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ZYPREXA RELPREVV (olanzapine) For Extended Release Injectable Suspension
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ZYPREXA RELPREVV safely and effectively. See full prescribing information for ZYPREXA RELPREVV.
ZYPREXA RELPREVV (olanzapine) For Extended Release Injectable Suspension
Initial U.S. Approval: 1996
WARNING: POST-INJECTION DELIRIUM/SEDATION SYNDROME AND INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
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Patients are at risk for severe sedation (including coma) and/or delirium after each injection and must be observed for at least 3 hours in a registered facility with ready access to emergency response services. Because of this risk, ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment. (2.1, 5.1, 5.2, 10.2, 17.2)
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Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis. (5.3, 5.14, 17.3)
RECENT MAJOR CHANGES
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Dosage and Administration: |
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Instructions to Reconstitute and Administer ZYPREXA RELPREVV (2.2) |
09/2015 |
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Warnings and Precautions: |
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Metabolic Changes (5.6) |
12/2014 |
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Orthostatic Hypotension (5.8) |
07/2015 |
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Hyperprolactinemia (5.15) |
12/2014 |
INDICATIONS AND USAGE
ZYPREXA® RELPREVV™ is a long-acting atypical antipsychotic for intramuscular injection indicated for the treatment of schizophrenia. (1.1)
Efficacy was established in two clinical trials in patients with schizophrenia: one 8-week trial in adults and one maintenance trial in adults. (14.1)
DOSAGE AND ADMINISTRATION
150 mg/2 wks, 300 mg/4 wks, 210 mg/2 wks, 405 mg/4 wks, or 300 mg/2 wks. See Table 1 for dosing recommendations. (2.1)
ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only.
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Do not administer intravenously or subcutaneously. (2.1)
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Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. (2.1)
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Establish tolerability with oral olanzapine prior to initiating treatment. (2.1)
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ZYPREXA RELPREVV doses above 405 mg every 4 weeks or 300 mg every 2 weeks have not been eva luated in clinical trials. (2.1)
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Use in specific populations (including renal and hepatic impaired, and pediatric population) has not been studied. (2.1)
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Must be suspended using only the diluent for ZYPREXA RELPREVV provided in the convenience kit. (2.2)
DOSAGE FORMS AND STRENGTHS
Powder for suspension for intramuscular use only: 210 mg/vial, 300 mg/vial, and 405 mg/vial (3, 11, 16)
WARNINGS AND PRECAUTIONS
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Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g. stroke, transient ischemic attack). (5.3)
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Suicide: The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy. (5.4)
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Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.5)
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Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. (5.6)
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Hyperglycemia and Diabetes Mellitus: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.6)
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Dyslipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.6)
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Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. (5.6)
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Tardive Dyskinesia: Discontinue if clinically appropriate. (5.7)
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Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses. (5.8)
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Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including ZYPREXA. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA RELPREVV should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.9)
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Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. (5.11)
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Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery. (5.12)
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Hyperprolactinemia: May elevate prolactin levels. (5.15)
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Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment. (5.16)
ADVERSE REACTIONS
Most common adverse reactions (≥5% in at least one of the treatment groups and greater than placebo) associated with ZYPREXA RELPREVV treatment: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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CNS Acting Drugs: Caution should be used when used in combination with other centrally acting drugs and alcohol. (7.2)
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Antihypertensive Agents: Enhanced antihypertensive effect. (7.2)
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Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists. (7.2)
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Diazepam: May potentiate orthostatic hypotension. (7.1, 7.2)
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Alcohol: May potentiate orthostatic hypotension. (7.1)
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Carbamazepine: Increased clearance of olanzapine. (7.1)
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Fluvoxamine: May increase olanzapine levels. (7.1)
USE IN SPECIFIC POPULATIONS
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Pregnancy: ZYPREXA RELPREVV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1)
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Nursing Mothers: Breast-feeding is not recommended. (8.3)
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Pediatric Use: Safety and effectiveness of ZYPREXA RELPREVV in children <18 years of age have not been established. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ZYPREXA RELPREVV is available only through a restricted distribution program [see Warnings and Precautions (5.2)]. ZYPREXA RELPREVV must not be dispensed directly to a patient. For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.
1.1 Schizophrenia
ZYPREXA RELPREVV is indicated for the treatment of schizophrenia. Efficacy was established in two clinical trials in patients with schizophrenia: one 8-week trial in adults and one maintenance trial in adults [see Clinical Studies (14.1)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only and should not be administered intravenously or subcutaneously.
Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. Refer to the package insert for ZYPREXA IntraMuscular for more information about that product.
Establish tolerability with oral olanzapine prior to initiating treatment.
ZYPREXA RELPREVV should be administered by a healthcare professional every 2 to 4 weeks by deep intramuscular gluteal injection using a 19-gauge, 1.5-inch needle. Following insertion of the needle into the muscle, aspiration should be maintained for several seconds to ensure that no blood is drawn into the syringe. If any blood is aspirated into the syringe, it should be discarded and fresh drug should be prepared using a new convenience kit. The injection should be performed at a steady, continuous pressure. Do not massage the injection site.
Dose Selection — The efficacy of ZYPREXA RELPREVV has been demonstrated within the range of 150 mg to 300 mg administered every 2 weeks and with 405 mg administered every 4 weeks. Dose recommendations considering oral ZYPREXA and ZYPREXA RELPREVV are shown in Table 1.
ZYPREXA RELPREVV doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been eva luated in clinical trials.
Post-Injection Delirium/Sedation Syndrome — During premarketing clinical studies, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10.1)]. Patients should be informed of this risk and how to recognize related symptoms [see Patient Counseling Information (17.1, 17.2)]. 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 (10)].
Dosing in Specific Populations — Tolerance of oral ZYPREXA should be established prior to initiating treatment with ZYPREXA RELPREVV. The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be undertaken with caution in these patients [see Warnings and Precautions (5.16), Drug Interactions (7), and Clinical Pharmacology (12.3)].
ZYPREXA RELPREVV has not been studied in subjects under 18 years of age [see Warnings and Precautions (5.6)].
Maintenance Treatment — Although no controlled studies have been conducted to determine how long patients should be treated with ZYPREXA RELPREVV, efficacy has been demonstrated over a period of 24 weeks in patients with stabilized schizophrenia. Additionally, oral ZYPREXA has been shown to be effective in maintenance of treatment response in schizophrenia in longer-term use. Patients should be periodically reassessed to determine the 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.
2.2 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:
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Vial of ZYPREXA RELPREVV powder
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3-mL vial of diluent
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One 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro® needle with needle protection device
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Two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device
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For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used for administration.
ZYPREXA RELPREVV must be suspended using only the diluent supplied in the convenience kit.
It is recommended that gloves are used when reconstituting, as ZYPREXA RELPREVV may be irritating to the skin. Flush with water if contact is made with skin.
See additional insert entitled “Instructions to Reconstitute and Administer ZYPREXA RELPREVV” (included) for more information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.
Step 2: Determining Reconstitution Volume
Refer to the table below to determine the amount of diluent to be added to powder for reconstitution of each vial strength.
It is important to note that there is more diluent in the vial than is needed to reconstitute.
Step 3: Reconstituting ZYPREXA RELPREVV
Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needlestick injury.
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Loosen the powder by lightly tapping the vial.
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Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.
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Withdraw the pre-determined diluent volume ( Step 2) into the syringe.
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Inject the diluent into the powder vial.
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Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.
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Remove the needle from the vial, holding the vial upright to prevent any loss of material.
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Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).
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Pad a hard surface to cushion impact ( see Figure 1). Tap the vial firmly and repeatedly on the surface until no powder is visible.
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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).
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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).
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If foam forms, let vial stand to allow foam to dissipate.
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If the product is not used right away, it should be shaken vigorously to re-suspend. Reconstituted ZYPREXA RELPREVV remains stable 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.
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