERIT 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 ZERIT 2 mg/kg/day in combination with
`didanosine and nelfinavir from birth through 4 weeks of age.
`
`Page 14 of 27
`
`Reference ID: 4193815
`
`14
`
`

`

`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 ZERIT (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 ZERIT 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 symp