Zyprexa Relprevv, an extended-release injectable suspension of olanzapine, received FDA approval in December 2009 for the treatment of schizophrenia in adults. Due to the risk of post-injection delirium/sedation syndrome (PDSS) associated with Zyprexa Relprevv usage, the injection is only available through a restricted distribution program. This article reviews the impact of PDSS on the use of Zyprexa Relprevv.

Zyprexa Relprevv, an extended-release injectable suspension of olanzapine, received FDA approval in December 2009 for the treatment of schizophrenia in adults.1 Zyprexa Relprevv can be administered once every two to four weeks, depending on the patient's target oral olanzapine dose. Due to the risk of post-injection delirium/sedation syndrome (PDSS) associated with Zyprexa Relprevv usage, the injection is only available through a restricted distribution program, requiring enrollment by the healthcare facility administering the injection, as well as the patient, prescriber, and pharmacy dispensing the injection. Though PDSS is rare and has occurred in less than 0.1 % of injections and in approximately 2% of patients who received injections up to 46 months, it is still an alarming adverse effect that warrants careful administration and monitoring.

The occurrence of PDSS has been associated with an unpredictable rapid attainment of supra-therapeutic plasma concentrations of olanzapine. Approximately 80% of PDSS cases have developed within one hour of receiving the injection, while <1/1000 injections and <1/10,000 injections have resulted in PDSS one to three hours and greater than three hours post-injection, respectively. The exact mechanism describing the rapid entrance of olanzapine into the circulation is unknown, since it is a deep intramuscular gluteal injection designed to provide slow-release, rate-controlled absorption of olanzapine. Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing have been excluded as possible causes, and instead PDSS is thought to result from accidental partial intravascular injection or blood vessel injury during injection causing olanzapine to enter into the circulation.2 

Because of the risk of PDSS, Zyprexa Relprevv cannot be dispensed directly to the patient and can only be administered in a registered healthcare facility with immediate access to emergency services.1 Additionally, patients must be observed for symptoms similar to an olanzapine overdose, including sedation and/or delirium (e.g., confusion, disorientation, agitation, anxiety) by a healthcare professional for a minimum of 3 hours post-injection. Before the patient can be released, the healthcare professional must confirm the patient is alert, oriented, and absent of signs and symptoms consistent with PDSS. Patients must also be accompanied to their final destination upon leaving the facility. Because of the complicated logistics surrounding the use of Zyprexa Relprevv, I was curious to learn what type of facilities were administering this injection and the experience of members who have used or attempted to use Zyprexa Relprevv in their patients.

In a survey included in the November issue of the Mental Health Clinician, six CPNP members stated they had difficulty dedicating a staff member to observe the patient for a minimum of 3 hours post-injection. Four members endorsed the injection was too expensive for their facility, while one member stated they had a patient receiving Zyprexa Relprevv who either decompensated or required oral supplementation in addition to the injection. Another member claimed their facility had difficulty getting their staff trained. Two members confirmed that they had encountered no barriers to usage.

Tables 1 and 2 were compiled from information provided by CPNP members on their experiences with Zyprexa Relprevv. Of the 16 members who responded to an email inquiry through the list serve requesting information about their experiences, twelve responses (75%) were provided by clinicians (or administrators) practicing in an inpatient psychiatric unit or at a psychiatric hospital, while one response was received from clinicians at each of the following practice sites: a county jail, a state-supported living center for mentally-ill/disabled patients, an outpatient clinic, an independent psychiatric pharmacy, and an inpatient psychiatric unit affiliated with an outpatient psychiatric clinic. One inpatient psychiatric unit, one state hospital, and one state-supported living center have added Zyprexa Relprevv to their formularies; however, two of these facilities have imposed restrictions on its use. An additional state hospital is currently in the process of obtaining formulary approval for the injection but is experiencing delays due to a lack of outpatient clinics registered to dispense and administer the injection. Seventy-five percent (9/12) of inpatient psychiatry units and psychiatric hospitals have not added Zyprexa Relprevv to their formulary. Barriers to Zyprexa Relprevv usage identified by members responding to the email inquiry include: a) the high cost of the injection and/or reimbursement issues (44%; 7 members), b) a lack of registered outpatient clinics (25%; 4 members), and c) limited staff availability for required monitoring (19%; 3 members). It appears facilities administering the injection have had Eli Lilly drug representatives provide training to their staff with much success (3 members). Based on the information provided by 16 members, up to 25 patients have been initiated on Zyprexa Relprevv. Though many members did not or were unable to provide information on the efficacy and/or tolerability of the injection, 6 patients were stated to be doing well on the injection, while about 4 patients were described as not deriving benefit from the injection. To optimize Zyprexa Relprevv usage, Kelly Williams, a Clinical Pharmacy Specialist at Wishard Health Services/Midtown Community Mental Health Center has developed a prescriber referral form to prevent patients from being inappropriately initiated on Zyprexa Relprevv. She also created an observation form to assist with monitoring for PDSS. Overall, if cost and/or reimbursement issues are surmounted, the facilities are well-staffed, and all involved entities (i.e., pharmacy, provider, facility administering the injection, patient) have registered with the Zyprexa Relprevv program, it appears the injection may be a viable option for those responding to the oral formulation of Zyprexa but with medication adherence issues; however, it should be noted that long-acting injectables do not guarantee adherence and patients stabilized on 20 mg/day of oral Zyprexa will require an injection once every two weeks rather than monthly.

Zyprexa Relprevv [package insert]
Eli Lilly and Company
Indianapolis, IN
July 2011
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et al
Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism
BMC Psychiatry
DOI: 10.1186/1471-244X-10-45. PubMed PMID: 20537130; PubMed Central PMCID: PMC2895590