Long-acting injectable antipsychotics: focus on olanzapine pamoateMedication zyprexa decanoate in patients with schizophrenia continues to be a significant problem and threatens successful treatment outcomes. Medication non-adherence is often associated with negative consequences, including symptom exacerbation, more frequent emergency room visits, re-hospitalizations and relapse. Long-acting injectable LAI forms of antipsychotics allow for rapid zyprexa decanoate of non-adherence, obviate the need for the patient to take the medication on a daily basis and increase adherence to some zyprexa decanoate degree. Eli Lilly has developed a long-acting depot formulation of olanzapine, olanzapine pamoate, which crazy bulk black friday deals recently been approved by the FDA for the US market, and which will be reviewed here. Olanzapine Zyprexa decanoate appears to be an effective antipsychotic at dosages of mg every 2 weeks, mg every 2 weeks and mg every 4 weeks in patients with acute schizophrenia, and at mg every 2 weeks, mg every 2 weeks and at mg every 4 weeks for the maintenance treatment of stable patients.
Long-acting injectable antipsychotics: focus on olanzapine pamoate
Medication non-adherence in patients with schizophrenia continues to be a significant problem and threatens successful treatment outcomes. Medication non-adherence is often associated with negative consequences, including symptom exacerbation, more frequent emergency room visits, re-hospitalizations and relapse. Long-acting injectable LAI forms of antipsychotics allow for rapid identification of non-adherence, obviate the need for the patient to take the medication on a daily basis and increase adherence to some significant degree.
Eli Lilly has developed a long-acting depot formulation of olanzapine, olanzapine pamoate, which has recently been approved by the FDA for the US market, and which will be reviewed here. Olanzapine LAI appears to be an effective antipsychotic at dosages of mg every 2 weeks, mg every 2 weeks and mg every 4 weeks in patients with acute schizophrenia, and at mg every 2 weeks, mg every 2 weeks and at mg every 4 weeks for the maintenance treatment of stable patients.
Oral supplementation appears not to be needed, particularly not at the onset of treatment with the LAI as is necessary with risperidone LAI. Its efficacy is in general comparable to the efficacy seen with oral olanzapine at a corresponding dose. The side effect profile is also comparable to the side effects observed with oral olanzapine, including lower rates of extrapyramidal symptoms, prolactin elevation and cardiovascular side effects, but significant metabolic effects.
The latter include significant weight gain, lipid abnormalities and glucose dysregulation. While the injection site adverse events are overall mild, the most significant serious adverse event is the post-injection delirium sedation syndrome PDSS. While rare, this syndrome results from inadvertent intravascular injection of olanzapine LAI and can cause a range of olanzapine overdose-type of symptoms.
Olanzapine LAI needs therefore to be administered by trained personnel in settings where a post-injection observation period for at least 3 hours by medical personnel is available. Patients who have a history of good response to oral olanzapine and are in need of assured medication administration may present a good indication for its use, provided that the appropriate mental health delivery setting is available.
Hence, treatments that can increase medication adherence are critically important in the pharmacological treatment of schizophrenia. Long-acting injectable LAI forms of antipsychotics fulfill an important role in this domain of treatment. LAI antipsychotics allow for rapid identification of non-adherence, obviate the need for the patient to take the medication every day and increase adherence to some significant degree.
Both typical antipsychotics fluphenazine and haloperidol decanoate and 2 atypicals risperidone LAI and paliperidone palmitate are available in the US as LAI formulations. Clinicians need a wider range of long-acting depot compounds to choose from within the atypical range of antipsychotics as, at present, only 1 atypical is available as a LAI antipsychotic.
We will review in the following sections its pharmacology and mode of action, its efficacy and safety profile and its place among the present second-generation LAI formulations. The terms olanzapine pamoate and olanzapine long-acting injectable were systematically searched for on pubmed as well as on www.
In addition, the FDA website http: Finally, the Eli Lilly website was reviewed for any additional reported data on olanzapine pamoate. The following meetings were reviewed for reports on olanzapine LAI: Four peer reviewed studies were found on olanzapine pamoate, 5 — 8 4 entries on www.
Olanzapine LAI is the salt of pamoic acid and olanzapine that is suspended in an aqueous solution and is injected into the gluteal muscle. The rate of dissolution of the salt is slow, allowing for a gradual release of olanzapine into the circulation over 2 to 4 weeks.
Long-chain esters show high oil solubility and low water solubility. Long-acting injectable formulations of these drugs contain long-chain drug esters eg, decanoate dissolved in a vegetable oil. When injected intramuscularly, the oil forms a depot of drug: Modification of release characteristics is brought about by other means: The optimal time to peak concentration should be short to minimize the need for bridging with oral antipsychotic. The absorption is slow and only reaches peak plasma levels after 2 weeks and requires therefore a transition with oral risperidone for 2 weeks initially.
The absorption of paliperidone LAI is based on the palmitate ester of paliperidone, which is an aqueous suspension utilizing nanocrystal molecules. This formulation increases its surface area and leads to initial rapid medication release and in a short time to steady state. Active paliperidone plasma levels are detected systemically at day one. The slow rate of dissolution of paliperidone palmitate results in a longer half-life that ranges from 25 to 49 days, allowing a once-monthly intramuscular injection schedule.
The first-generation anti-psychotics haloperidol and prolixin use ester formations with a decanoate, which dissolve slowly over time. The doses of olanzapine LAI were chosen based on pharmacokinetic and safety results of phase I studies. Olanzapine plasma concentrations increased 2- to 3-fold with multiple dosing reaching eventually steady state after about 3 months of dosing.
Olanzapine plasma concentrations were sustained throughout the 2- and 4-week injection intervals. Maximum olanzapine plasma concentrations and area under the concentration vs time curve were proportionate to the LAI dose.
Time to peak concentration after the injection was 4 days with a half-life of approximatively 26 days. This is an important pharmacokinetic feature as the time to onset of action after an injection is an important criterion for the clinician.
The distribution of olanzapine plasma concentration after olanzapine LAI doses of mg every 2 weeks, mg every 2 weeks and mg every 4 weeks were within the 10th and 90th percentiles of the range of olanzapine plasma concentrations found with the olanzapine oral formulation dosed at 5 mg once daily 10th percentile and 20 mg once daily 90th percentile.
Going from oral to olanzapine LAI, Gulliver et al 19 recommend the following conversion strategies: The patient can then be reduced after 2 months to a lower maintenance dose of mg every 2 weeks or mg every 4 weeks.
For patients stabilized on 15 mg of oral olanzapine the starting olanzapine LAI dose should be mg every 2 weeks, which after 2 months can be reduced to mg or mg every 4 weeks.
For patients stabilized on 20 mg of oral olanzapine the starting dose of olanzapine LAI should be mg every 2 weeks and should remain at that level, if clinically indicated.
The olanzapine pamoate salt dissolves much more rapidly when it is in contact with a larger amount of blood or plasma, resulting in the release of a large amount of olanzapine over a shorter period of time. Therefore, if olanzapine LAI is accidentally injected into vascular or capillary rich tissue, this property can result in very high olanzapine plasma levels rapidly after the injection with significant clinical acute morbidity. It has been observed in clinical trials and will be reviewed below.
Mamo et al 6 reported results on a study examining D 2 receptor occupancy of olanzapine LAI during a multicenter, open-label study exploring D 2 receptor occupancy of a fixed dose of olanzapine LAI given every 4 weeks. Patients with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to olanzapine LAI mg by intramuscular injection every 4 weeks for 6 months.
No within-group significant changes were found in scores of the Brief Psychiatric Rating Scale Total or in the Clinical Global Impressions-Severity of Illness score, although 7 patients received oral olanzapine supplementation during the first four injection cycles.
To minimize impact on D 2 occupancy by the supplemental oral olanzapine, positron emission tomography PET scans were not completed during injection cycles that required supplemental oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles. One large, double-blind, placebo controlled, 8-week study of olanzapine LAI in inpatients with acute schizophrenia patients compared mg every 2 weeks, mg every 2 weeks, mg every 4 weeks and placebo in a 1: The two higher doses separated from placebo on the PANSS at day 3, while all three doses separated at day 7 from placebo.
The mean daily benzodiazepine dose used during the trial was not statistically significantly different in the four treatment groups. There were no in-between group differences in the incidence of use of anticholinergics between the four groups; 8.
Sedation and increased appetite were more frequently reported for the mg group than for the placebo group. The three olanzapine groups showed a significantly higher change in mean weight gain compared to placebo 3. Few injection site reactions were reported and no patient dropped out of the study because of injection site reaction.
In a more recent post-hoc comparison of these study results with a corresponding set of three studies of oral olanzapine, haloperidol and placebo in similarly acutely ill patients, olanzapine LAI was found to show a comparable magnitude of symptom reduction compared to patients treated with a dose range of 2.
It appeared that the incidence of parkinsonism was slightly lower for olanzapine LAI with 2. Olanzapine LAI was compared to oral olanzapine for the maintenance of antipsychotic response in stable outpatients with schizophrenia in a week double-blind study. The oral olanzapine group assignment was constrained by whichever oral dose patients had been stabilized on before entering the trial for 4 to 8 weeks.
Each of the olanzapine LAI doses was statistically superior to the olanzapine LAI 45 mg every 4 weeks dose group based on time to exacerbation. Conversely, the three active olanzapine LAI groups mg; mg; mg showed non-inferiority as compared to the oral olanzapine groups in terms of exacerbation of symptoms.
Treatment related adverse events leading to discontinuation were overall low and comparable over the four olanzapine LAI groups 3. Clinically significant weight gain from baseline to endpoint was approximatively dose related: There were significant increases in total cholesterol and fasting LDL cholesterol in the three active olanzapine LAI groups over the low dose group of 45 mg every 4 weeks, while no significant in-between group differences in change were seen in fasting triglyceride and glucose levels.
No significant differences in treatment emergent extrapyramidal symptoms were reported between any of the olanzapine LAI dose groups and the overall rate of extrapyramidal symptoms was low throughout the trial.
Incidence of injection site reactions was low 2. Interim results from another long-term, open-label safety extension study of olanzapine LAI with maximum treatment duration of weeks were recently reported. During the open-label extension, all patients received flexibly-dosed olanzapine LAI at injection intervals of approximately 2 to 4 weeks.
At the time of the report, the rate of study discontinuation was Discontinuation rate at 18 months was The most common reasons for discontinuation were: Of note were 26 occurrences of PDSS following possible accidental intravascular injection of a portion of the dose; all of the patients fully recovered within 72 hours.
Percentages of patients who showed an increase from normal to high on fasting glucose, random total cholesterol, or random triglycerides were 5. Mean CGI-S scores remained stable throughout the open label follow-up of the three studies 2.
Two switching strategies from oral antipsychotics to olanzapine LAI were compared in a recent report: Investigators, at their discretion, could either directly switch patients or taper their previous antipsychotic medication during the first 2 weeks of treatment. At the time of study entry, 62 patients were receiving typical antipsychotics, were receiving atypical antipsychotics 76 receiving oral olanzapine , and 34 were not receiving any antipsychotic; a total of 16 were on prior injectable antipsychotic medication.
Some patients were taking more than one antipsychotic at baseline. Of a total of patients, The two groups did not significantly differ in discontinuation rates direct: There did not appear to be clinically significant differences for those who were directly switched to olanzapine LAI versus those who were tapered.
The signs and symptoms include feelings of tiredness, dizziness and fatigue progressing to delirium and or excessive sedation and are probably related to an inadvertent intravascular injection of part or the entire olanzapine LAI dose. In a poster by the manufacturer, all safety data of all completed or ongoing olanzapine LAI trials were pooled up to data lock up to May 31 Two patients experienced significant blood pressure increases, but no other changes in vitals signs were observed.
Time to onset varied between 0 to minutes with a mean of 48 minutes. Pharmacokinetic data collected at the time of the event revealed that olanzapine plasma concentrations were much higher than expected relative to the post injection concentration previously collected for the same patients. There was no relationship of the PDSS event and any concomitant medications.
All patients recovered completely after 3 to 72 hours. PDSS occurred at any injection time point as it was observed from the first injection to the 66th injection.
It is interesting to note that PDSS like events have not been reported with other long-acting depot antipsychotics. The pathophysiology of the PDSS is most likely related to the observation that the olanzapine pamoate salt dissolves much more rapidly when it is in contact with a larger amount of blood or plasma, releasing therefore a large amount of olanzapine over a short period of time.