ZYPREXA

1 INDICATIONS AND USAGE ZYPREXA RELPREVV is available only through a restricted distribution program [see Warnings and Precautions ( 5.2 )] . ZYPREXA RELPREVV must not be dispensed directly to a patient. For a patient to receive treatment, the prescriber, healthcare setting, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV REMS. To enroll, call 1-877-772-9390. ZYPREXA ® RELPREVVTM is a long-acting atypical antipsychotic for intramuscular injection indicated for the treatment of schizophrenia. ( 1.1 ) Efficacy was established in two clinical trials in patients with schizophrenia: one 8-week trial in adults and one maintenance trial in adults. ( 14.1 ) 1.1 Schizophrenia ZYPREXA RELPREVV is indicated for the treatment of schizophrenia. Efficacy was established in two clinical trials in patients with schizophrenia: one 8-week trial in adults and one maintenance trial in adults [see Clinical Studies ( 14.1 )] .

2 DOSAGE AND ADMINISTRATION 150 mg/2 wks, 300 mg/4 wks, 210 mg/2 wks, 405 mg/4 wks, or 300 mg/2 wks. See Table 1 for dosing recommendations. ( 2.1 ) ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only. Do not administer intravenously or subcutaneously. ( 2.1 ) Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. ( 2.1 ) Establish tolerability with oral olanzapine prior to initiating treatment. ( 2.1 ) ZYPREXA RELPREVV doses above 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials. ( 2.1 ) Use in specific populations (including renal and hepatic impaired, and pediatric population) has not been studied. ( 2.1 ) Must be suspended using only the diluent for ZYPREXA RELPREVV provided in the convenience kit. ( 2.2 ) 2.1 Dosage ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only and should not be administered intravenously or subcutaneously. Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. Refer to the package insert for ZYPREXA IntraMuscular for more information about that product. Establish tolerability with oral olanzapine prior to initiating treatment. ZYPREXA RELPREVV should be administered by a healthcare professional every 2 to 4 weeks by deep intramuscular gluteal injection using a 19-gauge, 1.5-inch needle. Following insertion of the needle into the muscle, aspiration should be maintained for several seconds to ensure that no blood is drawn into the syringe. If any blood is aspirated into the syringe, it should be discarded and fresh drug should be prepared using a new convenience kit. The injection should be performed at a steady, continuous pressure. Do not massage the injection site. Dose Selection — The efficacy of ZYPREXA RELPREVV has been demonstrated within the range of 150 mg to 300 mg administered every 2 weeks and with 405 mg administered every 4 weeks. Dose recommendations considering oral ZYPREXA and ZYPREXA RELPREVV are shown in Table 1 . Table 1: Recommended Dosing for ZYPREXA RELPREVV Based on Correspondence to Oral ZYPREXA Doses Target Oral ZYPREXA Dose Dosing of ZYPREXA RELPREVV During the First 8 Weeks Maintenance Dose After 8 Weeks of ZYPREXA RELPREVV Treatment 10 mg/day 210 mg/2 weeks or 150 mg/2 weeks or 405 mg/4 weeks 300 mg/4 weeks 15 mg/day 300 mg/2 weeks 210 mg/2 weeks or 405 mg/4 weeks 20 mg/day 300 mg/2 weeks 300 mg/2 weeks ZYPREXA RELPREVV doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials. Post-Injection Delirium/Sedation Syndrome — During premarketing clinical studies, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see Boxed Warning , Warnings and Precautions ( 5.1 ), and Overdosage ( 10.1 )] . Patients should be informed of this risk and how to recognize related symptoms [see Patient Counseling Information ( 17 )] . ZYPREXA RELPREVV must be administered in a certified healthcare setting with ready access to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare professional must continuously observe the patient at the healthcare setting for at least 3 hours for symptoms consistent with olanzapine overdose, including sedation (ranging from mild in severity to coma) and/or delirium (including confusion, disorientation, agitation, anxiety, and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension, and convulsion. The potential for onset of an event is greatest …

3 DOSAGE FORMS AND STRENGTHS ZYPREXA RELPREVV is a powder for suspension for intramuscular use only. ZYPREXA RELPREVV is present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine single-dose per vial. The diluent is a clear, colorless to slightly yellow solution in a glass vial [see Description ( 11 ) and How Supplied/Storage and Handling ( 16 )] . The reconstituted suspension will be yellow and opaque [see Dosage and Administration ( 2.2 )] . Powder for suspension for single-dose intramuscular use only: 210 mg/vial, 300 mg/vial, and 405 mg/vial. ( 3 , 11 , 16 )

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS Most common adverse reactions (≥5% in at least one of the treatment groups and greater than placebo) associated with ZYPREXA RELPREVV treatment: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact the Safety Call Center at 1-866-770-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 or predict the rates observed in practice. The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for ZYPREXA RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral olanzapine studies was reported using the COSTART and MedDRA dictionaries. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA RELPREVV. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied. Adverse Reactions Associated with Discontinuation of Treatment in a Short-Term, Placebo-Controlled Trial Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial. Commonly Observed Adverse Reactions in a Short-Term, Placebo-Controlled Trial In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting. Adverse Reactions Occurring at an Incidence of 2% or More among ZYPREXA RELPREVV-Treated Patients in a Short-Term, Placebo-Controlled Trial Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial. Table 9: Treatment-Emergent Adver …

7 DRUG INTERACTIONS CNS Acting Drugs: Caution should be used when used in combination with other centrally acting drugs and alcohol. ( 7.2 ) Antihypertensive Agents: Enhanced antihypertensive effect. ( 7.2 ) Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists. ( 7.2 ) Diazepam: May potentiate orthostatic hypotension. ( 7.1 , 7.2 ) Alcohol: May potentiate orthostatic hypotension. ( 7.1 ) Carbamazepine: Increased clearance of olanzapine. ( 7.1 ) Fluvoxamine: May increase olanzapine levels. ( 7.1 ) 7.1 Potential for Other Drugs to Affect Olanzapine Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7.2 )] . Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7.2 )] . Inhibitors of CYP1A2 — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine. Inhibitors of CYP2D6 — Fluoxetine caused a small decrease in olanzapine clearance leading to a minimal change in olanzapine steady-state concentrations and, therefore dose modification is not routinely recommended. Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions ( 7.2 )] . Inducers of CYP1A2 or Glucuronyl Transferase Enzymes — Omeprazole and rifampin may cause an increase in olanzapine clearance. Anticholinergic Drugs — Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. ZYPREXA RELPREVV should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions ( 5.16 )] . 7.2 Potential for Olanzapine to Affect Other Drugs CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol. Antihypertensive Agents — Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents. Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine agonists. Lorazepam (IM) — Co-administration of lorazepam does not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of lorazepam with olanzapine potentiated the somnolence observed with either drug alone. Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium. Valproate — Olanzapine (10 mg daily for 2 weeks) did not affect the steady-state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate. Effect of Olanzapine on Drug Metabolizing Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Pediatric Use: Safety and effectiveness of ZYPREXA RELPREVV in children <18 years of age have not been established. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ZYPREXA RELPREVV, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including ZYPREXA RELPREVV, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) . Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ZYPREXA RELPREVV, during pregnancy (see Clinical Considerations) . Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m 2 body surface area; some fetal toxicities were observed at these doses (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ZYPREXA RELPREVV, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown. Published data from observational studies, birth registries, case reports and meta-analyses that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m 2 body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and incre …

12.1 Mechanism of Action The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism.

11 DESCRIPTION ZYPREXA RELPREVV is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)-,4,4′-methylenebis[3-hydroxy-2-naphthalenecarboxylate] (1:1), monohydrate. The formula is C 17 H 22 N 4 S•C 23 H 14 O 6 •H 2 O, which corresponds to a molecular weight of 718.8. The chemical structure is: ZYPREXA RELPREVV is a long-acting form of olanzapine and is intended for deep intramuscular gluteal injection only. ZYPREXA RELPREVV includes a single-dose vial of the drug product and a vial of the sterile diluent for ZYPREXA RELPREVV. The drug product is olanzapine pamoate monohydrate, present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine base per vial. The diluent for ZYPREXA RELPREVV is a clear, colorless to slightly yellow solution in a glass vial and is composed of carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection. The drug product is suspended in the diluent for ZYPREXA RELPREVV to a target concentration of 150 mg olanzapine per mL prior to intramuscular injection. Chemical Structure

10 OVERDOSAGE 10.1 Human Experience During premarketing clinical studies of ZYPREXA RELPREVV, adverse reactions that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see Boxed Warning and Dosage and Administration ( 2.1 )] . These reactions occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These reactions were correlated with an unintentional rapid increase in serum olanzapine concentrations to supra-therapeutic ranges in some cases. While a rapid and greater than expected increase in serum olanzapine concentration has been observed in some patients with these reactions, the exact mechanism by which the drug was unintentionally introduced into the blood stream is not known. Clinical signs and symptoms included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced level of consciousness ranging from mild sedation to coma. Time after injection to event ranged from soon after injection to greater than 3 hours after injection. The majority of patients were hospitalized and some required supportive care, including intubation, in several cases. All patients had largely recovered by 72 hours. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections) [see Warnings and Precautions ( 5.1 )] . In postmarketing reports of overdose with oral olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of oral olanzapine alone. In 1 case of death, the amount of acutely ingested oral olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine. 10.2 Management of Overdose Post-injection delirium/sedation syndrome may occur with each injection of ZYPREXA RELPREVV. Signs and symptoms consistent with olanzapine overdose have been observed, and access to emergency response services must be readily available for safe use [see Boxed Warning and Warnings and Precautions ( 5.1 )] . There is no specific antidote to olanzapine. Therefore, appropriate supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.) Respiratory support, including ventilation, may be required. Close medical supervision and monitoring should continue until the patient recovers. The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced e …

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZYPREXA RELPREVV convenience kit is supplied in single dose cartons. Each carton includes one vial of olanzapine pamoate monohydrate in dosage strengths that are equivalent to 210 mg olanzapine (483 mg olanzapine pamoate monohydrate), 300 mg olanzapine (690 mg olanzapine pamoate monohydrate), and 405 mg olanzapine (931 mg olanzapine pamoate monohydrate) per vial; one vial of approximately 3 mL of diluent for ZYPREXA RELPREVV used to suspend the drug product; one 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device; and two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device. Needle-Pro ® is a registered trademark of Smiths Medical. NDC 61269-660-20 — single-dose convenience kit: 210 mg vial (VL7635) with rust flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap NDC 61269-661-20 — single-dose convenience kit: 300 mg vial (VL7636) with olive flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap NDC 61269-662-20 — single-dose convenience kit: 405 mg vial (VL7637) with steel blue flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap 16.2 Storage and Handling ZYPREXA RELPREVV should be stored at room temperature not to exceed 30°C (86°F). When the drug product is suspended in the solution for ZYPREXA RELPREVV, it may be held at room temperature for 24 hours. The vial should be agitated immediately prior to product withdrawal. Once the suspension is withdrawn into the syringe, it should be used immediately [see Dosage and Administration ( 2.2 )] .

16.1 How Supplied ZYPREXA RELPREVV convenience kit is supplied in single dose cartons. Each carton includes one vial of olanzapine pamoate monohydrate in dosage strengths that are equivalent to 210 mg olanzapine (483 mg olanzapine pamoate monohydrate), 300 mg olanzapine (690 mg olanzapine pamoate monohydrate), and 405 mg olanzapine (931 mg olanzapine pamoate monohydrate) per vial; one vial of approximately 3 mL of diluent for ZYPREXA RELPREVV used to suspend the drug product; one 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device; and two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device. Needle-Pro ® is a registered trademark of Smiths Medical. NDC 61269-660-20 — single-dose convenience kit: 210 mg vial (VL7635) with rust flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap NDC 61269-661-20 — single-dose convenience kit: 300 mg vial (VL7636) with olive flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap NDC 61269-662-20 — single-dose convenience kit: 405 mg vial (VL7637) with steel blue flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap