Zyprexa Relprevv

Description

ZYPREXA RELPREVV is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)-,4,4´-methylenebis[3-hydroxy-2naphthalenecarboxylate] (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 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.

Indications

ZYPREXA RELPREVV is available only through a restricted distribution program [see WARNINGS AND PRECAUTIONS]. 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.

Schizophrenia

ZYPREXA RELPREVV is indicated for the treatment of schizophrenia. Efficacy was established in two clinical trials in patients with schizophrenia: one8-week trial in adults and one maintenance trial in adults [see Clinical Studies].

Dosage And Administration

Dosage

ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only and should not be administered intravenously or subcutaneously.

Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA Intra Muscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. Refer to the package insert for ZYPREXA Intra Muscular 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 isdrawn into the syringe. If any blood is aspirated into the syringe, it should be discarded and fresh drug should be prepared using a new convenience kit. The injection should be performed at a steady, continuous pressure. Do not massage the injection site.

Dose Selection

The efficacy of ZYPREXA RELPREVV has been demonstrated within the range of 150 mg to 300 mg administered every 2 weeks and with 405 mg administered every 4 weeks. Dose recommendations considering oral ZYPREXA and ZYPREXA RELPREVV are shown in Table 1.

Table 1: Recommended Dosing for ZYPREXA RELPREVV Based on Correspondence to Oral ZYPREXA Doses

Target Oral ZYPREXA Dose	Dosing of ZYPREXA RELPREW During the First 8 Weeks	Maintenance Dose After 8 Weeks of ZYPREXA RELPREW Treatment
10 mg/day	210 mg/2 weeks or	150 mg/2 weeks or
	405 mg/4 weeks	300 mg/4 weeks
15 mg/day	300 mg/2 weeks	210 mg/2 weeks or 405 mg/4 weeks
20 mg/day	300 mg/2 weeks	300 mg/2 weeks

 

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

Post-Injection Delirium/Sedation Syndrome

During premarketing clinical studies, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXARELPREVV [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and OVERDOSAGE]. Patients should be informed of this risk and how torecognize related symptoms [see Patient Counseling Information]. ZYPREXA RELPREVV must be administered in a registered healthcare facility 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 for symptoms consistent with olanzapine overdose, including sedation (ranging from mild in severity to coma) and/or delirium (including confusion, disorientation, agitation, anxiety, and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension, and convulsion. The potential for onset of an event is greatest within the first hour. The majority of cases have occurred within the first 3 hours after injection; however, the event has occurred after 3 hours. Following the 3-hour observation period, healthcare professionals must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation [see OVERDOSAGE].

Dosing In Specific Populations

Tolerance of oral ZYPREXA should be established prior to initiating treatment with ZYPREXA RELPREVV. The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be undertaken with caution in these patients [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

ZYPREXA RELPREVV has not been studied in subjects under 18 years of age [see WARNINGS AND PRECAUTIONS].

Maintenance Treatment

Although no controlled studies have been conducted to determine how long patients should be treated with ZYPREXARELPREVV, efficacy has been demonstrated over a period of 24 weeks in patients with stabilized schizophrenia. Additionally, oral ZYPREXA has beenshown to be effective in maintenance of treatment response in schizophrenia in longer-term use. Patients should be periodically reassessed to determinethe need for continued treatment.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address how to switch patients with schizophrenia from other antipsychotics to ZYPREXA RELPREVV.

Instructions To Reconstitute And Administer ZYPREXA RELPREVV

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.

 

Dose	Vial Strength	Diluent to Add
150 mg	210 mg	1.3 mL
210 mg	210 mg	1.3 mL
300 mg	300 mg	1.8 mL
405 mg	405 mg	2.3 mL

 

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.

Figure 1 : Tap firmly to mix.

 

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).

Figure 2: Check for unsuspended powder and repeat tapping if needed.

 

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).

Figure 3: Vigorously shake vial.

 

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.

 

Dose	Final Volume to Inject
150 mg	1 mL
210 mg	1.4 mL
300 mg	2 mL
405 mg	2.7 mL

 

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.

How Supplied

Dosage Forms And Strengths

ZYPREXA RELPREVV is a powder for suspension for intramuscular use only. ZYPREXA RELPREVV is present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine single-dose per vial. The diluent is a clear, colorless to slightly yellow solution in a glass vial [see DESCRIPTION and HOW SUPPLIED/Storage And Handling]. The reconstituted suspension will be yellow and opaque [see DOSAGE AND ADMINISTRATION].

Storage And Handling

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 ZYPREXARELPREVV 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.

NDC 0002-7635-11 – single-dose convenience kit: 210 mg vial (VL7635) with rust flip-off cap and 3-mL vial of sterile diluent (VL7622) with grayflip-off cap

NDC 0002-7636-11 – single-dose convenience kit: 300 mg vial (VL7636) with olive flip-off cap and 3-mL vial of sterile diluent (VL7622) with grayflip-off cap

NDC 0002-7637-11 – single-dose convenience kit: 405 mg vial (VL7637) with steel blue flip-off cap and 3-mL vial of sterile diluent (VL7622) withgray flip-off cap

Storage And Handling

ZYPREXA RELPREVV should be stored at room temperature not to exceed 30°C (86°F).

When the drug product is suspended in the solution for ZYPREXA RELPREVV, it may be held at room temperature for 24 hours. The vial should be agitated immediately prior to product withdrawal. Once the suspension is withdrawn into the syringe, it should be used immediately [see DOSAGE AND ADMINISTRATION].

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Nov /2021

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparatorstudies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine arealso presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and theresults 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 us ualmedical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Adverse Reactions Associated With Discontinuation Of Treatment In A Short-Term, Placebo-Controlled Trial

Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.

Commonly Observed Adverse Reactions In A Short-Term, Placebo-Controlled Trial

In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

Adverse Reactions Occurring At An Incidence Of 2% Or More Among ZYPREXA RELPREVV-Treated Patients in a Short-Term, Placebo-Controlled Trial

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.

Table 9: Treatment-Emergent Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV

Body System/Adverse Reaction	Percentage of Patients Reporting Adverse Event
	Placebo (N=98)	ZYPREXA RELPREW 405 mg/4 wks (N=100)	ZYPREXA RELPREW 210 mg/2 wks (N=106)	ZYPREXA RELPREW 300 mg/2 wks (N=100)
Ear and Labyrinth Disorders
Ear pain	2	1	1	4
Gastrointestinal Disorders
Abdominal paina	2	3	3	3
Diarrhea	4	2	7	5
Dry mouth	1	2	6	4
Flatulence	0	2	2	1
Nausea	2	5	5	4
Toothache	0	3	4	3
Vomiting	2	6	1	2
General Disorders and Administration Site Conditions
Fatigue	2	4	2	3
Injection site pain	0	2	3	2
Pain	0	0	2	3
Pyrexia	0	2	0	0
Infections and Infestations
Nasopharyngitis	2	3	6	1
Tooth infectionb	0	4	0	0
Upper respiratory tract infection	2	3	1	4
Viral infection	0	0	0	2
Injury, Poisoning and Procedural Complications
Procedural pain	0	2	0	0
Investigations
Electrocardiogram QT-corrected interval prolonged	1	0	0	2
Hepatic enzyme increasedc	1	4	1	3
Weight increased	5	5	6	7
Metabolism and Nutrition Disorders
Increased appetite	0	1	4	6
Musculoskeletal and Connective Tissue Disorders
Arthralgia	0	3	3	3
Back pain	4	4	3	5
Muscle spasms	0	3	1	2
Musculoskeletal stiffness	1	1	4	4
Nervous System Disorders
Dizziness	2	4	4	1
Dysarthria	0	0	1	2
Headached	8	13	15	18
Sedatione	7	13	8	13
Tremor	1	3	0	1
Psychiatric Disorders
Abnormal dreams	0	0	0	2
Hallucination, auditory	2	3	1	0
Restlessness	2	2	3	1
Sleep disorder	1	0	0	2
Thinking abnormal	1	3	0	0
Reproductive System and Breast Disorders
Vaginal discharge	0	0	4	4
Respiratory, Thoracic and Mediastinal Disorders
Cough	5	3	5	9
Nasal congestionf	3	2	1	7
Pharyngolaryngeal pain	2	2	3	3
Sneezing	0	0	0	2
Skin and Subcutaneous Tissue Disorders
Acne	0	2	0	2
Vascular Disorders
Hypertension	0	3	2	0
aThe term abdominal pain upper was combined under abdominal pain. bThe term tooth abscess was combined under tooth infection. cThe terms alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased were combined under hepatic enzymeincreased. dThe term tension headache was combined under headache. eThe term somnolence was combined under sedation. fThe term sinus congestion was combined under nasal congestion.

 

Dose Dependency Of Adverse Reactions

Dose group differences have been observed for weight, fasting triglycerides and prolactin elevation for ZYPREXA RELPREVV [see WARNINGS AND PRECAUTIONS].

A dose group difference for oral olanzapine has been observed for fatigue, dizziness, weight gain and prolactin elevation. 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 fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see WARNINGS AND PRECAUTIONS].

Extrapyramidal Symptoms

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 10: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia – Acute Phase

	Percentage of Patients Reporting Event
	Placebo	Olanzapine 5 ± 2.5 mg/day	Olanzapine 10 ± 2.5 mg/day	Olanzapine 15 ± 2.5 mg/day
Parkinsonisma	15	14	12	14
Akathisiab	23	16	19	27
aPercentage of patients with a Simpson-Angus Scale total score >3. bPercentage of patients with a Barnes Akathisia Scale global score ≥2.

 

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 11: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia – Acute Phase

	Percentage of Patients Reporting Event
	Placebo (N=68)	Olanzapine 5 ± 2.5 mg/day (N=65)	Olanzapine 10 ± 2.5 mg/day (N=64)	Olanzapine 15 ± 2.5 mg/day (N=69)
Dystonic eventsa	1	3	2	3
Parkinsonism eventsb	10	8	14	20
Akathisia eventsc	1	5	11	10
Dyskinetic eventsd	4	0	2	1
Residual eventse	1	2	5	1
Any extrapyramidal event	16	15	25	32
aPatients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. bPatients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, maskedfacies, tremor. cPatients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. dPatients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. ePatients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

 

Dystonia, Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with highpotency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Other Adverse Reactions

Local Injection Site Reactions

Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients experienced treatment-emergent injection-related adverse reactions (injection site pain, buttock pain, injection site mass, induration, injection site induration) in the placebo-controlled database. The most frequently occurring treatment-emergent adverse reaction was injection site pain (2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated).

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of Olanzapine For Extended-Release Injectable Suspension

Injection site abscess has been reported in clinical trials with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

Commonly Observed Adverse Reactions During The Clinical Trial Evaluation Of Oral Olanzapine

In clinical trials of oral olanzapine monotherapy for the treatment of schizophrenia in adult patients, treatment-emergent adverse reactions with anincidence of 5% or greater in the olanzapine treatment arm and at least twice that of placebo were: postural hypotension, constipation, weight gain,dizziness, personality disorder, and akathisia.

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinicaltrials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause wasremote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurredat a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole – Infrequent: chills, face edema, photosensitivity reaction, suicide attempt¹; Rare: chills and fever, hangover effect, sudden death¹.

Cardiovascular System – Infrequent: cerebrovascular accident, vasodilatation.

Digestive System – Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System – Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders – Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System – Rare: osteoporosis.

Nervous System – Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System – Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages – Infrequent: alopecia.

Special Senses – Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System – Infrequent: amenorrhea², breast pain, decreased menstruation, impotence², increased menstruation², menorrhagia², metrorrhagia², polyuria², urinary frequency, urinary retention, urinary urgency, urination impaired.

¹These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.
²Adjusted for gender.

Vital Signs And Laboratory Studies

Laboratory Changes

ZYPREXA RELPREVV In Adults

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from placebo, were observed for the following: eosinophils, monocytes, cholesterol, low-density lipoprotein (LDL), triglycerides, and directbilirubin. There were no statistically significant differences between ZYPREXA RELPREVV and placebo in the incidence of potentially clinically significant changes in any of the laboratory values studied.

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from oral olanzapine (in a 24-week double-blind study), were observed for the following: gamma-glutamyltransferase (GGT) and sodium.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGTlevels were recorded in ≥1% (88/5245) of patients.

Statistically significant differences were observed between ZYPREXA RELPREVV and oral olanzapine for the incidence of treatment-emergent low platelet count (0% ZYPREXA RELPREVV vs 1% oral olanzapine); and low total bilirubin (2.8% ZYPREXA RELPREVV vs 0.7% for oral olanzapine).There was a statistically significant difference between ZYPREXA RELPREVV and oral olanzapine in potentially clinically significant changes for high leukocyte count (0% ZYPREXA RELPREVV vs 1% oral olanzapine).

Changes in aminotransferases observed with ZYPREXA RELPREVV treatment were similar to those reported with ZYPREXA treatment. In placebo-controlled ZYPREXA RELPREVV studies, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2.7%(8/291) of patients exposed to olanzapine compared to 3.2% (3/94) of the placebo patients. None of these patients experienced jaundice. In 3 of these patients, liver enzymes reverted to the normal range despite continued treatment, and in 5 cases enzymes values decreased, but were still above thenormal range at the end of therapy.

Within the larger premarketing ZYPREXA RELPREVV database of 1886 patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to>200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changesthat tended to normalize while ZYPREXA RELPREVV treatment was continued.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy In Adults

An assessment of the premarketing experience for oral olanzapine revealed an association with asymptomaticincreases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence ofALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

In placebo-controlled oral olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patientsexposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) ofplacebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy’s Rule.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Oral olanzapine administration was also associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

ECG Changes

Comparison of ZYPREXA RELPREVV and oral olanzapine, in a 24 week study, revealed no significant differences on ECG changes. Between-group comparisons for pooled placebo-controlled trials revealed no significant oral olanzapine/placebo differences in the proportions of patientsexperiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Oral olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related toolanzapine’s potential for inducing orthostatic changes [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

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 drugexposure.

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, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). 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 ZYPREXARELPREVV therapy. Isolated cases required surgical intervention.

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

Potential For Other Drugs To Affect Olanzapine

Diazepam

The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see DRUG INTERACTIONS].

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].

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].

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 havinganticholinergic (antimuscarinic) effects [see WARNINGS AND PRECAUTIONS].

Potential For Olanzapine To Affect Other Drugs

CNS Acting Drugs

Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents

Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa And Dopamine Agonists

Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (IM)

Co-administration of lorazepam does not significantly affect the pharmacokinetics of olanzapine, un conjugated 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 toinhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated byt hese 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].

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].

Alcohol

Multiple doses of olanzapine did not influence the kinetics of ethanol [see DRUG INTERACTIONS].

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.

Drug Abuse And Dependence

Dependence

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or nopotential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administeredoral doses up to 8 times the daily oral MRHD based on mg/m body surface area.

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

Included as part of the PRECAUTIONS section.

Precautions

Post-Injection Delirium/Sedation Syndrome

During premarketing clinical studies of ZYPREXA RELPREVV, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see BOXED WARNING and DOSAGE AND ADMINISTRATION]. 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].

Healthcare professionals are advised to discuss this potential risk with patients each time they prescribe and administer ZYPREXA RELPREVV [see Patient Counseling Information].

Prescribing And Distribution Program For ZYPREXA RELPREVV

ZYPREXA RELPREVV is available only through a restricted distribution program [see BOXED WARNING, INDICATIONS AND USAGE, and Patient Counseling Information]. 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 syndromeis suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation [see OVERDOSAGE]. 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.

Elderly Patients With Dementia-Related Psychosis

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, and Patient Counseling Information].

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].

Suicide

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

Neuroleptic Malignant Syndrome (NMS)

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 andevidence 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 clinicalpresentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signsand 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 treatmentsare 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]. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information].

Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)

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].

Metabolic Changes

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

Hyperglycemia And Diabetes Mellitus

Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic wasdiscontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus inthe general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases inglucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy In Adults

In an analysis of 5 placebo-controlled adult olanzapine mono therapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline(patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucoselevel ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).

Olanzapine-treated patients had a greater mean HbA increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levelsfrom adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Ann	Up to 12 weeks exposure		At least 48 weeks exposure
			N	Patients	N	Patients
FastingGlucose	Normal to High	Olanzapine	543	2.2%	345	12.8%
	(<100 mg/dL to ≥126 mg/dL)	Placebo	293	3.4%	NAa	NAa
	Borderline to High	Olanzapine	178	17.4%	127	26.0%
	(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	Placebo	96	11.5%	NAa	NAa
aNot Applicable.

 

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy In Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescent patients (13-17 years), including those with schizophrenia(6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fastingglucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent oral olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Oral Olanzapine Monotherapy Studies

Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Ann	Up to 12 weeks exposure		At least 24 weeks exposure
			N	Patients	N	Patients
Fasting Glucose	Normal to High	Olanzapine	124	0%	108	0.9%
	(<100 mg/dL to ≥126 mg/dL)	Placebo	53	1.9%	NAa	NAa
	Borderline to High	Olanzapine	14	14.3%	13	23.1%
	(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	Placebo	13	0%	NAa	NAa
a Not Applicable.

 

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipidevaluations in patients using olanzapine, is recommended [see Patient Counseling Information].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy In Adults

In an analysis of 5 placebo-controlled olanzapine mono therapy studies with treatment duration up to 12 weeks,olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL,4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides)were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean non fasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, orchanges in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Ann	Up to 12 weeks exposure		At least 48 weeks exposure
			N	Patients	N	Patients
Fasting Triglycerides	Increase by ≥50 mg/dL	Olanzapine	745	39.6%	487	61.4%
		Placebo	402	26.1%	NAa	NAa
	Normal to High (<150 mg/dL to ≥200 mg/dL)	Olanzapine	457	9.2%	293	32.4%
		Placebo	251	4.4%	NAa	NAa
	Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	135	39.3%	75	70.7%
		Placebo	65	20.0%	NAa	NAa
Fasting Total Cholesterol	Increase by ≥40 mg/dL	Olanzapine	745	21.6%	489	32.9%
		Placebo	402	9.5%	NAa	NAa
	Normal to High (<200 mg/dL to ≥240 mg/dL)	Olanzapine	392	2.8%	283	14.8%
		Placebo	207	2.4%	NAa	NAa
	Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)	Olanzapine	222	23.0%	125	55.2%
		Placebo	112	12.5%	NAa	NAa
Fasting LDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	536	23.7%	483	39.8%
		Placebo	304	14.1%	NAa	NAa
	Normal to High (<100 mg/dL to ≥160 mg/dL)	Olanzapine	154	0%	123	7.3%
		Placebo	82	1.2%	NAa	NAa
	Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)	Olanzapine	302	10.6%	284	31.0%
		Placebo	173	8.1%	NAa	NAa
a Not Applicable.

 

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Dose group differences with respect to increases in fasting triglycerides have been observed. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, statistically significant differences among dose groups have been observed for fasting triglycerides. Incidence of changes from normal to high levels of fasting triglycerides at any time during the trial indicated significant differences between the highest dose group (300 mg/2weeks, 24.5% [13/53]) and the lower dose groups (150 mg/2 weeks, 6.5% [4/62]; 405 mg/4 weeks, 9.8% [13/133]).

Olanzapine Monotherapy In Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescents (13-17 years), including those with schizophrenia (6 weeks) orbipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fastingHDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes infasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Oral Olanzapine Monotherapy Studies

Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Ann	Up to 6 weeks exposure		At least 24 weeks exposure
			N	Patients	N	Patients
Fasting Triglycerides	Increase by ≥50 mg/dL	Olanzapine	138	37.0%	122	45.9%
		Placebo	66	15.2%	NAa	NAa
	Normal to High (<90 mg/dL to >130 mg/dL)	Olanzapine	67	26.9%	66	36.4%
		Placebo	28	10.7%	NAa	NAa
	Borderline to High (≥90 mg/dL and ≤130 mg/dL to >130 mg/dL)	Olanzapine	37	59.5%	31	64.5%
		Placebo	17	35.3%	NAa	NAa
Fasting Total Cholesterol	Increase by ≥40 mg/dL	Olanzapine	138	14.5%	122	14.8%
		Placebo	66	4.5%	NAa	NAa
	Normal to High (<170 mg/dL to ≥200 mg/dL)	Olanzapine	87	6.9%	78	7.7%
		Placebo	43	2.3%	NAa	NAa
	Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	36	38.9%	33	57.6%
		Placebo	13	7.7%	NAa	NAa
Fasting LDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	137	17.5%	121	22.3%
		Placebo	63	11.1%	NAa	NAa
	Normal to High (<110 mg/dL to >130 mg/dL)	Olanzapine	98	5.1%	92	10.9%
		Placebo	44	4.5%	NAa	NAa
	Borderline to High(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)	Olanzapine	29	48.3%	21	47.6%
		Placebo	9	0%	NAa	NAa
a Not Applicable.

 

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information].

Olanzapine Monotherapy In Adults

In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained anaverage of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults

Amount Gained kg (lb)	6 Weeks (N=7465) (%)	6 Months (N=4162) (%)	12 Months (N=1345) (%)	24 Months (N=474) (%)	36 Months (N=147) (%)
≤0	26.2	24.3	20.8	23.2	17.0
0 to ≤5 (0-11 lb)	57.0	36.0	26.0	23.4	25.2
>5 to ≤10 (11-22 lb)	14.9	24.6	24.2	24.1	18.4
>10 to ≤15 (22-33 lb)	1.8	10.9	14.9	11.4	17.0
>15 to ≤20 (33-44 lb)	0.1	3.1	8.6	9.3	11.6
>20 to ≤25 (44-55 lb)	0	0.9	3.3	5.1	4.1
>25 to ≤30 (55-66 lb)	0	0.2	1.4	2.3	4.8
>30 (>66 lb)	0	0.1	0.8	1.2	2

 

Dose group differences with respect to weight gain have been observed in some studies. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, mean baseline-to-endpoint increase in weight (150 mg/2 weeks, n=140: 0.67 kg; 405 mg/4 weeks, n=315: 0.89 kg; 300 mg/2weeks, n=140: 1.70 kg) was observed with significant differences between the lowest and highest dose groups (150 vs 300 mg/2 weeks). 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, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy In Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of18 years.

Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Oral Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

	Olanzapine-treated patients	Placebo-treated patients
Mean change in body weight from baseline (median exposure = 3 weeks)	4.6 kg (10.1 lb)	0.3 kg (0.7 lb)
Percentage of patients who gained at least 7% of baseline body weight	40.6% (median exposure to 7% = 4 weeks)	9.8% (median exposure to 7% = 8 weeks)
Percentage of patients who gained at least 15% of baseline body weight	7.1% (median exposure to 15% = 19 weeks)	2.7% (median exposure to 15% = 8 weeks)

 

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal(N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents

Amount Gained kg (lb)	6 Weeks (N=243) (%)	6 Months (N=191) (%)
≤0	2.9	2.1
0 to ≤5 (0-11 lb)	47.3	24.6
>5 to ≤10(11-22 lb)	42.4	26.7
>10 to ≤15 (22-33 lb)	5.8	22.0
>15 to ≤20 (33-44 lb)	0.8	12.6
>20 to ≤25 (44-55 lb)	0.8	9.4
>25 to ≤30 (55-66 lb)	0	2.1
>30 to ≤35 (66-77 lb)	0	0
>35 to≤40 (77-88 lb)	0	0
>40 (>88 lb)	0	0.5

 

Tardive Dyskinesia

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 topredict, 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 mayrequire treatment with olanzapine despite the presence of the syndrome.

Orthostatic Hypotension

ZYPREXA RELPREVV may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, probably reflecting its α1-adrenergic antagonistic properties [see Patient Counseling Information]. Syncope-related adverse reactions were reportedin 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 oralolanzapine prior to initiating treatment with ZYPREXA RELPREVV [see DOSAGE AND ADMINISTRATION].

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or centralnervous system depression [see DRUG INTERACTIONS].

Falls

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.

Leukopenia, Neutropenia, And Agranulocytosis

Class Effect

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychoticagents, including ZYPREXA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-inducedleukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their completeblood 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.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly ifsuch symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm³) should discontinue ZYPREXA RELPREVV andhave their WBC followed until recovery.

Dysphagia

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.

Seizures

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 thesecases.

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 maybe more prevalent in a population of 65 years or older.

Potential For Cognitive And Motor Impairment

Sedation was a commonly reported adverse reaction associated with ZYPREXA RELPREVV treatment, occurring at an incidence of 8% in ZYPREXARELPREVV 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, WARNINGS AND PRECAUTIONS, and Patient Counseling Information].

Body Temperature Regulation

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].

Anticholinergic (antimuscarinic) Effects

Olanzapine exhibits in vitro muscarinic receptor affinity [see CLINICAL PHARMACOLOGY]. 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 adversereactions were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with a current diagnosis orprior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see DRUG INTERACTIONS].

Hyperprolactinemia

As with other drugs that antagonize dopamine D 2receptors, 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 reproductivefunction 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 whichincrease prolactin release, an increase in mammary gland neoplasia was observed in the oral olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronicadministration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% ofadults 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 mixedepisodes), 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-relatedevents³ (2% [3/168] of females, 2% [7/286] of males) [see Use In Specific Populations].

¹Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.
²Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.
³Based 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, incidenceof 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.

Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see WARNINGS AND PRECAUTIONS and Patient Counseling Information].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA RELPREVV. Patients should be advised to call their doctor if they do not think they are getting better or have concerns about their condition.

Post-Injection Delirium/Sedation Syndrome

During premarketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose have been reported inpatients following an injection of ZYPREXA RELPREVV. It is mandatory that patients be enrolled in the ZYPREXA RELPREVV Patient Care Programto 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]. 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].

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 mentalstatus, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS].

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].

Hyperglycemia And Diabetes Mellitus

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions related to ZYPREXA RELPREVV. Patients should bemonitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor’s instructions about how often to check theirblood sugar while taking ZYPREXA RELPREVV [see WARNINGS AND PRECAUTIONS].

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].

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].

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 and DRUG INTERACTIONS]. 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 and WARNINGS AND PRECAUTIONS].

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].

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 prescriptionor over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see DRUG INTERACTIONS].

Alcohol

Patients should be advised to avoid alcohol while taking ZYPREXA RELPREVV [see DRUG INTERACTIONS].

Use In Specific Populations

Pregnancy

Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZYPREXARELPREVV. 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].

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].

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].

Pediatric Use

Safety and effectiveness of ZYPREXA RELPREVV in patients under 18 years have not been established [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the daily oral MRHD based on mg/m² body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the daily oral MRHD based on mg/m² body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m² body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 2 times the daily oral MRHD based on mg/m² body surface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m² body surface area; in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4mg/kg/day (0.5 and 2 times the daily oral MRHD based on mg/m² body surface area, respectively). Rats were also treated intramuscularly withZYPREXA RELPREVV once a month for 2 years at doses of 5, 10, 20 mg/kg (males) and 10, 25, 50 mg/kg (females) (equivalent to 0.08-0.8 times the daily oral MRHD of 300 mg every 2 weeks based on mg/m² body surface area; dosing was limited due to local reactions at the IM injection site). The incidence of tumors in this study was not altered when compared to solution for ZYPREXA RELPREVV control or pamoic acid treated animals. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold inrats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administrationof other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated end ocrinetumors in rodents is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis

No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test inmouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Impairment Of Fertility

In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m² bodysurface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital periodwas increased and the mating index reduced at 5 mg/kg/day (2.5 times the daily oral MRHD based on mg/m² body surface area). Diestrous wasprolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m² body surface area); therefore olanzapine may produce a delay in ovulation.

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ZYPREXARELPREVV, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for AtypicalAntipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including ZYPREXA RELPREVV, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed tool anzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ZYPREXA RELPREVV, during pregnancy (see Clinical Considerations).

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m² body surface area; some fetal toxicities were observed at these doses (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background riskof birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal And Embryo/Fetal Risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a directresult of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ZYPREXA RELPREVV, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Someneonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, case reports and meta-analyses that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based onmg/m² body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m² body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m² body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m² body surface area). No evidence of teratogenicity or embryo-fetal toxicity was observed in rats or rabbits with olanzapine at intramuscular doses up to 75 mg/kg (1 and 2 times the MRHD of 300 mg every 2 weeks, respectively, based on mg/m² body surface area).

Lactation

Risk Summary

Olanzapine pamoate is present in human milk. There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors andabnormal muscle movements) in infants exposed to olanzapine pamoate through breast milk (see Clinical Considerations). There is no information onthe effects of olanzapine pamoate on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZYPREXA RELPREVV and any potential adverse effects on the breastfed child from ZYPREXA RELPREVV or from the mother’s underlying condition. Clinical Considerations

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

Females And Males Of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of olanzapine (D 2receptor 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].

Pediatric Use

Safety and effectiveness of ZYPREXA RELPREVV in children and adolescent patients have not been established [see WARNINGS AND PRECAUTIONS].

Compared to patients from adult clinical trials, adolescents treated with oral ZYPREXA were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.

Geriatric Use

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 ofolanzapine 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 least2% 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 witholanzapine 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, and Patient Counseling Information]. 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 toconsideration of a lower starting dose for any geriatric patient [see BOXED WARNING, DOSAGE AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS].

Human Experience

During premarketing clinical studies of ZYPREXA RELPREVV, adverse reactions that presented with signs and symptoms consistent with olanzapineoverdose, 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]. 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 tosupra-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 signsand 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 fromsoon 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 iscumulative (i.e., increases with the number of injections) [see WARNINGS AND PRECAUTIONS].

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 amountof 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 tosurvive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

Management Of Overdose

Post-injection delirium/sedation syndrome may occur with each injection of ZYPREXA RELPREVV. Signs and symptoms consistent with olanzapineoverdose have been observed, and access to emergency response services must be readily available for safe use [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

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 adequateoxygenation 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.

Contraindications

None.

Mechanism Of Action

The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism.

Pharmacodynamics

Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT 6(Ki=4, 11, and 5 nM, respectively), dopamine D 1-4(Ki=11-31 nM), histamine H 1(Ki=7 nM), and adrenergic α 1receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding forserotonin 5HT 3(Ki=57 nM) and muscarinic M 1-5(Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABAA, BZD,and α-adrenergic receptors (Ki>10 μM).

Pharmacokinetics

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 ZYPREXARELPREVV results in prolonged systemic olanzapine plasma concentrations that are sustained over a period of weeks to months. An injection every 2 or4 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 ahalf-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 tothe 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.

Dose Proportionality And Oral Dose Correspondence

ZYPREXA RELPREVV provides a dose of 150, 210, 300, or 405 mg olanzapine. An injection of a larger dose produces a dose-proportional increase in the systemic exposure. The olanzapine exposure after doses of ZYPREXA RELPREVV corresponds to exposure for oral doses of olanzapine. A ZYPREXA RELPREVV dose of 300 mg olanzapine injected every two weeks delivers approximately 20 mg olanzapine per day and a ZYPREXA RELPREVV dose of 150 mg olanzapine injected every two weeks delivers approximately10 mg per day. These ZYPREXA RELPREVV doses sustain steady-state olanzapine concentrations over long periods of treatment.

Pharmacokinetic Impact Of Switching To ZYPREXA RELPREVV From Oral Olanzapine

The switch from oral olanzapine to ZYPREXA RELPREVV changes the pharmacokinetics from an elimination-rate-controlled to an absorption-rate-controlled process. The switch to ZYPREXA RELPREVV may require treatment for a period of approximately 3 months to re-establish steady-state conditions. Initial treatment with ZYPREXA RELPREVV is recommended at a dose corresponding to the mg/day oral dose [see DOSAGE AND ADMINISTRATION]. Plasma concentrations of olanzapine during thefirst injection interval may be lower than those maintained by a corresponding oral dose. Even though the concentrations are lower, the olanzapine concentrations remained within a therapeutically effective range and supplementation with orally administered olanzapine was generally not necessary inclinical trials.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein.

Metabolism And Elimination

Following a single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine asunchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. Aftermultiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4′-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing mono oxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be aminor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Intramuscular Formulations

There are two formulations of ZYPREXA which are available for intramuscular injection. One form (ZYPREXARELPREVV) is described in this package insert. The other formulation (ZYPREXA Intra Muscular) is a solution of olanzapine. When ZYPREXA Intra Muscular is injected intramuscularly, olanzapine (as the free base) is rapidly absorbed and peak plasma concentrations occur within 15 to 45minutes. With the exception of higher maximum plasma concentrations, the pharmacokinetics of olanzapine after ZYPREXA Intra Muscular are similarto those for orally administered olanzapine. Refer to the package insert for ZYPREXA Intra Muscular for additional information.

Specific Populations

In general, the decision to use ZYPREXA RELPREVV in specific populations should be thoughtfully considered. For patients who have never taken oral olanzapine, tolerability should be established with oral olanzapine prior to initiating treatment with ZYPREXA RELPREVV.The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks, in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients>65 years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be performed with cautionin these patients [see DOSAGE AND ADMINISTRATION]. Precautions noted below need to be carefully weighed.

Renal Impairment

Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction aloneis unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of orally administered olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.

Hepatic Impairment

Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on thepharmacokinetics of orally administered olanzapine.

Geriatric

In a study involving 24 healthy subjects, the mean elimination half-life of orally administered olanzapine was about 1.5 times greater in elderly (≥65 years) than in nonelderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that mightadditively influence drug metabolism and/or pharmacodynamic sensitivity [see DOSAGE AND ADMINISTRATION].

Gender

For both oral ZYPREXA and ZYPREXA RELPREVV higher average plasma concentrations of olanzapine were observed in women than inmen. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gendershould not be needed.

Smoking Status

For both oral ZYPREXA and ZYPREXA RELPREVV, studies have demonstrated that the clearance of olanzapine is higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.

Race

In vivo studies of orally administered olanzapine have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended.

Combined Effects

The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessaryin patients who exhibit a combination of factors that may result in slower metabolism of olanzapine [see DOSAGE AND ADMINISTRATION].

Animal Toxicology And/Or Pharmacology

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17times 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/m²body surface area) in studies of 3 months’ duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving22.5 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.

Clinical Studies

Schizophrenia

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, orplacebo 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 NegativeSyndrome Scale (PANSS) score (mean baseline total PANSS score 101). Total PANSS scores showed statistically significant improvement from baselineto 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 ZYPREXARELPREVV 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 4weeks, and 300 mg every 2 weeks were each statistically significantly superior to low dose ZYPREXA RELPREVV (45 mg every 4 weeks).