Zyprexa
Olanzapine pamoate · Tablet · Oral, Intramuscular
Uses
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 ® RELPREVV™ 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 )] .
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 within the first hour. The majority of cases have occurred within the first 3 hours after injection; however, the event has occurred after 3 hours. Following the 3-hour observation period, healthcare professionals must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation [see Overdosage ( 10 )] . Dosing in Specific Populations — Tolerance of oral ZYPREXA should be established prior to initiating treatment with ZYPREXA RELPREVV. The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be undertaken with caution in these patients [see Warnings and Precautions ( 5.18 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )] . ZYPREXA RELPREVV has not been studied in subjects under 18 years of age [see Warnings and Precautions ( 5.7 )] . Maintenance Treatment — Although no controlled studies have been conducted to determine how long patients should be treated with ZYPREXA RELPREVV, efficacy has been demonstrated over a period of 24 weeks in patients with stabilized schizophrenia.
Dosage forms and strengths
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 )
Contraindications
None. None.
Warnings and precautions
Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g. stroke, transient ischemic attack). ( 5.3 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy. ( 5.4 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. ( 5.5 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected. ( 5.6 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. ( 5.7 ) Hyperglycemia and Diabetes Mellitus: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. ( 5.7 ) Dyslipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. ( 5.7 ) Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. ( 5.7 ) Tardive Dyskinesia: Discontinue if clinically appropriate. ( 5.8 ) Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses. ( 5.9 ) Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including ZYPREXA. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA RELPREVV should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. ( 5.11 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. ( 5.13 ) Anticholinergic (antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. ( 5.16 , 7.1 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery. ( 5.14 ) Hyperprolactinemia: May elevate prolactin levels. ( 5.17 ) Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment. ( 5.18 ) 5.1 Post-Injection Delirium/Sedation Syndrome During premarketing clinical studies of ZYPREXA RELPREVV, 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 and Dosage and Administration ( 2.1 )] . These events occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These events 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 events, 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 Overdosage ( 10.1 )] . Healthcare professionals are advised to discuss this potential risk with patients each time they prescribe and administer ZYPREXA RELPREVV [see Patient Counseling Information ( 17 )] . 5.2 ZYPREXA RELPREVV REMS ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV REMS because of the risks of Post-Injection Delirium/Sedation Syndrome [see Boxed Warning , Indications and Usage ( 1 ), and Patient Counseling Information ( 17 )] . 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 RELPREVV must be administered in a certified healthcare setting (such as a hospital, clinic, residential treatment center, or community healthcare center) 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 and must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility.
Side effects
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 Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV a The term abdominal pain upper was combined under abdominal pain. b The term tooth abscess was combined under tooth infection. c The terms alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased were combined under hepatic enzyme increased. d The term tension headache was combined under headache. e The term somnolence was combined under sedation. f The term sinus congestion was combined under nasal congestion.
Drug interactions
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 by these enzymes. Imipramine — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine. Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions ( 7.1 )] . Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Drug Interactions ( 7.1 )] . Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions ( 7.1 )] . Biperiden — Multiple doses of olanzapine did not influence the kinetics of biperiden. Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.
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 increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m 2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m 2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m 2 body surface area). No evidence of teratogenicity or embryo-fetal toxicity was observed in rats or rabbits with olanzapine at intramuscular doses up to 75 mg/kg (1 and 2 times the MRHD of 300 mg every 2 weeks, respectively, based on mg/m 2 body surface area). 8.2 Lactation Risk Summary Olanzapine pamoate is present in human milk. There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine pamoate through breast milk (see Clinical Considerations) . There is no information on the effects of olanzapine pamoate on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZYPREXA RELPREVV and any potential adverse effects on the breastfed child from ZYPREXA RELPREVV or from the mother's underlying condition. Clinical Considerations Infants exposed to ZYPREXA RELPREVV should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of olanzapine (D 2 receptor antagonism), treatment with ZYPREXA RELPREVV may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.17 )] .
Pregnancy
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 increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m 2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m 2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m 2 body surface area). No evidence of teratogenicity or embryo-fetal toxicity was observed in rats or rabbits with olanzapine at intramuscular doses up to 75 mg/kg (1 and 2 times the MRHD of 300 mg every 2 weeks, respectively, based on mg/m 2 body surface area).
Pediatric use
8.4 Pediatric Use Safety and effectiveness of ZYPREXA RELPREVV in children and adolescent patients have not been established [see Warnings and Precautions ( 5.7 )] . Compared to patients from adult clinical trials, adolescents treated with oral ZYPREXA were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.
Geriatric use
8.5 Geriatric Use Clinical studies of ZYPREXA RELPREVV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In the premarketing clinical studies with oral olanzapine, there was no indication of any different tolerability of olanzapine in elderly patients compared to younger patients with schizophrenia. Oral olanzapine studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.3 ), and Patient Counseling Information ( 17 )] . Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see Boxed Warning , Dosage and Administration ( 2.1 ), and Warnings and Precautions ( 5.3 )] .
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 emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
Description
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
Mechanism of action
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.
How supplied
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
Storage
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 )] .
Patient information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA RELPREVV. Patients should be advised to call their doctor if they do not think they are getting better or have concerns about their condition. Post-Injection Delirium/Sedation Syndrome During premarketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose have been reported in patients following an injection of ZYPREXA RELPREVV. It is mandatory that patients be enrolled in the ZYPREXA RELPREVV REMS to receive ZYPREXA RELPREVV treatment. Patients should be advised of the risk of post-injection delirium/sedation syndrome each time they receive an injection [see Warnings and Precautions ( 5.1 , 5.2 )] . Patient and caregivers should be advised that after each ZYPREXA RELPREVV injection, patients must be observed at the healthcare setting for at least 3 hours and must be accompanied to their destination upon leaving the facility. The Medication Guide should be distributed each time patients receive an injection. Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with ZYPREXA had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo. ZYPREXA RELPREVV is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.3 )] . Neuroleptic Malignant Syndrome (NMS) Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including ZYPREXA. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions ( 5.5 )] . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Patients should be advised to report to their health care provider at the earliest onset of any signs or symptoms that may be associated with drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions ( 5.6 )] . Hyperglycemia and Diabetes Mellitus Patients should be advised of the potential risk of hyperglycemia-related adverse reactions related to ZYPREXA RELPREVV. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking ZYPREXA RELPREVV [see Warnings and Precautions ( 5.7 )] . Dyslipidemia Patients should be counseled that dyslipidemia has occurred during treatment with ZYPREXA RELPREVV. Patients should have their lipid profile monitored regularly [see Warnings and Precautions ( 5.7 )] . Weight Gain Patients should be counseled that weight gain has occurred during treatment with ZYPREXA RELPREVV. Patients should have their weight monitored regularly [see Warnings and Precautions ( 5.7 )] . Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension, and in association with the use of concomitant drugs that may potentiate the orthostatic effect of ZYPREXA RELPREVV, e.g., diazepam or alcohol [see Warnings and Precautions ( 5.9 ) and Drug Interactions ( 7 )] . Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting. Potential for Cognitive and Motor Impairment Because ZYPREXA RELPREVV has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ZYPREXA RELPREVV therapy does not affect them adversely. Additionally, due to the risk of post-injection delirium/sedation syndrome, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 , 5.14 )] . Body Temperature Regulation Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions ( 5.15 )] . Concomitant Medication Patients should be advised to inform their healthcare providers if they are taking, or plan to take, ZYPREXA or Symbyax ® (olanzapine/fluoxetine combination). Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions ( 7 )] . Alcohol Patients should be advised to avoid alcohol while taking ZYPREXA RELPREVV [see Drug Interactions ( 7.1 )] . Use in Specific Populations Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZYPREXA RELPREVV.
Label text from the FDA structured product label by H2-Pharma LLC (revised May 19, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Olanzapine in 11 products
Zyprexa NDC products (14)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 61269-630 | Olanzapine 2.5 mg/1 Tablet | H2-Pharma LLC | NDA |
| 61269-631 | Olanzapine 5 mg/1 Tablet | H2-Pharma LLC | NDA |
| 61269-632 | Olanzapine 7.5 mg/1 Tablet | H2-Pharma LLC | NDA |
| 61269-633 | Olanzapine 10 mg/1 Tablet | H2-Pharma LLC | NDA |
| 61269-634 | Olanzapine 15 mg/1 Tablet | H2-Pharma LLC | NDA |
| 61269-635 | Olanzapine 20 mg/1 Tablet | H2-Pharma LLC | NDA |
| 61269-640 | Olanzapine 10 mg/2mL Injection, Powder, For Solution | H2-Pharma LLC | NDA |
| 61269-650 | Olanzapine 5 mg/1 Tablet, Orally Disintegrating | H2-Pharma LLC | NDA |
| 61269-651 | Olanzapine 10 mg/1 Tablet, Orally Disintegrating | H2-Pharma LLC | NDA |
| 61269-652 | Olanzapine 15 mg/1 Tablet, Orally Disintegrating | H2-Pharma LLC | NDA |
| 61269-653 | Olanzapine 20 mg/1 Tablet, Orally Disintegrating | H2-Pharma LLC | NDA |
| 61269-660 | Kit | H2-Pharma LLC | NDA |
| 61269-661 | Kit | H2-Pharma LLC | NDA |
| 61269-662 | Kit | H2-Pharma LLC | NDA |
Frequently asked questions
What is Zyprexa used for?
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 ®…
What are the side effects of Zyprexa?
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… See the full label for the complete list.
Who makes Zyprexa?
Zyprexa is listed by 1 labeler in the FDA NDC directory, including H2-Pharma LLC.