Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties


Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines thiazepines and oxepines, ATC code N05A_H03.

Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100 nM) for serotonin 5-HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; -1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5-HT2 than dopamine D2 receptors and greater 5- HT2 than D2 activity in vivo, models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an “anxiolytic” test.


In a Positron Emission Tomography (PET) study in patients treated with ZYPADHERA (300 mg/4 weeks), mean D2 receptor occupancy was 60% or higher at the end of a 6 month period, a level consistent with that found during treatment with oral olanzapine.

Clinical efficacy
The effectiveness of ZYPADHERA in the treatment and maintenance treatment of schizophrenia is consistent with the established effectiveness of the oral formulation of olanzapine.


A total of 1469 patients with schizophrenia were included in 2 pivotal trials: The first, an 8-week, placebo controlled trial conducted in adult patients (n=404) who were experiencing acute psychotic symptoms. Patients were randomized to receive injections of ZYPADHERA 405 mg every 4 weeks, 300 mg every 2 weeks, 210 mg every 2 weeks, or placebo every 2 weeks. No oral antipsychotic supplementation was allowed. Total Positive and Negative Symptom Scores (PANSS) showed significant improvement from baseline (baseline mean Total PANSS Score 101) to endpoint (mean changes -22.57, -26.32, -22.49, respectively) with each dose of ZYPADHERA (405 mg every 4 weeks, 300 mg every 2 weeks, and 210 mg every 2 weeks) as compared to placebo (mean change -8.51). Visitwise mean change from baseline to endpoint in PANSS Total score indicated that by Day 3, patients in the 300 mg/2 weeks and 405 mg/4 weeks treatment groups had statistically significantly greater reductions in PANSS Total score compared to placebo (-8.6, -8.2, and -5.2, respectively). All 3 ZYPADHERA treatment groups showed statistically significantly greater improvement than placebo beginning by end of Week 1. These results support efficacy for ZYPADHERA over 8 weeks of treatment and a drug effect that was observed as early as 1 week after starting treatment with ZYPADHERA.

The second, a long term study in clinically stable patients (n=1065) (baseline mean Total PANSS Score 54.33 to 57.75) who were initially treated with oral olanzapine for 4 to 8 weeks and then switched to continue on oral olanzapine or to ZYPADHERA for 24 weeks. No oral antipsychotic supplementation was allowed. ZYPADHERA treatment groups of 150 mg and 300 mg given every 2 weeks (doses pooled for analysis) and 405 mg given every 4 weeks were non inferior to the combined doses of 10, 15 and 20 mg of oral olanzapine (doses pooled for analysis) as measured by rates of exacerbation of symptoms of schizophrenia (respective exacerbation rates, 10%, 10% 7%).
Exacerbation was measured by worsening of items on the PANSS derived BPRS Positive scale and hospitalization due to worsening of positive psychotic symptoms. The combined 150 mg and 

300 mg/2 week treatment group was non inferior to the 405 mg/4 week treatment group (exacerbation rates 10% for each group) at 24 weeks after randomisation.

Paediatric population
ZYPADHERA has not been studied in the paediatric population. Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term oral olanzapine studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Oral olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with oral olanzapine, adolescents gained significantly more weight compared with adults.
The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine.

After a single IM injection with ZYPADHERA the slow dissolution of the olanzapine pamoate salt in muscle tissue begins immediately and provides a slow continuous release of olanzapine for more than four weeks. The release becomes diminishingly smaller within eight to twelve weeks. Antipsychotic supplementation is not required at the initiation of ZYPADHERA treatment (see section 4.2).

The combination of the release profile and the dosage regimen (IM injection every two or four weeks) result in sustained olanzapine plasma concentrations. Plasma concentrations remain measurable for several months after each ZYPADHERA injection. The half-life of olanzapine after ZYPADHERA is 30 days compared to 30 hours following oral administration. The absorption and elimination are complete approximately six to eight months after the last injection.

Distribution
Oral olanzapine is rapidly distributed. The plasma protein binding of olanzapine is about 93% over the concentration range of 7 to about 1000 ng/mL. In plasma, olanzapine is bound to albumin and α1-acid glycoprotein.

After repeated IM injections with 150 to 300 mg ZYPADHERA every two weeks, the 10th to 90th percentile of steady-state plasma concentrations of olanzapine were between 4.2 and 73.2 ng/ml. The plasma concentrations of olanzapine observed across the dose range of 150 mg every 4 weeks to 300 mg every 2 weeks illustrate increased systemic olanzapine exposure with increased ZYPADHERA doses. During the initial three months of treatment with ZYPADHERA, accumulation of olanzapine was observed but there was no additional accumulation during long-term use (12 months) in patients who were injected with up to 300 mg every two weeks.

Elimination
Olanzapine plasma clearance after oral olanzapine is lower in females (18.9 l/hr) versus males (27.3 l/hr), and in non-smokers (18.6 l/hr) versus smokers (27.7 l/hr). Similar pharmacokinetic differences between males and females and smokers and nonsmokers were observed in ZYPADHERA clinical trials. However, the magnitude of the impact of gender, or smoking on olanzapine clearance is small in comparison to the overall variability between individuals.

Elderly

No specific investigations have been conducted in the elderly with ZYPADHERA. ZYPADHERA is not recommended for treatment in the elderly population (65 years and over) unless a well-tolerated and effective dosage regimen using oral olanzapine has been established. In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hours) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.

Renal impairment
In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hours) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites. Although patients with renal impairment were not studied with ZYPADHERA, it is recommended that a well-tolerated and effective dosage regimen using oral olanzapine is established in patients with renal impairment before treatment with ZYPADHERA is initiated (see section 4.2).

Smokers
In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hours) of orally administered olanzapine was prolonged and clearance (18.0 l/hr) was reduced analogous to non- smoking healthy subjects (48.8 hours and 14.1 l/hr, respectively). Although patients with hepatic impairment were not studied with ZYPADHERA, it is recommended that a well-tolerated and effective dosage regimen using oral olanzapine is established in patients with hepatic impairment before treatment with ZYPADHERA is initiated (see section 4.2).

In a study of oral olanzapine given to Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.