Olanzapine pamoate: a stick in time?
Disclosures No writing assistance or external financial support was utilised in the production of this review article. Leslie Citrome, is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Pfizer Inc. and Vanda Pharmaceuticals.
As Psychiatry Section Editor for the Journal, Leslie Citrome withdrew from the review process and deferred all editorial decisions to Graham Jackson.
Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA
Tel.: 1 845 398 5595
Fax: 1 845 398 5483
Olanzapine pamoate, a long-acting depot preparation of olanzapine, is being evaluated by regulatory agencies for the treatment of schizophrenia. Clinical trial information was accessed by on-line query of http://www.pubmed.gov, http://www.clinicaltrials.gov and http://www.fda.gov, along with an examination of poster presentations at scientific meetings held in 2008.
Two double-blind randomised clinical trials of olanzapine pamoate were conducted and demonstrate efficacy for both the acute treatment of schizophrenia and for the maintenance of antipsychotic response. Long-term open-label studies provide additional information on safety. The overall tolerability profile for olanzapine pamoate is similar to that for the oral formulation; however, with the depot there is a risk of a postinjection delirium sedation syndrome which resembles an overdose of oral olanzapine and which occurs in 0.07% of injections, requiring patients to be observed for 3 h after injection. At present, there are no studies available that directly compare olanzapine pamoate with other antipsychotics other than oral olanzapine.
On-line query of http://www.pubmed.gov, http://www.clinicaltrials.gov and http://www.fda.gov for `olanzapine’ and ‘depot’ or ‘long-acting’ or ‘pamoate’. Poster presentations at scientific meetings held in 2008.
Message for the Clinic
Olanzapine pamoate, a depot injectable preparation of olanzapine, is under consideration for approval for the treatment of schizophrenia by several regulatory agencies. It can be administered every 2 weeks or every 4 weeks by intramuscular injection into the buttocks. Overall, the tolerability and efficacy profile is similar to that for oral olanzapine; however in a small number of injections, the emergence of postinjection delirium sedation syndrome makes postinjection monitoring mandatory for all patients.
Long-acting injectable preparations of antipsychotic medication have been used as an alternative to oral medication therapy for patients for whom adherence is a clinically significant problem. Non-adherence and partial adherence to antipsychotic medication treatment can be observed in about half of all patients with schizophrenia (1,2), and is associated with an increased risk for relapse and hospitalization (3–5). With the administration of a depot antipsychotic, a therapeutic amount of an antipsychotic is available for an extended period of time. Covert non-adherence is not possible. Non-adherence can be readily identified early if the patient fails to appear for their next injection.
Although several first-generation antipsychotics have been available in a depot formulation for several decades, up to now there has been only one second-generation antipsychotic licensed in this form – risperidone microspheres (6). Newly developed is an intramuscular depot formulation of olanzapine, whose oral form was commercialised in 1996. Olanzapine itself is robustly efficacious for the treatment of schizophrenia, as evidenced by meta-analyses such as conducted by Davis et al. (7) and large effectiveness studies such as the Clinical Antipsychotic Trials of Intervention Effectiveness (8) and the European First-Episode Schizophrenia Trial (9). Olanzapine is extensively used, and in addition to schizophrenia, oral olanzapine has received regulatory approvals for the treatment of bipolar mania, and, in combination with fluoxetine, for bipolar depression. A rapid-acting non-depot intramuscular preparation of olanzapine is also available and approved for the treatment of agitation associated with schizophrenia and bipolar mania. Similar to most other second-generation antipsychotics, olanzapine has a favourable profile in terms of extra-pyramidal side effects and is relatively prolactin-sparing compared with first-generation antipsychotics. However, olanzapine can be associated with substantial weight gain and the development of hyperlipidaemia, as well as hyperglycaemia, and thus monitoring these effects becomes crucial (10). Orthostatic hypotension, syncope, sedation and somnolence can also occur, as noted in product labelling (11).
This review focuses on the efficacy and safety of the new long-acting preparation of olanzapine, and places its use within a clinical context.
Clinical trial information was accessed by on-line query of http://www.pubmed.gov, and http://www.clinicaltrials.gov for ‘olanzapine’ and ‘depot’ or ‘long-acting’ or ‘pamoate.’ No date or language constraints were utilised. Proceedings of paper and poster presentations of the following scientific meetings were searched: 63rd Annual Scientific Convention and Program of the Society of Biological Psychiatry, Washington, DC, 1–3 May 2008; 161st Annual Meeting of the American Psychiatric Association, Washington, DC, 3–8 May 2008; 48th Annual Meeting of the NCDEU, Phoenix, AZ, 27–30 May 2008; 26th Congress of the Collegium Internationale Neuro-psychopharmacologicum, Munich, Germany, 13–17 July 2008. Where there are differences between the submitted abstract and the copy of the poster made available, the data from the poster copy are used. Additional information was obtained through available documents on the website maintained by the United States Food and Drug Administration (FDA) at http://www.fda.gov. To ensure that all publicly available information was collected, a request for information was made to Eli Lilly and Company of Indianapolis, IN, USA for any other copies of reports or presentations that were missed in the initial search.
The above search strategy resulted in the finding of two peer-reviewed published reports of olanzapine pamoate (12,13), one peer-reviewed report describing another depot formulation of olanzapine (14), four records contained in http://www.clinicaltrials.gov (15–18), nine abstracts of poster presentations (19–27) and two comprehensive reviews on the FDA website (28,29). This paper is a synthesis of this data. Where possible, effect sizes for categorical outcomes are presented as number needed to treat (NNT) (30,31).
Description of formulation and pharmacokinetics
The depot intramuscular formulation of olanzapine is a crystalline salt formulation, olanzapine pamoate monohydrate, composed of olanzapine and pamoic acid (28). The individual crystals are micron-sized and suspended in water. When injected into the muscle, the salt slowly dissolves and, in solution, dissociates into separate molecular entities of olanzapine (base) and pamoic acid at the site of injection, and both components enter systemic circulation. The rate of dissolution of the crystalline salt formulation is slow, resulting in the absorption of olanzapine over a period of several weeks. This is in direct contrast to the rapid-acting intramuscular formulation of olanzapine used to treat agitation associated with schizophrenia and bipolar mania where the aqueous solution of olanzapine base is quickly absorbed, resulting in peak plasma levels within 1 h of injection (32).
The pharmacokinetics of multiple doses of olanzapine pamoate has been described in an open-label study in 282 symptom-stabilised patients with schizophrenia (19,28). Patients with schizophrenia stabilised on daily oral olanzapine received multiple olanzapine depot injections at doses of 100, 150, 160, 200 and 300 mg q2 weeks, and 200, 255, 300 and 405 mg q4 weeks for 24 weeks. Plasma olanzapine concentrations were sustained throughout both the 2- and 4-week injection intervals and olanzapine concentrations accumulated two- to threefold upon multiple dosing and reached steady-state conditions after about 3 months of dosing. Peak-to-trough fluctuation in concentrations averaged 51% for the 2-week injection interval and 75% for the 4-week interval. Maximum concentration and area under the concentration vs. time curve for olanzapine were proportionate to depot dose. Time to peak concentration following injection was 4 days and the half-life was approximately 26 days, in contrast to 6 and 29 h for the time to peak concentration and half-life, respectively, for oral olanzapine. Overall, the average steady-state concentrations observed with depot olanzapine approximated that obtained by using oral olanzapine within the dose range of 5–20 mg/day.
When the olanzapine pamoate monohydrate crystalline salt comes into contact with a substantial amount of blood or plasma, the salt dissolves more quickly, resulting in the release of a large amount of olanzapine. Thus accidental injection into vasculature can lead to potentially very high plasma levels of olanzapine with a matter of minutes to hours. This can occur if a blood vessel or rich capillary bed is entered or damaged by the injection needle. This property of olanzapine pamoate has significant clinical implications in terms of postinjection monitoring, to be described later.
Clinical trials: efficacy and safety
Table 1 lists the clinical trials of olanzapine pamoate that have been registered on http://www.clinicaltrials.gov, a repository operated by the US National Institutes of Health and the National Library of Medicine and/or disclosed by Eli Lilly in their briefing document to the FDA (28). All have been conducted among adults.
Table 1. Olanzapine pamoate clinical trials
|NCT00088478||HGJZ||12,17,23,28||8 weeks||Double-blind, placebo-controlled, fixed-dose pharmacokinetic, efficacy superiority, and safety study in patients with schizophrenia; phase III||404 randomised||210 mg q2 weeks, 300 mg q2 weeks, or 405 mg q4 weeks||Placebo||Conducted in the USA, Croatia and Russia. Began June 2004. Completed April 2005|
|NCT00088491||HGKA||18,24,26,28||24 weeks||Double-blind, olanzapine-controlled, fixed-dose study of non-inferiority of maintenance of efficacy, superiority of three therapeutic olanzapine pamoate doses compared with reference dose, safety, and pharmacokinetics in patients with schizophrenia; phase III||1065 randomised (1205 enrolled)||45 mg q4 weeks (reference dose), 405 mg q4 weeks, 150 mg q2 weeks, or 300 mg q2 weeks||Oral olanzapine 10, 15, or 20 mg/day||Conducted in Finland and Turkey. Began June 2004. Completed October 2006|
|NCT00088465||HGKB||15,21,28||4 years||Long-term, open-label safety, effectiveness, and pharmacokinetics (subset) study in patients with schizophrenia or schizoaffective disorder who have previously completed an olanzapine pamoate clinical trial (HGJZ, HGKA or LOBS); phase III||931 enrolled||Flexible doses ranging from 45 to 405 mg given at 2-, 3- or 4-week intervals||None||Began August 2004, USA and international sites. Ongoing. Not recruiting|
|NCT00320489||HGLQ||16,28||2 years||Randomised, open-label study of safety, effectiveness, and health outcomes in treatment with olanzapine pamoate or oral olanzapine in patients with schizophrenia who are at risk for relapse; phase III||524 randomised||150–405 mg q4 weeks||Oral olanzapine 5–20 mg/day||Began April 2006, USA and international sites. Ongoing. Not recruiting|
|None||LOBE||19,22,28||24 weeks||Open-label, single- and multiple-dose study of safety and pharmacokinetics in symptom-stabilised patients with schizophrenia||282 enrolled||Single dose 50–450 mg; multi-dose 100–405 mg q2 to q4 weeks||None||Concluded|
|None||LOBO||28||8 weeks||Open-label study of safety, pharmacokinetics, and olanzapine pamoate metabolites in patients with schizophrenia or schizoaffective disorder||9 enrolled||Four injections of 300 mg q2 weeks||None||Concluded|
|None||LOBS||28||7 weeks||Oral lead-in phase followed by a fixed-sequence, parallel-design, open-label study of safety, particle size distribution, and product quality bioavailability performance of olanzapine pamoate compared with oral olanzapine or rapid-acting intramuscular olanzapine in stable patients with schizophrenia or schizoaffective disorder||134 randomised||Single-dose 405 mg oral||Oral olanzapine 5, 10, 15 or 20 mg daily; rapid-acting intramuscular olanzapine single-dose 5 mg||Concluded|
|None||HGJW||13,28||24 weeks||Open-label, one-arm, positron emission tomography study of receptor occupancy, safety, and efficacy in patients with schizophrenia||14 enrolled||300 mg q4 weeks||None||Concluded|
|None||LOAZ||28||Single dose||Healthy volunteer subjects received a single, very low dose of olanzapine pamoate||18||10–40 mg||None||Concluded|
|None||LOBQ||28||Not disclosed||Healthy volunteer subjects received a marketed pamoate salt, hydroxyzine pamoate, to provide reference information on pamoic acid exposure||6||None||None||Concluded|
At the time of this review, there has been only one published efficacy trial of olanzapine pamoate, and was conducted among acutely ill patients with schizophrenia (12). In this 8-week phase III study, 404 subjects were randomised to receive on a 1 : 1 : 1 : 1 ratio double-blind olanzapine pamoate 210 mg q2 weeks, 300 mg q2 weeks, or 405 mg q4 weeks, or placebo, without any oral antipsychotic supplementation. A moderate to high symptom severity rating was required for study entry as defined by a specific rating scale cutoff. All patients were hospitalised upon study entry and were required to be inpatients during the washout period and for the first 2 weeks after randomisation. Mean baseline-to-end-point change in the Positive and Negative Syndrome Scale (PANSS) total score was the primary outcome measure and was significantly greater for all olanzapine regimens relative to placebo. Separation from placebo occurred at 3 days (the first time point where the PANSS was measured postbaseline) for the 300 mg q2 weeks and 405 mg q4 weeks treatment arms, and occurred at 7 days for the 210 mg q2 weeks treatment group. Overall clinical improvement as determined by end-point Clinical Global Impressions-Improvement scale scores ≤ 3 was higher for all olanzapine pamoate groups vs. placebo. Use of benzodiazepine was reported in 78.6% of the placebo group and from 69.0% to 76.0% in the olanzapine pamoate groups, with no statistically significant differences between treatment groups in the rates of use or mean daily dose. Likewise, no significant between-group differences were observed in the incidence of anticholinergic use or mean anticholinergic daily dose, with 8.2% of patients randomised to placebo receiving anticholinergic medications vs. 5.0–12.3% for those receiving olanzapine pamoate. Other categorical outcomes are outlined in Table 2. NNT for study completion for olanzapine pamoate vs. placebo ranged from seven to 11, and was statistically significant only for the 405 mg q4 weeks dosing regimen. NNT for at least a 40% improvement from baseline PANSS ranged from four to six for olanzapine pamoate vs. placebo. Discontinuation rates because of adverse events were low for all groups.
Table 2. The double-blind randomised clinical trials of olanzapine pamoate for the treatment of schizophrenia
|Length||8 weeks||24 weeks|
|Arms, completion rate, NNT for completion vs. placebo (or placebo equivalent) and 95% confidence interval||Placebo ( n = 98), 57%|
Olanzapine pamoate 210 mg q2 weeks (n = 106), 68%, NNT 10 (ns)
Olanzapine pamoate 300 mg q2 weeks (n = 100), 67%, NNT 11 (ns)
Olanzapine pamoate 405 mg q4 weeks (n = 100), 72%, NNT 7 (4, 60)
|Olanzapine pamoate 45 mg q4 weeks* (n = 144), 52.8%|
Olanzapine pamoate 150 mg q2 weeks (n = 140), 64.3%, NNT 9 (5, 825)
Olanzapine pamoate 300 mg q2 weeks (n = 141) , 75.9%, NNT 5 (3, 9)
Olanzapine pamoate 405 mg q4 weeks (n = 318) , 70.0%, NNT 6 (4, 14)
Olanzapine oral 10, 15 or 20 mg/day (n = 322) , 80.1%, NNT 4 (3, 6)
|Timing of improvement over placebo||Olanzapine pamoate 210 mg q2 weeks – day 7|
Olanzapine 300 mg q2 weeks – day 3
Olanzapine 405 mg q4 weeks – day 3
|Response by at least 40% improvement in the PANSS total score from baseline to end-point, NNT vs. placebo and 95% confidence interval||Placebo, 20.4%|
Olanzapine pamoate 210 mg q2 weeks, 47.2%, NNT 4 (3, 7)
Olanzapine pamoate 300 mg q2 weeks, 48.0%, NNT 4 (3, 7)
Olanzapine pamoate 405 mg q4 weeks, 40.0%, NNT 6 (4, 15)
|Free of exacerbation at 24 weeks, NNT vs. placebo-equivalent and 95% confidence interval||NA||Olanzapine pamoate 45 mg q4 weeks, 69%|
Olanzapine pamoate 150 mg q2 weeks, 84%, NNT 7 (4, 18)
Olanzapine pamoate 300 mg q2 weeks, 95%, NNT 4 (3, 6)
Olanzapine pamoate 405 mg q4 weeks, 90%, NNT 5 (4, 8)
Olanzapine oral 10, 15, or 20 mg/day, 93%, NNT 5 (4, 7)
|Treatment-related adverse events leading to discontinuation, NNT vs. placebo (or placebo equivalent) and 95% confidence interval||Placebo, 5.1%|
Olanzapine pamoate 210 mg q2 weeks, 2.8%, NNT 44 (ns)
Olanzapine pamoate 300 mg q2 weeks, 6.0%, NNT −112 (ns)
Olanzapine pamoate 405 mg q4 weeks, 4.0%, NNT 91 (ns)
|Olanzapine pamoate 45 mg q4 weeks, 4.2%|
Olanzapine pamoate 150 mg q2 weeks, 5.0%, NNT −125 (ns)
Olanzapine pamoate 300 mg q2 weeks, 2.8%, NNT 76 (ns)
Olanzapine pamoate 405 mg q4 weeks, 3.1%, NNT 98 (ns)
Olanzapine oral 10, 15 or 20 mg/day, 2.5%, NNT 60 (ns)
|Weight gain of at least 7% of baseline, NNT vs. placebo (or placebo equivalent) and 95% confidence interval||Placebo, 12.4%|
Olanzapine pamoate 210 mg q2 weeks, 23.6%, NNT 9 (5, 102)
Olanzapine pamoate 300 mg q2 weeks, 35.4%, NNT 5 (3, 9)
Olanzapine pamoate 405 mg q4 weeks, 27.0%, NNT 7 (4, 26)
|Olanzapine pamoate 45 mg q4 weeks, 8.3%|
Olanzapine pamoate 150 mg q2 weeks, 16.4%, NNT 13 (7, 205)
Olanzapine pamoate 300 mg q2 weeks, 20.7%, NNT 9 (5, 24)
Olanzapine pamoate 405 mg q4 weeks, 15.2%, NNT 15 (8, 130)
Olanzapine oral 10, 15 or 20 mg/day, 21.4%, NNT 8 (6, 15)
|Changes in plasma cholesterol||Significant group differences were observed for mean baseline-to-end-point changes in fasting total cholesterol (210 mg q2 weeks, 8.2 mg/dl; 300 mg q2 weeks, 5.5 mg/dl; 405 mg q4 weeks, 10.4 mg/dl vs. placebo, −7.0 mg/dl)||Increases in fasting total cholesterol and fasting LDL cholesterol were significantly greater for the therapeutic olanzapine pamoate doses relative to the 45 mg q4 weeks dose; No significant between group differences were observed for baseline-to-end-point changes in HDL cholesterol levels; Analyses of categorical changes in cholesterol at any time revealed no significant group differences|
|Changes in plasma triglycerides||Significant group differences were observed for mean baseline-to-end-point changes in fasting triglycerides (olanzapine pamoate 210 mg q2 weeks, 26.3 mg/dl; 405 mg q4 weeks, 30.3 mg/dl groups vs. placebo, −9.4 mg/dl); A significantly greater percentage of patients in the olanzapine pamoate 210 mg q2 weeks (12.8%) and 300 mg q2 weeks (14.3%) groups experienced changes in triglyceride levels from < 150 to 200–500 mg/dl vs. placebo (3.4%), with a NNT of 11 and 10 respectively||No significant between group differences were observed for baseline-to-end-point changes in fasting triglyceride levels; analyses of categorical changes in fasting triglycerides evidenced a greater proportion of patients shifting from < 150 mg/dl to high in the olanzapine pamoate 300 mg q2 weeks group (26%) relative to the 405 mg q4 weeks (9%), 150 mg q2 weeks (5%) and 45 mg q4-week (4%) groups (NNT of 6, 5 and 5 respectively)|
|Changes in plasma glucose||Mean baseline-to-end-point changes in fasting glucose did not differ significantly between treatment groups||No significant between group differences were observed for baseline-to-end-point changes in fasting glucose; analyses of categorical changes in fasting glucose at any time revealed no significant group differences|
|Extra-pyramidal adverse events||Extrapyramidal symptoms were low at baseline for all treatment groups, and none of the group differences in baseline-to-end-point changes on the Simpson-Angus or Barnes Akathisia scales or AIMS were clinically meaningful||Extrapyramidal symptoms were low at baseline and throughout the study for all treatment groups; no statistically significant differences were observed between treatment groups with respect to changes in on the Simpson-Angus or Barnes Akathisia scales or AIMS; no statistically significant differences in treatment-emergent extrapyramidal symptoms|
|Changes in plasma prolactin||Not reported||Increases in prolactin were significantly greater for the therapeutic olanzapine pamoate doses relative to the 45 mg q4 weeks dose; as dose increased, mean changes in prolactin were greater|
Sedation and increased appetite were significantly higher for the highest dose of olanzapine pamoate (300 mg q2 weeks) relative to placebo. Mean weight gain (3.2–4.8 kg vs. 0.3 kg) and incidence of weight gain at least 7% of baseline (23.6–35.4% vs. 12.4%) were significantly greater for olanzapine pamoate vs. placebo. In addition, significant differences between all olanzapine pamoate groups and placebo were observed regarding mean baseline-to-end-point changes in fasting total cholesterol (5.5–10.4 vs. −7.0 mg/dl). Significant differences for fasting triglycerides were observed between the 210 mg q2 weeks and 405 mg q4 weeks groups vs. placebo (26.3–30.3 vs. −9.4 mg/dl), but not the 300 mg q2 weeks group (17.6 mg/dl), vs. placebo.
Maintenance of antipsychotic response
A double-blind randomised clinical trial of olanzapine pamoate was conducted among stabilised patients with schizophrenia but has not yet been published in a peer-reviewed journal. The study has been disclosed in a number of other venues including documents available on the FDA website (28) and in poster presentations (18,24,26). In contrast to the 8-week acute study (12), this was a clinical trial to test the maintenance of effect of olanzapine pamoate compared with oral olanzapine over a 24-week period among outpatients with schizophrenia. It was not placebo-controlled and was conducted entirely outside of the USA. Out of 1205 enrolled subjects, 1065 were randomised to receive on a 2 : 1 : 1 : 1 : 2 ratio to five treatment groups: olanzapine pamoate 405 mg q4 weeks, 300 mg q2 weeks, 150 mg q2 weeks, 45 mg q4 weeks, or 10, 15 or 20 mg/day oral olanzapine (whichever oral dose they had been stabilised on prior to randomisation). The therapeutic doses of olanzapine pamoate 150 mg q2 weeks, 405 mg q4 weeks and 300 mg q2 weeks were selected to correspond to oral doses of 10, 15 and 20 mg/day respectively. A subtherapeutic dose of olanzapine pamoate (45 mg q4 weeks) was included to serve as a comparator for the superiority analysis for the therapeutic doses of olanzapine pamoate, and can be considered as a possible placebo-equivalent. As with the acute study described earlier, no supplementation with oral antipsychotic therapy was permitted after randomisation. Patients were eligible to be randomised provided they had maintained stability on open-label oral olanzapine (10, 15 or 20 mg/day) for 4–8 weeks. Mean PANSS total score at the time of randomisation was 56 and thus the patients tested were minimally symptomatic. There were two primary outcomes that were considered: superiority of the three therapeutic olanzapine pamoate doses vs. 45 mg q4 weeks in terms of time to exacerbation of symptoms, and non-inferiority of the pooled q2 week regimens of olanzapine pamoate 150 mg and 300 mg vs. oral olanzapine in terms of exacerbation rate over the 24 weeks of maintenance treatment. Exacerbation was defined as either the worsening of positive symptoms (conceptual disorganization, hallucinatory behaviour, suspiciousness, unusual thought content) since randomisation, or the need for hospitalisation due to worsening of positive psychotic symptoms. In the superiority analysis, each of the therapeutic olanzapine pamoate doses was statistically superior to the 45 mg q4 weeks dose with respect to time to exacerbation of symptoms. This finding was consistent with an analysis of visit-wise PANSS total scores, which showed that the three therapeutic doses of olanzapine pamoate were effective in maintaining a response for the 24-week duration of the study but that the 45 mg q4 weeks dose showed a statistically significant worsening of total PANSS scores. In the non-inferiority analysis, the pooled q2 week 150 mg and 300 mg olanzapine pamoate dosing regimen was non-inferior to the oral olanzapine treatment group in terms of the 24-week non-exacerbation rate (90% vs. 93% for depot and oral respectively). In addition, each of the therapeutic olanzapine pamoate doses demonstrated non-inferiority to oral olanzapine with respect to rates of exacerbation of symptoms. In an additional analysis, the olanzapine pamoate 405 mg q4 weeks group was non-inferior to the oral olanzapine and the pooled q2 weeks depot dosing groups. Categorical outcomes are described in Table 2. NNT for study completion for the therapeutic doses of olanzapine pamoate or oral olanzapine vs. olanzapine pamoate 45 mg q4 weeks ranged from four to nine. This was consistent with the NNT for being free of exacerbation at 24 weeks, which ranged from four to seven when comparing therapeutic doses of olanzapine pamoate or oral olanzapine vs. olanzapine pamoate 45 mg q4 weeks. As with the acute study, discontinuation rates because of adverse events were low for all groups.
In a poster presentation (26), pharmacokinetic and efficacy data for olanzapine pamoate were analysed to more precisely determine the dose correspondence relative to oral olanzapine, and to make suggestions on which doses of olanzapine pamoate should be used depending on the oral dose the patient was stabilised on. To accomplish this, periodic sampling of plasma olanzapine concentrations was performed in a subset of 346 patients who had participated in the 24-week maintenance of response study (18,24,26,28). Olanzapine pamoate doses of 150 mg q2 weeks, 405 mg q4 weeks and 300 mg q2 weeks produced 10th–90th percentile steady-state plasma concentrations (5–41, 8–51 and 7–73 ng/ml) similar to those for 10, 15 and 20 mg/day oral olanzapine (13–48, 21–63 and 21–85 ng/ml), with steady-state concentrations achieved after approximately 3 months of depot treatment. Moreover, patients stabilised on 10 mg/day oral olanzapine who were subsequently randomised to 405 mg q4 weeks of olanzapine pamoate showed approximately equal risk of relapse as those who remained on a 10 mg/day oral dose. Patients stabilised on 15 or 20 mg/day oral olanzapine who were randomised to 300 mg q2 weeks of olanzapine pamoate demonstrated lower or approximately equal risk of relapse relative to staying on oral olanzapine. The percentage of patients who experienced relapse by 24 weeks ranged from a low 1.5% (when switched from 10 mg/day oral olanzapine to 300 mg q2 weeks of olanzapine pamoate) to 18.8% (when switched from 20 mg/day oral olanzapine to 150 mg q2 weeks of olanzapine pamoate). In order to minimise the risk for exacerbation of psychosis, the authors recommended the following switching strategies: for patients stabilised on oral olanzapine 10 mg/day, the starting olanzapine pamoate dose should be 210 mg q2 weeks or 405 mg q4 weeks, and then if clinically indicated, patients can be evaluated 2 months later for a reduction to a maintenance dose of 150 mg q2 weeks or 300 mg q4 weeks; for patients stabilised on oral olanzapine 15 mg/day, the starting olanzapine pamoate dose should be 300 mg q2 weeks, and then if clinically indicated, patients can be evaluated 2 months later for a reduction to a maintenance dose of 210 mg q2 weeks or 405 mg q4 weeks; for patients stabilised on oral olanzapine 20 mg/day, the recommended starting and maintenance dose is 300 mg q2 weeks. These recommendations are also consistent with the data obtained from a 6-month multi-centre open-label study that examined dopamine D2 receptor occupancy of olanzapine in 14 patients with schizophrenia or schizoaffective disorder previously stabilised on oral olanzapine (mean 15 mg/day) and switched over to the pamoate depot formulation at a dose of 300 mg q4 weeks (13). Mean striatal D2 receptor occupancy, as measured by [11C] – raclopride positron emission tomography, was 69% on oral olanzapine (5–20 mg/day) and 50% (trough) on olanzapine pamoate at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections and olanzapine pamoate resulted in mean D2 receptor occupancy of approximately 60% or higher at the end of the 6-month study period. A significant correlation was observed between D2 receptor occupancy and plasma olanzapine concentrations. The authors suggested that supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles. On the other hand, the randomised double-blind clinical trials that tested the acute efficacy and maintenance of response of olanzapine pamoate did not allow for supplemental antipsychotic medication, and yet demonstrated favourable efficacy outcomes.
In a poster presentation, the data from the 24-week study (18,24,26,28) was used to characterise the metabolic changes observed with therapeutic doses of olanzapine pamoate (150 mg q2 weeks, 300 mg q2 weeks, 405 mg q4 weeks; n = 599) vs. the oral formulation (n = 322) (24). Mean and categorical changes in metabolic measures [weight, body mass index (BMI), fasting glucose and fasting lipids] were assessed from the time of randomisation. Mean changes in weight, glucose and most lipids were not significantly different between treatment groups. Weight changes over time followed similar patterns and were not significantly different at end-point between patients treated with depot vs. oral olanzapine (+1.0 kg vs. +1.3 kg respectively). Among patients who were obese (BMI ≥ 30 kg/m2) at baseline, only those receiving oral treatment showed significantly increased mean weight (+1.7 kg vs. −0.3 kg). This is inconsistent with the observation that low-density lipoprotein (LDL) cholesterol decreased significantly less among patients receiving olanzapine pamoate vs. oral olanzapine (−1.5 mg/dl vs. −6.4 mg/dl). No significant difference was seen between treatment groups for weight increase reported as an adverse event, and the incidence rates of diabetes- or dyslipidaemia-related adverse events were low in both groups and not significantly different between treatment groups. NNT (none statistically significant) for potentially clinically significant disadvantages for oral olanzapine vs. the depot formulation was 22 for weight gain of ≥ 7% from baseline, 111 for fasting glucose ≥ 126 mg/dl following a baseline of < 100 mg/dl, 59 for fasting triglycerides ≥ 200 mg/dl following a baseline of < 150 mg/dl, 250 for total fasting cholesterol ≥ 240 mg/dl following a baseline of < 200 mg/dl, ∞ for fasting LDL ≥ 160 mg/dl following a baseline of < 100 mg/dl and 17 for fasting high-density lipoprotein (HDL) < 40 mg/dl following a baseline of ≥ 40 mg/dl.
Long-term safety data are available from 931 patients enrolled in an ongoing open-label study of olanzapine pamoate (15,21,28) designed for subjects who had completed a prior randomised controlled olanzapine pamoate clinical trial. During this extension study, all patients receive flexibly dosed olanzapine pamoate at injection intervals of approximately 2–4 weeks. Interim results (160 weeks) as presented in a poster in July 2008 (21) reported a study discontinuation of 39.6%, with the most common reasons being withdrawal of consent (20.1%), adverse event (6.3%) and lost to follow-up (5.6%). Adverse events observed in ≥ 5% of patients were increased weight, insomnia, somnolence, anxiety, headache and nasopharyngitis. Mean weight change was +1.4 kg, with 28.1% of patients experiencing ≥ 7% weight gain. The percentage of patients with a fasting glucose increase from baseline < 100 mg/dl to ≥ 126 mg/dl at any time was 4.7%. Percentage of patients with a random total cholesterol increase from baseline < 200 mg/dl to ≥ 200 mg/dl and < 240 mg/dl at any time was 29.6%. Percentage of patients with a random total cholesterol increase from baseline < 200 mg/dl to ≥ 240 mg/dl at any time was 5.2%. Percentage of patients with a random LDL cholesterol increase from baseline < 100 mg/dl to ≥ 100 mg/dl and < 160 mg/dl at any time was 47.7%. Percentage of patients with a random LDL cholesterol increase from baseline < 100 mg/dl to ≥ 160 mg/dl at any time was 3.1%. Percentage of patients with a random HDL cholesterol decrease from baseline ≥ 40 mg/dl to < 40 mg/dl at any time was 23.1%. Percentage of patients with a random triglycerides increase from baseline < 150 mg/dl to ≥150 mg/dl and < 200 mg/dl at any time was 19.5%. Percentage of patients with a random triglycerides increase from baseline < 150 mg/dl to ≥200 mg/dl at any time was 11.9%. Percentage of patients with a random triglycerides increase from baseline < 150 mg/dl to ≥500 mg/dl at any time was 0.4%.
Patients receiving olanzapine pamoate on an open-label basis at one study site were the subjects of a single-authored poster (20). Described were 12 consecutive patients who were started on olanzapine pamoate 300 mg q2 weeks and followed for 3 years. In two of the patients, the dose was reduced to 405 mg q4 weeks. Clinically significant improvements in psychopathology were described. Although a substantial percentage of patients gained weight in excess of 7% of baseline (42% at 3 years), a similar number lost weight in excess of 7% of baseline (also 42% at 3 years). It was not reported whether or not any weight management plan was implemented for any of the patients who had lost weight.
During the clinical trials of olanzapine pamoate, a small number of adverse events termed postinjection delirium sedation syndrome (PDSS) was observed in about 1% of patients and appeared related to potential intravascular injection of a portion of the dose (25,28). These events led to the initial issuance of a not approvable letter from the FDA for olanzapine pamoate (33). Although at the conclusion of the FDAs Psychopharmacologic Drugs Advisory Committee hearing on 6 February 2008, the committee voted that there were circumstances under which olanzapine pamoate would be acceptably safe and effective for the treatment of acutely exacerbated schizophrenia and maintenance treatment of schizophrenia in adults, additional information was made available of a case of excessive sedation that began between 3 and 5 h after injection whereas all previous excessive sedation events had begun within 3 h of injection (33).
In a review presented as a poster (25), safety data from completed and ongoing trials of olanzapine pamoate were pooled in order to examine injection site reactions in all patients assigned to olanzapine pamoate (eight studies, n = 2058) and in a single study comparing olanzapine pamaote (n = 306) to placebo injection (n = 98). The incidence of any injection site reaction was 8.0% in all olanzapine pamoate patients. In the placebo-controlled study, the incidence was 3.6% for olanzapine pamoate vs. 0.0% for placebo (NNT 28). As of 31 May 2008, the incidence of PDSS with olanzapine pamoate was 29 events in 28 patients, per > 40,000 injections, for a rate of 0.07% of injections. The 28 patients with PDSS presented with symptoms consistent with olanzapine overdose, including sedation, dizziness, confusion, slurred speech, altered gait, weakness or unconsciousness. Time to onset postinjection ranged from 0 to 300 min (mean 48 min, median 25 min). Approximately 80% of the PDSS events occurred within 1 h of injection; however, 17% of the PDSS events occurred between 1 and 3 h, and 3% (one case) occurred after 3 h. Time to incapacitation postinjection ranged from 10 to 300 min (mean 78 min, median 60 min). Although the majority of events were classified as being mild in severity, progression can occur. PDSS typically begins with milder symptoms, which can then progress in severity and/or number. Early symptoms may not necessarily include delirium or sedation but may begin with feelings of weakness, dizziness, irritability or general malaise before progressing to delirium and/or sedation. Of note, PDSS can occur at any injection as it was observed anywhere from the first injection to the 66th injection. There were no clinically significant decreases in vital sign measures during any of the PDSS occurrences, including orthostatic hypotension, arrhythmias or cardiorespiratory depression; two patients had clinically significantly increased blood pressure, which responded to antihypertensive medication. No relationship between PDSS and concomitant medications or other substances was noted. Seventy-nine per cent of patients were hospitalised during the PDSS occurrence and treatment ranged from observation only to supportive medical care, including two cases of prophylactic ventilation. All patients fully recovered with time of full recovery ranging from 1.5 to 72 h. Approximately, 70% of patients continued to receive injections after the event.
The explanation of why PDSS sometimes occurs is likely related to the higher solubility of olanzapine pamoate in blood than in muscle. It is thought that increased contact with a substantial volume of blood can occur by partial injection into vasculature and vessel injury associated with the intramuscular injection such as with a nick or puncture of the blood vessel, or substantial bleeding at the injection site. This results in a rapid release of a portion of the olanzapine pamoate dose and is consistent with the observed higher than expected systemic olanzapine concentrations in patients with a PDSS event. The potential risk for PDSS appears to exist for each injection regardless of how many prior uneventful injections the patient may have had.
In the typical use of olanzapine pamoate, a momentary spike in olanzapine release probably does not occur. This was assessed in a specific pharmacokinetic investigation undertaken as an addendum to a long-term, open-label safety and effectiveness study in patients with schizophrenia or schizoaffective disorder who have previously completed an olanzapine pamoate clinical trial (15,28). In 10 patients, a series of blood samples was collected immediately before and then at 5, 10, 15, 30 and 45 min, and at 1, 2, 4, 6 and 8 h after a 300 mg injection of olanzapine pamoate. Olanzapine concentration after the injection remained essentially unchanged compared with the pre-injection concentration.
Special precautions, including proper injection technique and a postinjection observation period, are recommended (25). Injection technique recommendations include the aspiration of the syringe for about 5 s to ensure that no blood is visible, and to not proceed with injection if blood is visible. In these circumstances, the syringe is discarded, a new vial reconstituted and injection placed into the alternate buttock, deep into the gluteal muscle at a ventrogluteal site in order to decrease the risk of accessing a major nerve or blood vessel. Additional risk management recommendations include that after each injection, clinicians observe the patient for at least 3 h at a healthcare facility for symptoms of PDSS, that patients have someone accompany them to their destination following the observation period, and that for the remainder of day of the injection, patients not drive or operate machinery, and should be advised to be vigilant for symptoms of postinjection adverse reactions and be able to obtain assistance if needed (25).
Comparisons with other depot formulations
There are no studies currently available that directly compare olanzapine pamoate with other depot antipsychotics. However, an attempt was made to compare olanzapine pamoate and risperidone microspheres by examining treatment completion rates in single-arm open label studies, with the assumption that treatment completion rates are a proxy measure of treatment effectiveness (27). In one comparison that included populations with similar baseline treatment and patient characteristics, 12-month completion rates for olanzapine pamoate and risperidone microspheres were 81.5% and 47.0%, respectively (NNT 3). In the second comparison, which included all available patients, 12-month completion rates were 72.9% and 59.1%, respectively (NNT 8). No individual risperidone microsphere study had a 12-month completion rate greater than that seen for olanzapine pamoate. However, the differing study designs and populations tested may explain these results. A controlled study directly comparing these two depot medications would be desirable.
Is olanzapine pamoate worth using?
Long-acting injectable depot preparations of antipsychotics offer a guaranteed delivery system that eliminates the possibility of covert non-adherence, such as ‘cheeking’ (i.e. surreptitiously not swallowing the medication and then spitting it out). By not coming to the clinic for the next injection, non-adherence becomes readily identifiable and further outreach can be expeditiously done. By providing a steady amount of a therapeutic dose of an antipsychotic, maintenance of response is enhanced and relapse can be prevented or delayed.
Olanzapine pamoate was demonstrated to be efficacious in acutely ill patients (12), with separation from placebo on measures of psychopathology as early as 3 days without the use of supplemental oral antipsychotic medication. Olanzapine pamoate was also efficacious in the maintenance of antipsychotic response. It can be administered at 2 or 4 week dosing intervals, and does not need to be refrigerated.
Olanzapine pamoate shares the same safety profile as oral olanzapine. This includes both favourable aspects (low potential for extrapyramidal effects) and an unfavourable metabolic profile (high potential for weight gain, lipid abnormalities and insulin resistance) (11,34). Monitoring for metabolic issues is still required.
Additional risks of olanzapine pamoate include injection site adverse events. The majority of patients who experienced an injection site-related adverse event reported it to be mild and the incidence is similar to that seen with haloperidol decanoate (28). However of greater concern is the possibility of PDSS. The greatest potential risk is that a patient might experience this event in an unsafe situation such as while driving a car or operating machinery. Thus, a risk management plan is mandatory in order to reduce this chance for harm, as described earlier. The requirement for supervision by clinical personnel may restrict the usage of olanzapine pamoate to persons attending clinics, day hospitals, partial hospitalization programmes or who are inpatients.
When weighing both benefits and risks, olanzapine pamoate may be best for patients who have a clear history of response to olanzapine and for whom a depot may enhance their ability to remain adherent. For patients who have not received olanzapine, it would be prudent to assess antipsychotic response with the oral formulation first.
A limitation to the currently available data is that with one exception (12), none of the controlled efficacy studies have been published in a peer-reviewed journal. Although the general efficacy and tolerability profile of olanzapine pamoate and oral olanzapine are the same, there is no controlled data directly comparing olanzapine pamoate with oral antipsychotics other than olanzapine. Moreover, in the absence of controlled studies comparing olanzapine pamoate to other available depot preparations, it is unknown if olanzapine pamoate has any advantages in the prevention of exacerbation, relapse and/or hospitalizations over risperidone microspheres or first-generation antipsychotic depot preparations.
The availability of generic olanzapine in several countries is spurring the development of alternative depot preparations of olanzapine, including a microsphere formulation (14). Whether these will ever be commercialised is unknown.
Treatment with olanzapine pamoate 210 mg q2 weeks, 405 mg q4 weeks and 300 mg q2 weeks appears efficacious in acutely ill patients with schizophrenia, without oral antipsychotic supplementation, with separation from placebo on measures of psychopathology occurring as early as 3 days for the higher doses. Olanzapine pamoate was also demonstrated to be efficacious in the maintenance of response with either the q2 weeks or q4 weeks dosing options, without the need for additional oral antipsychotic medication. The general safety profile for olanzapine pamoate is similar to that for oral olanzapine with comparable rates for extra-pyramidal side effects (low) and weight gain and metabolic effects (high). However, there is a small additional risk of a PDSS occurring at a rate of 0.07% of injections or 1.4% of patients. This syndrome resembles that for an overdose with oral olanzapine and requires a risk management plan that includes supervision of the patient by health care personnel for 3 h postinjection. Olanzapine pamoate appears to be an option to consider for a patient who has a history of response to olanzapine but for whom adherence has been difficult.