Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines. ATC code: N05A H03.
Pharmacology: Pharmacodynamics: 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 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 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 5HT2 than dopamine D2 receptors and greater 5HT2 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 single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.
Clinical efficacy: In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.
In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p = 0.001) favoring olanzapine (-6.0) versus haloperidol (-3.1).
In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.
In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.
In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055).
In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.
Paediatric population: Zyprexa: Coated tablet: Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see Precautions and Adverse Reactions) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see Precautions and Adverse Reactions). Information on long term safety is primarily limited to open-label, uncontrolled data.
Pharmacokinetics: In a pharmacokinetic study in healthy volunteers, a dose of 5 mg of ZYPREXA powder for solution for injection produced a maximum plasma concentration (Cmax) approximately 5 times higher than that seen with the same dose of olanzapine administered orally. The Cmax occurs earlier after intramuscular compared to oral use (15 to 45 minutes versus 5 to 8 hours). As with oral use, Cmax and area under the curve after intramuscular use are directly proportional to the dose administered. For the same dose of olanzapine administered intramuscularly and orally, the associated area under the curve, half-life, clearance and volume of distribution are similar. The metabolic profiles following intramuscular and oral use are similar.
In non-smoking versus smoking subjects (males and females) administered olanzapine intramuscularly the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 L/hr).
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets.
Absorption: Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to IV administration has not been determined.
Distribution: The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1,000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.
Biotransformation: Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. 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.
Elimination: After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.
In healthy elderly (65 and over) versus non-elderly subjects administered oral olanzapine, the mean elimination half-life was prolonged (51.8 versus 33.8 hr) 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.
In female versus male subjects administered oral olanzapine, the mean elimination half-life was somewhat prolonged (36.7 versus 32.3 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).
Renal impairment: In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects administered oral olanzapine, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabeled olanzapine appeared in urine, principally as metabolites.
Hepatic impairment: A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of orally administered olanzapine (2.5 - 7.5 mg single dose): Subjects with mild to moderate hepatic dysfunction had slightly increased systemic clearance and faster elimination half-time compared to subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis (4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %).
Smokers: In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18 L/hr) was reduced analogous to nonsmoking healthy subjects (48.8 hrs and 14.1 L/hr, respectively).
In non-smoking versus smoking subjects (males and females) the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 l/hr).
The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.
In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the 3 populations.
Paediatric population: Zyprexa: Coated tablet: Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 % higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.
Toxicology: Preclinical safety data: Acute (single-dose) toxicity: Signs of oral toxicity in rodents were characteristic of potent neuroleptic/antipsychotic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.
Repeated-dose toxicity: In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.
Haematologic toxicity: Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicity: Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Oestrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in fetal development and transient decreases in offspring activity levels were seen.
Mutagenicity: Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and oral in vivo mammalian tests.
Carcinogenicity: Based on the results of oral studies in mice and rats, it was concluded that olanzapine is not carcinogenic.