These Highlights Do Not Include All The Information Needed To Use Zyprexa Relprevv Safely And Effectively. See Full Prescribing Information For Zyprexa Relprevv.

Post-Injection Delirium/Sedation Syndrome — Adverse events with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, have been reported following injections of ZYPREXA RELPREVV. ZYPREXA RELPREVV must be administered in a registered healthcare facility with ready access to emergency response services. After each injection, patients must be observed at the healthcare facility by a healthcare professional for at least 3 hours. Because of this risk, ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2), Overdosage (10.2), and Patient Counseling Information (17)].

Medication Guide

ZYPREXA ^® RELPREVV™ (zy-PREX-a REL-prev)

(olanzapine)

For Extended Release Injectable Suspension

Read the Medication Guide that comes with ZYPREXA RELPREVV before you start taking it and each time before you get an injection. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor if there is something you do not understand or you want to learn more about ZYPREXA RELPREVV.

What is the most important information I should know about ZYPREXA RELPREVV?

Before you receive ZYPREXA RELPREVV treatment you must:

• understand the risks and benefits of ZYPREXA RELPREVV treatment. Your doctor will talk to you about the risks and benefits of ZYPREXA RELPREVV treatment.
• register in the ZYPREXA RELPREVV Patient Care Program. You must agree to the rules of the ZYPREXA RELPREVV Patient Care Program before you register.

ZYPREXA RELPREVV may cause serious side effects, including:

• Post-injection Delirium Sedation Syndrome (PDSS).
• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).
• High blood sugar (hyperglycemia).
• High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17.
• Weight gain, especially in teenagers age 13 to 17.

These serious side effects are described below.

• Post-injection Delirium Sedation Syndrome (PDSS).PDSS is a serious problem that can happen after you get a ZYPREXA RELPREVV injection if the medicine gets in your blood too fast. This problem usually happens within 3 hours after you receive ZYPREXA RELPREVV. If the medicine gets in your blood too fast, you may have some of the following symptoms:
  • feel more sleepy than usual
  • feel dizzy
  • feel confused or disoriented
  • trouble talking or walking
  • muscles feel stiff or shaking
  • feel weak
  • feel grouchy or angry
  • feel nervous or anxious
  • higher blood pressure
  • seizures (convulsions)
  • pass out (become unconscious or coma)

  You will need to stay at the clinic where you receive the injection for at least 3 hours so your doctor can make sure you do not have symptoms of PDSS. When you leave the clinic someone must be with you. If you have symptoms of PDSS after you leave the clinic, get medical help or go to an emergency room right away.

• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). ZYPREXA RELPREVV is not approved for treating psychosis in elderly people with dementia.
• High blood sugar (hyperglycemia).High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:
  • a build up of acid in your blood due to ketones (ketoacidosis)
  • coma
  • death

  Your doctor should do tests to check your blood sugar before you start taking ZYPREXA RELPREVV and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when ZYPREXA RELPREVV is stopped. People with diabetes and some people who did not have diabetes before taking ZYPREXA RELPREVV need to take medicine for high blood sugar even after they stop taking ZYPREXA RELPREVV.

  If you have diabetes, follow your doctor's instructions about how often to check your blood sugar while taking ZYPREXA RELPREVV.

  Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking ZYPREXA RELPREVV:

  • feel very thirsty
  • need to urinate more than usual
  • feel very hungry
  • feel weak or tired
  • feel sick to your stomach
  • feel confused or your breath smells fruity
• High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with ZYPREXA RELPREVV, especially in teenagers (13 to 17 years old). ZYPREXA RELPREVV is not approved in patients less than 18 years old. You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking ZYPREXA RELPREVV and during treatment.
• Weight gain. Weight gain is very common in people who take ZYPREXA RELPREVV. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. ZYPREXA RELPREVV is not approved in patients less than 18 years old. Some people may gain a lot of weight while taking ZYPREXA RELPREVV, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

What is ZYPREXA RELPREVV?

ZYPREXA RELPREVV is a long-acting prescription medicine given by injection and used to treat schizophrenia in adults. The symptoms of schizophrenia include:

• hearing voices
• seeing things that are not there
• having beliefs that are not true
• being suspicious or withdrawn

Some of your symptoms of schizophrenia may improve with treatment with ZYPREXA RELPREVV. If you do not think you are getting better, call your doctor.

It is not known if ZYPREXA RELPREVV is safe and effective in children under 18 years of age.

What should I tell my doctor before taking ZYPREXA RELPREVV?

ZYPREXA RELPREVV may not be right for you. Before starting ZYPREXA RELPREVV, tell your doctor if you have or had:

• heart problems
• seizures
• diabetes or high blood sugar levels (hyperglycemia)
• high cholesterol or triglyceride levels in your blood
• liver problems
• low or high blood pressure
• strokes or "mini-strokes" also called transient ischemic attacks (TIAs)
• Alzheimer's disease
• narrow-angle glaucoma
• enlarged prostate in men
• bowel obstruction
• breast cancer
• thoughts of suicide or hurting yourself
• any other medical condition
• are pregnant or plan to become pregnant. It is not known if ZYPREXA RELPREVV will harm your unborn baby.
  • If you become pregnant while receiving ZYPREXA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
• are breast-feeding or plan to breast-feed. ZYPREXA RELPREVV passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take ZYPREXA RELPREVV.

Tell your doctor if you exercise a lot or are in hot places often.

The symptoms of schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away.

Tell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. ZYPREXA RELPREVV and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take ZYPREXA RELPREVV with your other medicines. Do not start or stop any medicine while taking ZYPREXA RELPREVV without talking to your doctor first.

How should I receive ZYPREXA RELPREVV?

• ZYPREXA RELPREVV will be injected into the muscle in your buttock (gluteus) by your doctor or nurse at the clinic.
• After receiving ZYPREXA RELPREVV, you will need to stay at the clinic for at least 3 hours.
• When you leave the clinic, someone must be with you.
• Call your doctor if you do not think you are getting better or have any concerns about your condition while taking ZYPREXA RELPREVV.

What should I avoid while receiving ZYPREXA RELPREVV?

• ZYPREXA RELPREVV can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how ZYPREXA RELPREVV affects you. You should not drive or operate heavy machinery for the rest of the day after each injection.
• Avoid drinking alcohol while taking ZYPREXA RELPREVV. Drinking alcohol while you take ZYPREXA RELPREVV may make you sleepier than if you take ZYPREXA RELPREVV alone.

What are the possible side effects of ZYPREXA RELPREVV?

Serious side effects may happen when you take ZYPREXA RELPREVV, including:

• See "What is the most important information I should know about ZYPREXA RELPREVV?", which describes the risk of post-injection delirium sedation syndrome (PDSS), increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.
• Increased incidence of stroke or "mini-strokes" called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). ZYPREXA RELPREVV is not approved for these patients.
• Neuroleptic Malignant Syndrome (NMS):NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including ZYPREXA RELPREVV. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:
  • high fever
  • excessive sweating
  • rigid muscles
  • confusion
  • changes in your breathing, heartbeat, and blood pressure
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with ZYPREXA RELPREVV. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.
• Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking ZYPREXA RELPREVV. It may also start after you stop taking ZYPREXA RELPREVV. Tell your doctor if you get any body movements that you can not control.
• Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.
• Difficulty swallowing, that can cause food or liquid to get into your lungs.
• Seizures: Tell your doctor if you have a seizure during treatment with ZYPREXA RELPREVV.
• Problems with control of body temperature:You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:
  • sweating too much or not at all
  • dry mouth
  • feeling very hot
  • feeling thirsty
  • not able to produce urine

Common side effects of ZYPREXA RELPREVV include: headache, sleepiness or drowsiness, weight gain, dry mouth, diarrhea, nausea, common cold, eating more (increased appetite), vomiting, cough, back pain, or pain at the injection site.

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with ZYPREXA RELPREVV. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about ZYPREXA RELPREVV

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about ZYPREXA RELPREVV. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ZYPREXA RELPREVV that was written for healthcare professionals. For more information about ZYPREXA RELPREVV call 1-866-770-9010.

What are the ingredients in ZYPREXA RELPREVV?

Active ingredient: olanzapine

Inactive ingredients: carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Medication Guide revised October, 2023

Distributed by: H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by:

CHEPLAPHARM Registration GmbH

Weilerstr. 5e, 79540 Lörrach, Germany

CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH

None

PACKAGE LABEL - ZYPREXA Relprevv 210 mg

NDC 61269-660-20

ZYPREXA^® Relprevv^™

(olanzapine)

For Extended Release Injectable Suspension

210 mg/vial Single-Dose Vial Convenience Kit

Medication Guide is to be dispensed to patients.

VL7635/VL7622

Convenience kit includes:

Single-Dose vial of Zyprexa^® Relprevv^™ 210 mg/vial

One 3-mL vial of diluent

One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro^® needle with needle protection device

Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device

Hypodermic Needle-Pro is a registered trademark of Smiths Medical.

Reconstitute each vial with 1.3 mL of enclosed diluent. The resultant solution will contain 150 mg/mL.

Rx only

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.

Dosing Frequency: Once every two weeks

CHEPLAPHARM

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.

ZYPREXA RELPREVV doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials.

ZYPREXA RELPREVV may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy.

During premarketing testing of ZYPREXA RELPREVV, seizures occurred in 0.15% of patients. During premarketing testing of oral olanzapine, seizures occurred in 0.9% of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

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

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.

Infants exposed to ZYPREXA RELPREVV should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

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 C₁₇H₂₂N₄S•C₂₃H₁₄O₆•H₂O, 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.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral MRHD based on mg/m² body surface area.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Because ZYPREXA RELPREVV is to be administered by healthcare professionals, the potential for misuse or abuse by patients is low.

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)].

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

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.

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)].

The short-term effectiveness of ZYPREXA RELPREVV was established in an 8-week, placebo-controlled trial in adult patients (n=404) who were experiencing psychotic symptoms and met DSM-IV or DSM-IV-TR criteria for schizophrenia. Patients were randomized to receive injections of ZYPREXA RELPREVV 210 mg every 2 weeks, ZYPREXA RELPREVV 405 mg every 4 weeks, ZYPREXA RELPREVV 300 mg every 2 weeks, or placebo every 2 weeks. Patients were discontinued from their previous antipsychotics and underwent a 2-7 day washout period. No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was change from baseline to endpoint in total Positive and Negative Syndrome Scale (PANSS) score (mean baseline total PANSS score 101). Total PANSS scores showed statistically significant improvement from baseline to endpoint with each dose of ZYPREXA RELPREVV (210 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks) as compared to placebo. The effectiveness of ZYPREXA RELPREVV in the treatment of schizophrenia is further supported by the established effectiveness of the oral formulation of olanzapine.

A longer-term trial enrolled patients with schizophrenia (n=1065) who had remained stable for 4 to 8 weeks on open-label treatment with oral olanzapine (mean baseline total PANSS score 56) and were then randomized to continue their current oral olanzapine dose (10, 15, or 20 mg/day); or to ZYPREXA RELPREVV 150 mg every 2 weeks (405 mg every 4 weeks, 300 mg every 2 weeks, or 45 mg every 4 weeks). No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was time to exacerbation of symptoms of schizophrenia defined in terms of increases in Brief Psychiatric Rating Scale (BPRS) positive symptoms or hospitalization. ZYPREXA RELPREVV doses of 150 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks were each statistically significantly superior to low dose ZYPREXA RELPREVV (45 mg every 4 weeks).

None.

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

• 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)

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.

Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C, 5HT₆ (K_i=4, 11, and 5 nM, respectively), dopamine D_1-4 (K_i=11-31 nM), histamine H₁ (K_i=7 nM), and adrenergic α₁ receptors (K_i=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃ (K_i=57 nM) and muscarinic M_1-5 (K_i=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA_A, BZD, and β-adrenergic receptors (K_i>10 μM).

The fundamental pharmacokinetic properties of olanzapine are similar for ZYPREXA RELPREVV and orally administered olanzapine. Refer to the section below describing the pharmacokinetics of orally administered olanzapine for details.

Slow dissolution of ZYPREXA RELPREVV, a practically insoluble salt, after a deep intramuscular gluteal injection of a dose of ZYPREXA RELPREVV results in prolonged systemic olanzapine plasma concentrations that are sustained over a period of weeks to months. An injection every 2 or 4 weeks provides olanzapine plasma concentrations that are similar to those achieved by daily doses of oral olanzapine. The steady-state plasma concentrations for ZYPREXA RELPREVV for doses of 150 mg to 405 mg every 2 or 4 weeks are within the range of steady-state olanzapine plasma concentration known to have been associated with oral doses of 5 mg to 20 mg olanzapine once daily. The change to a slow release, rate-controlled absorption process is the only fundamental pharmacokinetic difference between the administration of ZYPREXA RELPREVV and orally administered olanzapine. The effective half-life for olanzapine after intramuscular ZYPREXA RELPREVV administration is approximately 30 days as compared to a half-life after oral administration of approximately 30 hours. Exposure to olanzapine may persist for a period of months after a ZYPREXA RELPREVV injection. The long persistence of systemic concentrations of olanzapine may be an important consideration for the long-term clinical management of the patient. Typical systemic olanzapine plasma concentrations reach a peak within the first week after injection and are at trough level immediately prior to the next injection. The olanzapine plasma concentration fluctuation between the peak and trough is comparable to the peak and trough fluctuations associated with once daily oral dosing.

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.7) and Patient Counseling Information (17)].

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

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 facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

As with other drugs that antagonize dopamine D₂ receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the oral olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events¹ (2% [49/3240] of females), sexual function-related events² (2% [150/8136] of females and males), and breast-related events³ (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events¹ (1% [2/168] of females), sexual function-related events² (0.7% [3/454] of females and males), and breast-related events³ (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)].

¹ Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

² Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

³ Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed in some studies. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, statistically significant differences among dose groups were observed for prolactin levels, with a mean baseline-to-endpoint increase observed in the highest dose group (300 mg/2 weeks, n=115: 3.57 ng/mL) relative to mean decreases in the lower dose groups (150 mg/2 weeks, n=109: -5.61 ng/mL; 405 mg/4 weeks, n=259: -2.76 ng/mL). In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

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 (5HT₂) antagonism.

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)].

• 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)

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.

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)

ZYPREXA RELPREVV may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, probably reflecting its α_1-adrenergic antagonistic properties [see Patient Counseling Information (17)]. Syncope-related adverse reactions were reported in 0.1% of patients treated with ZYPREXA RELPREVV in clinical studies.

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. For patients in this population who have never taken oral olanzapine, tolerability should be established with oral olanzapine prior to initiating treatment with ZYPREXA RELPREVV [see Dosage and Administration (2.1)].

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)].

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)].

The following adverse reactions have been identified during post-approval use of ZYPREXA and ZYPREXA RELPREVV. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea, or vomiting), drug reaction with eosinophilia and systemic symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering¹, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, somnambulism, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

¹ Stuttering was only studied in oral and long acting injection (LAI) formulations.

• 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)

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.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ZYPREXA RELPREVV for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17)].

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 Patient Care Program 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 facility 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. Advise patients that ZYPREXA RELPREVV may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZYPREXA RELPREVV during pregnancy [see Use in Specific Populations (8.1)].

Lactation — Advise breastfeeding women using ZYPREXA RELPREVV to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility — Advise females of reproductive potential that ZYPREXA RELPREVV may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

Pediatric Use — Safety and effectiveness of ZYPREXA RELPREVV in patients under 18 years have not been established [see Use in Specific Populations (8.4)].

Distributed by: H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by: CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany

CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered and tolerability with oral olanzapine should be established prior to initiating treatment with ZYPREXA RELPREVV [see Dosage and Administration (2.1)]. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17)].

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m² body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m² body surface area) in studies of 3 months' duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m² body surface area) for 3 months or 16 mg/kg (8 times the daily oral MRHD based on mg/m² body surface area) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

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)].

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2]. In premarketing clinical trials with oral olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].

Infertility

Females

Based on the pharmacologic action of olanzapine (D₂ 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)].

Sedation was a commonly reported adverse reaction associated with ZYPREXA RELPREVV treatment, occurring at an incidence of 8% in ZYPREXA RELPREVV patients compared to 2% in placebo patients. Somnolence and sedation adverse reactions led to discontinuation in 0.6% of patients in the premarketing ZYPREXA RELPREVV database.

Since olanzapine 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 olanzapine therapy does not affect them adversely. However, due to the risk of post-injection delirium/sedation syndrome after each injection, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Patient Counseling Information (17)].

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)].

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.

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)].

In placebo-controlled oral olanzapine clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of oral olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral olanzapine compared to patients treated with placebo. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17)].

ZYPREXA RELPREVV is available only through a restricted distribution program [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 facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

ZYPREXA RELPREVV must be administered in a registered healthcare facility (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 facility 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. 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)]. If parenteral benzodiazepines are required for patient management during an event of post-injection delirium/sedation syndrome, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

For deep intramuscular gluteal injection only. Not to be injected intravenously or subcutaneously.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Step 1: Preparing Materials

Convenience kit includes:

• Single-dose vial of ZYPREXA RELPREVV powder
• 3-mL vial of diluent
• One 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro^® needle with needle protection device
• Two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device— For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used for administration.

ZYPREXA RELPREVV must be suspended using only the diluent supplied in the convenience kit.

It is recommended that gloves are used when reconstituting, as ZYPREXA RELPREVV may be irritating to the skin. Flush with water if contact is made with skin.

See additional insert entitled "Instructions to Reconstitute and Administer ZYPREXA RELPREVV" (included) for more information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.

Step 2: Determining Reconstitution Volume

Refer to the table below to determine the amount of diluent to be added to powder for reconstitution of each vial strength.

It is important to note that there is more diluent in the vial than is needed to reconstitute.

Step 3: Reconstituting ZYPREXA RELPREVV

Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needlestick injury.

Loosen the powder by lightly tapping the vial.

Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.

Withdraw the pre-determined diluent volume (Step 2) into the syringe.

Inject the diluent into the powder vial.

Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.

Remove the needle from the vial, holding the vial upright to prevent any loss of material.

Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).

Pad a hard surface to cushion impact (see Figure 1). Tap the vial firmly and repeatedly on the surface until no powder is visible.

Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if large clumps remain (see Figure 2).

Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque (see Figure 3).

If foam forms, let vial stand to allow foam to dissipate.

If the product is not used right away, it should be shaken vigorously to re-suspend. Reconstituted ZYPREXA RELPREVV remains stable at room temperature for up to 24 hours in the vial.

Step 4: Injecting ZYPREXA RELPREVV

Before administering the injection, confirm there will be someone to accompany the patient after the 3-hour observation period. If this cannot be confirmed, do not give the injection.

Refer to the table below to determine the final volume to inject. Suspension concentration is 150 mg/mL ZYPREXA RELPREVV.

Attach a new safety needle to the syringe.

Slowly withdraw the desired amount into the syringe.

Some excess product will remain in the vial.

Engage the needle safety device and remove the needle from syringe.

For administration, select the 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device. For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used. To help prevent clogging, a 19-gauge or larger needle must be used.

Attach the new safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.

For deep intramuscular gluteal injection only. Do not inject intravenously or subcutaneously.

Select and prepare a site for injection in the gluteal area.

After insertion of the needle into the muscle, aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new convenience kit. The injection should be performed with steady, continuous pressure.

Do not massage the injection site.

Engage the needle safety device.

Dispose of the vials, needles, and syringe appropriately after injection. The vial is for single-dose only.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue ZYPREXA RELPREVV if DRESS is suspected [see Patient Counseling Information (17)].

WARNING: POST-INJECTION DELIRIUM/SEDATION SYNDROME and INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

• Patients are at risk for severe sedation (including coma) and/or delirium after each injection and must be observed for at least 3 hours in a registered facility with ready access to emergency response services. Because of this risk, ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment. (2.1, 5.1, 5.2, 10.2, 17)
• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis. (5.3, 8.5, 17)

Post-Injection Delirium/Sedation Syndrome — Adverse events with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, have been reported following injections of ZYPREXA RELPREVV. ZYPREXA RELPREVV must be administered in a registered healthcare facility with ready access to emergency response services. After each injection, patients must be observed at the healthcare facility by a healthcare professional for at least 3 hours. Because of this risk, ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2), Overdosage (10.2), and Patient Counseling Information (17)].

Medication Guide

ZYPREXA ^® RELPREVV™ (zy-PREX-a REL-prev)

(olanzapine)

For Extended Release Injectable Suspension

Read the Medication Guide that comes with ZYPREXA RELPREVV before you start taking it and each time before you get an injection. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor if there is something you do not understand or you want to learn more about ZYPREXA RELPREVV.

What is the most important information I should know about ZYPREXA RELPREVV?

Before you receive ZYPREXA RELPREVV treatment you must:

• understand the risks and benefits of ZYPREXA RELPREVV treatment. Your doctor will talk to you about the risks and benefits of ZYPREXA RELPREVV treatment.
• register in the ZYPREXA RELPREVV Patient Care Program. You must agree to the rules of the ZYPREXA RELPREVV Patient Care Program before you register.

ZYPREXA RELPREVV may cause serious side effects, including:

• Post-injection Delirium Sedation Syndrome (PDSS).
• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).
• High blood sugar (hyperglycemia).
• High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17.
• Weight gain, especially in teenagers age 13 to 17.

These serious side effects are described below.

• Post-injection Delirium Sedation Syndrome (PDSS).PDSS is a serious problem that can happen after you get a ZYPREXA RELPREVV injection if the medicine gets in your blood too fast. This problem usually happens within 3 hours after you receive ZYPREXA RELPREVV. If the medicine gets in your blood too fast, you may have some of the following symptoms:
  • feel more sleepy than usual
  • feel dizzy
  • feel confused or disoriented
  • trouble talking or walking
  • muscles feel stiff or shaking
  • feel weak
  • feel grouchy or angry
  • feel nervous or anxious
  • higher blood pressure
  • seizures (convulsions)
  • pass out (become unconscious or coma)

  You will need to stay at the clinic where you receive the injection for at least 3 hours so your doctor can make sure you do not have symptoms of PDSS. When you leave the clinic someone must be with you. If you have symptoms of PDSS after you leave the clinic, get medical help or go to an emergency room right away.

• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). ZYPREXA RELPREVV is not approved for treating psychosis in elderly people with dementia.
• High blood sugar (hyperglycemia).High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:
  • a build up of acid in your blood due to ketones (ketoacidosis)
  • coma
  • death

  Your doctor should do tests to check your blood sugar before you start taking ZYPREXA RELPREVV and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when ZYPREXA RELPREVV is stopped. People with diabetes and some people who did not have diabetes before taking ZYPREXA RELPREVV need to take medicine for high blood sugar even after they stop taking ZYPREXA RELPREVV.

  If you have diabetes, follow your doctor's instructions about how often to check your blood sugar while taking ZYPREXA RELPREVV.

  Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking ZYPREXA RELPREVV:

  • feel very thirsty
  • need to urinate more than usual
  • feel very hungry
  • feel weak or tired
  • feel sick to your stomach
  • feel confused or your breath smells fruity
• High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with ZYPREXA RELPREVV, especially in teenagers (13 to 17 years old). ZYPREXA RELPREVV is not approved in patients less than 18 years old. You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking ZYPREXA RELPREVV and during treatment.
• Weight gain. Weight gain is very common in people who take ZYPREXA RELPREVV. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. ZYPREXA RELPREVV is not approved in patients less than 18 years old. Some people may gain a lot of weight while taking ZYPREXA RELPREVV, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

What is ZYPREXA RELPREVV?

ZYPREXA RELPREVV is a long-acting prescription medicine given by injection and used to treat schizophrenia in adults. The symptoms of schizophrenia include:

• hearing voices
• seeing things that are not there
• having beliefs that are not true
• being suspicious or withdrawn

Some of your symptoms of schizophrenia may improve with treatment with ZYPREXA RELPREVV. If you do not think you are getting better, call your doctor.

It is not known if ZYPREXA RELPREVV is safe and effective in children under 18 years of age.

What should I tell my doctor before taking ZYPREXA RELPREVV?

ZYPREXA RELPREVV may not be right for you. Before starting ZYPREXA RELPREVV, tell your doctor if you have or had:

• heart problems
• seizures
• diabetes or high blood sugar levels (hyperglycemia)
• high cholesterol or triglyceride levels in your blood
• liver problems
• low or high blood pressure
• strokes or "mini-strokes" also called transient ischemic attacks (TIAs)
• Alzheimer's disease
• narrow-angle glaucoma
• enlarged prostate in men
• bowel obstruction
• breast cancer
• thoughts of suicide or hurting yourself
• any other medical condition
• are pregnant or plan to become pregnant. It is not known if ZYPREXA RELPREVV will harm your unborn baby.
  • If you become pregnant while receiving ZYPREXA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
• are breast-feeding or plan to breast-feed. ZYPREXA RELPREVV passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take ZYPREXA RELPREVV.

Tell your doctor if you exercise a lot or are in hot places often.

The symptoms of schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away.

Tell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. ZYPREXA RELPREVV and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take ZYPREXA RELPREVV with your other medicines. Do not start or stop any medicine while taking ZYPREXA RELPREVV without talking to your doctor first.

How should I receive ZYPREXA RELPREVV?

• ZYPREXA RELPREVV will be injected into the muscle in your buttock (gluteus) by your doctor or nurse at the clinic.
• After receiving ZYPREXA RELPREVV, you will need to stay at the clinic for at least 3 hours.
• When you leave the clinic, someone must be with you.
• Call your doctor if you do not think you are getting better or have any concerns about your condition while taking ZYPREXA RELPREVV.

What should I avoid while receiving ZYPREXA RELPREVV?

• ZYPREXA RELPREVV can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how ZYPREXA RELPREVV affects you. You should not drive or operate heavy machinery for the rest of the day after each injection.
• Avoid drinking alcohol while taking ZYPREXA RELPREVV. Drinking alcohol while you take ZYPREXA RELPREVV may make you sleepier than if you take ZYPREXA RELPREVV alone.

What are the possible side effects of ZYPREXA RELPREVV?

Serious side effects may happen when you take ZYPREXA RELPREVV, including:

• See "What is the most important information I should know about ZYPREXA RELPREVV?", which describes the risk of post-injection delirium sedation syndrome (PDSS), increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.
• Increased incidence of stroke or "mini-strokes" called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). ZYPREXA RELPREVV is not approved for these patients.
• Neuroleptic Malignant Syndrome (NMS):NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including ZYPREXA RELPREVV. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:
  • high fever
  • excessive sweating
  • rigid muscles
  • confusion
  • changes in your breathing, heartbeat, and blood pressure
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with ZYPREXA RELPREVV. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.
• Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking ZYPREXA RELPREVV. It may also start after you stop taking ZYPREXA RELPREVV. Tell your doctor if you get any body movements that you can not control.
• Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.
• Difficulty swallowing, that can cause food or liquid to get into your lungs.
• Seizures: Tell your doctor if you have a seizure during treatment with ZYPREXA RELPREVV.
• Problems with control of body temperature:You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:
  • sweating too much or not at all
  • dry mouth
  • feeling very hot
  • feeling thirsty
  • not able to produce urine

Common side effects of ZYPREXA RELPREVV include: headache, sleepiness or drowsiness, weight gain, dry mouth, diarrhea, nausea, common cold, eating more (increased appetite), vomiting, cough, back pain, or pain at the injection site.

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with ZYPREXA RELPREVV. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about ZYPREXA RELPREVV

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about ZYPREXA RELPREVV. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ZYPREXA RELPREVV that was written for healthcare professionals. For more information about ZYPREXA RELPREVV call 1-866-770-9010.

What are the ingredients in ZYPREXA RELPREVV?

Active ingredient: olanzapine

Inactive ingredients: carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Medication Guide revised October, 2023

Distributed by: H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by:

CHEPLAPHARM Registration GmbH

Weilerstr. 5e, 79540 Lörrach, Germany

CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH

None

PACKAGE LABEL - ZYPREXA Relprevv 210 mg

NDC 61269-660-20

ZYPREXA^® Relprevv^™

(olanzapine)

For Extended Release Injectable Suspension

210 mg/vial Single-Dose Vial Convenience Kit

Medication Guide is to be dispensed to patients.

VL7635/VL7622

Convenience kit includes:

Single-Dose vial of Zyprexa^® Relprevv^™ 210 mg/vial

One 3-mL vial of diluent

One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro^® needle with needle protection device

Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device

Hypodermic Needle-Pro is a registered trademark of Smiths Medical.

Reconstitute each vial with 1.3 mL of enclosed diluent. The resultant solution will contain 150 mg/mL.

Rx only

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.

Dosing Frequency: Once every two weeks

CHEPLAPHARM

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.

ZYPREXA RELPREVV doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials.

ZYPREXA RELPREVV may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy.

During premarketing testing of ZYPREXA RELPREVV, seizures occurred in 0.15% of patients. During premarketing testing of oral olanzapine, seizures occurred in 0.9% of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

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

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.

Infants exposed to ZYPREXA RELPREVV should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

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 C₁₇H₂₂N₄S•C₂₃H₁₄O₆•H₂O, 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.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral MRHD based on mg/m² body surface area.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Because ZYPREXA RELPREVV is to be administered by healthcare professionals, the potential for misuse or abuse by patients is low.

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)].

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

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.

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)].

The short-term effectiveness of ZYPREXA RELPREVV was established in an 8-week, placebo-controlled trial in adult patients (n=404) who were experiencing psychotic symptoms and met DSM-IV or DSM-IV-TR criteria for schizophrenia. Patients were randomized to receive injections of ZYPREXA RELPREVV 210 mg every 2 weeks, ZYPREXA RELPREVV 405 mg every 4 weeks, ZYPREXA RELPREVV 300 mg every 2 weeks, or placebo every 2 weeks. Patients were discontinued from their previous antipsychotics and underwent a 2-7 day washout period. No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was change from baseline to endpoint in total Positive and Negative Syndrome Scale (PANSS) score (mean baseline total PANSS score 101). Total PANSS scores showed statistically significant improvement from baseline to endpoint with each dose of ZYPREXA RELPREVV (210 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks) as compared to placebo. The effectiveness of ZYPREXA RELPREVV in the treatment of schizophrenia is further supported by the established effectiveness of the oral formulation of olanzapine.

A longer-term trial enrolled patients with schizophrenia (n=1065) who had remained stable for 4 to 8 weeks on open-label treatment with oral olanzapine (mean baseline total PANSS score 56) and were then randomized to continue their current oral olanzapine dose (10, 15, or 20 mg/day); or to ZYPREXA RELPREVV 150 mg every 2 weeks (405 mg every 4 weeks, 300 mg every 2 weeks, or 45 mg every 4 weeks). No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was time to exacerbation of symptoms of schizophrenia defined in terms of increases in Brief Psychiatric Rating Scale (BPRS) positive symptoms or hospitalization. ZYPREXA RELPREVV doses of 150 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks were each statistically significantly superior to low dose ZYPREXA RELPREVV (45 mg every 4 weeks).

None.

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

• 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)

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.

Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C, 5HT₆ (K_i=4, 11, and 5 nM, respectively), dopamine D_1-4 (K_i=11-31 nM), histamine H₁ (K_i=7 nM), and adrenergic α₁ receptors (K_i=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃ (K_i=57 nM) and muscarinic M_1-5 (K_i=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA_A, BZD, and β-adrenergic receptors (K_i>10 μM).

The fundamental pharmacokinetic properties of olanzapine are similar for ZYPREXA RELPREVV and orally administered olanzapine. Refer to the section below describing the pharmacokinetics of orally administered olanzapine for details.

Slow dissolution of ZYPREXA RELPREVV, a practically insoluble salt, after a deep intramuscular gluteal injection of a dose of ZYPREXA RELPREVV results in prolonged systemic olanzapine plasma concentrations that are sustained over a period of weeks to months. An injection every 2 or 4 weeks provides olanzapine plasma concentrations that are similar to those achieved by daily doses of oral olanzapine. The steady-state plasma concentrations for ZYPREXA RELPREVV for doses of 150 mg to 405 mg every 2 or 4 weeks are within the range of steady-state olanzapine plasma concentration known to have been associated with oral doses of 5 mg to 20 mg olanzapine once daily. The change to a slow release, rate-controlled absorption process is the only fundamental pharmacokinetic difference between the administration of ZYPREXA RELPREVV and orally administered olanzapine. The effective half-life for olanzapine after intramuscular ZYPREXA RELPREVV administration is approximately 30 days as compared to a half-life after oral administration of approximately 30 hours. Exposure to olanzapine may persist for a period of months after a ZYPREXA RELPREVV injection. The long persistence of systemic concentrations of olanzapine may be an important consideration for the long-term clinical management of the patient. Typical systemic olanzapine plasma concentrations reach a peak within the first week after injection and are at trough level immediately prior to the next injection. The olanzapine plasma concentration fluctuation between the peak and trough is comparable to the peak and trough fluctuations associated with once daily oral dosing.

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.7) and Patient Counseling Information (17)].

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

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 facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

As with other drugs that antagonize dopamine D₂ receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the oral olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events¹ (2% [49/3240] of females), sexual function-related events² (2% [150/8136] of females and males), and breast-related events³ (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events¹ (1% [2/168] of females), sexual function-related events² (0.7% [3/454] of females and males), and breast-related events³ (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)].

¹ Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

² Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

³ Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed in some studies. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, statistically significant differences among dose groups were observed for prolactin levels, with a mean baseline-to-endpoint increase observed in the highest dose group (300 mg/2 weeks, n=115: 3.57 ng/mL) relative to mean decreases in the lower dose groups (150 mg/2 weeks, n=109: -5.61 ng/mL; 405 mg/4 weeks, n=259: -2.76 ng/mL). In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

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 (5HT₂) antagonism.

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)].

• 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)

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.

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)

ZYPREXA RELPREVV may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, probably reflecting its α_1-adrenergic antagonistic properties [see Patient Counseling Information (17)]. Syncope-related adverse reactions were reported in 0.1% of patients treated with ZYPREXA RELPREVV in clinical studies.

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. For patients in this population who have never taken oral olanzapine, tolerability should be established with oral olanzapine prior to initiating treatment with ZYPREXA RELPREVV [see Dosage and Administration (2.1)].

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)].

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)].

The following adverse reactions have been identified during post-approval use of ZYPREXA and ZYPREXA RELPREVV. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea, or vomiting), drug reaction with eosinophilia and systemic symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering¹, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, somnambulism, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

¹ Stuttering was only studied in oral and long acting injection (LAI) formulations.

• 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)

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.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ZYPREXA RELPREVV for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17)].

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 Patient Care Program 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 facility 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. Advise patients that ZYPREXA RELPREVV may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZYPREXA RELPREVV during pregnancy [see Use in Specific Populations (8.1)].

Lactation — Advise breastfeeding women using ZYPREXA RELPREVV to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility — Advise females of reproductive potential that ZYPREXA RELPREVV may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

Pediatric Use — Safety and effectiveness of ZYPREXA RELPREVV in patients under 18 years have not been established [see Use in Specific Populations (8.4)].

Distributed by: H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by: CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany

CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered and tolerability with oral olanzapine should be established prior to initiating treatment with ZYPREXA RELPREVV [see Dosage and Administration (2.1)]. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17)].

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m² body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m² body surface area) in studies of 3 months' duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m² body surface area) for 3 months or 16 mg/kg (8 times the daily oral MRHD based on mg/m² body surface area) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

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)].

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2]. In premarketing clinical trials with oral olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].

Infertility

Females

Based on the pharmacologic action of olanzapine (D₂ 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)].

Sedation was a commonly reported adverse reaction associated with ZYPREXA RELPREVV treatment, occurring at an incidence of 8% in ZYPREXA RELPREVV patients compared to 2% in placebo patients. Somnolence and sedation adverse reactions led to discontinuation in 0.6% of patients in the premarketing ZYPREXA RELPREVV database.

Since olanzapine 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 olanzapine therapy does not affect them adversely. However, due to the risk of post-injection delirium/sedation syndrome after each injection, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Patient Counseling Information (17)].

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)].

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.

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)].

In placebo-controlled oral olanzapine clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of oral olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral olanzapine compared to patients treated with placebo. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17)].

ZYPREXA RELPREVV is available only through a restricted distribution program [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 facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

ZYPREXA RELPREVV must be administered in a registered healthcare facility (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 facility 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. 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)]. If parenteral benzodiazepines are required for patient management during an event of post-injection delirium/sedation syndrome, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

For deep intramuscular gluteal injection only. Not to be injected intravenously or subcutaneously.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Step 1: Preparing Materials

Convenience kit includes:

• Single-dose vial of ZYPREXA RELPREVV powder
• 3-mL vial of diluent
• One 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro^® needle with needle protection device
• Two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device— For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used for administration.

ZYPREXA RELPREVV must be suspended using only the diluent supplied in the convenience kit.

It is recommended that gloves are used when reconstituting, as ZYPREXA RELPREVV may be irritating to the skin. Flush with water if contact is made with skin.

See additional insert entitled "Instructions to Reconstitute and Administer ZYPREXA RELPREVV" (included) for more information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.

Step 2: Determining Reconstitution Volume

Refer to the table below to determine the amount of diluent to be added to powder for reconstitution of each vial strength.

It is important to note that there is more diluent in the vial than is needed to reconstitute.

Step 3: Reconstituting ZYPREXA RELPREVV

Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needlestick injury.

Loosen the powder by lightly tapping the vial.

Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.

Withdraw the pre-determined diluent volume (Step 2) into the syringe.

Inject the diluent into the powder vial.

Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.

Remove the needle from the vial, holding the vial upright to prevent any loss of material.

Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).

Pad a hard surface to cushion impact (see Figure 1). Tap the vial firmly and repeatedly on the surface until no powder is visible.

Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if large clumps remain (see Figure 2).

Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque (see Figure 3).

If foam forms, let vial stand to allow foam to dissipate.

If the product is not used right away, it should be shaken vigorously to re-suspend. Reconstituted ZYPREXA RELPREVV remains stable at room temperature for up to 24 hours in the vial.

Step 4: Injecting ZYPREXA RELPREVV

Before administering the injection, confirm there will be someone to accompany the patient after the 3-hour observation period. If this cannot be confirmed, do not give the injection.

Refer to the table below to determine the final volume to inject. Suspension concentration is 150 mg/mL ZYPREXA RELPREVV.

Attach a new safety needle to the syringe.

Slowly withdraw the desired amount into the syringe.

Some excess product will remain in the vial.

Engage the needle safety device and remove the needle from syringe.

For administration, select the 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device. For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used. To help prevent clogging, a 19-gauge or larger needle must be used.

Attach the new safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.

For deep intramuscular gluteal injection only. Do not inject intravenously or subcutaneously.

Select and prepare a site for injection in the gluteal area.

After insertion of the needle into the muscle, aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new convenience kit. The injection should be performed with steady, continuous pressure.

Do not massage the injection site.

Engage the needle safety device.

Dispose of the vials, needles, and syringe appropriately after injection. The vial is for single-dose only.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue ZYPREXA RELPREVV if DRESS is suspected [see Patient Counseling Information (17)].

WARNING: POST-INJECTION DELIRIUM/SEDATION SYNDROME and INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

• Patients are at risk for severe sedation (including coma) and/or delirium after each injection and must be observed for at least 3 hours in a registered facility with ready access to emergency response services. Because of this risk, ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment. (2.1, 5.1, 5.2, 10.2, 17)
• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis. (5.3, 8.5, 17)