Pharmacology: Pharmacodynamics: Mechanism of Action: Quetiapine fumarate immediate-release, a dibenzothiazepine derivative, is an antipsychotic agent. Quetiapine and the active plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. The extent to which the norquetiapine metabolite contributes to the pharmacological activity of quetiapine is not known.
Quetiapine: Quetiapine exhibits affinity for brain serotonin 5HT2 and 5HT1A receptors (in vitro, Ki = 288 and 557 nM, respectively), and dopamine D1 and D2 receptors (in vitro, Ki = 558 and 531 nM, respectively). It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2 receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal symptoms (EPS) liability of quetiapine compared to typical antipsychotics. Quetiapine also has high affinity for histamine H1 receptors (in vitro, Ki = 10 nM) and adrenergic α1 receptors (in vitro, Ki = 13 nM), with a lower affinity for adrenergic α2 receptors (in vitro, Ki = 782 nM), but no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors and at the norepinephrine reuptake transporter (NET).
Norquetiapine: Norquetiapine, similar to quetiapine, exhibits affinity for brain serotonin 5HT2 and 5HT1A receptors (in vitro, Ki = 2.9 nM and 191 nM, respectively), and dopamine D1 and D2 receptors (in vitro, Ki = 42 nM and 191 nM respectively). Additionally, like quetiapine, norquetiapine also has high affinity at histaminergic and adrenergic α1 receptors, with a lower affinity at adrenergic α2 receptors. Contrary to quetiapine, norquetiapine exhibits high affinity for NET and has moderate to high affinity for several muscarinic receptor subtypes. This contributes to adverse drug reactions reflecting anticholinergic effects when quetiapine is used at therapeutic doses, when used concomitantly with other medications that possess anticholinergic effects, and in the setting of overdose (see Neurologic: Anticholinergic (Muscarinic) Effects under Precautions).
Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to the therapeutic efficacy of quetiapine as an antidepressant; however, the clinical relevance of these interactions has not been established. Although affinity at 5HT2B has been observed for norquetiapine, norquetiapine is found to be an antagonist and not an agonist at the receptor.
Clinical Trials: Comparative Bioavailability Studies: A single center, randomized, single dose blinded, 2-period, 2-sequence crossover comparative bioavailability study was performed in 25 healthy male volunteers under fasting conditions on Quetiapine Tablets using Pharmascience Inc. 25 mg tablets versus the reference product, SEROQUEL 25 mg Tablets, by AstraZeneca Canada Inc. The pms-QUETIAPINE 25 mg tablet administered in this study was proportionally formulated to the pms-QUETIAPINE 100, 150, 200 and 300 mg tablets. This proportionally formulated pms-QUETIAPINE 25 mg tablets is not available commercially. The pharmacokinetic data calculated for the pms-QUETIAPINE 25 mg (proportional) and SEROQUEL tablets formulation are tabulated as follows: See Table 1.
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A single center, randomized, single dose blinded, 2-period, 2-sequence crossover comparative bioavailability study was performed in 26 healthy male volunteers under fasting conditions on Quetiapine Tablets using Pharmascience Inc. 25 mg tablets versus the reference product, SEROQUEL 25 mg Tablets, by AstraZeneca Canada Inc. The pms-QUETIAPINE 25 mg tablet administered in this study is not proportionally formulated to the pms-QUETIAPINE 100, 150, 200 and 300 mg tablets. The pms-QUETIAPINE 25 mg tablet administered in this study is the commercial formulation. The pharmacokinetic data calculated for the pms-QUETIAPINE 25 mg (non-proportional) and SEROQUEL tablets formulation are tabulated as follows: See Table 2.
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Study Results: Schizophrenia: The efficacy of quetiapine fumarate immediate-release in the short-term management of schizophrenia was demonstrated in 3 short-term (6-week) controlled trials of inpatients who met a DSM-III-R diagnosis of schizophrenia. The results of the trials follow: 1. In a 6-week, placebo-controlled trial (n = 361) involving 5 fixed doses of quetiapine fumarate (75, 150, 300, 600 and 750 mg/day on a t.i.d. schedule), the 4 highest doses of quetiapine fumarate were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 to 750 were generally indistinguishable. Quetiapine fumarate, at a dose of 300 mg/day, was superior to placebo on the SANS.
2. In a 6-week, placebo-controlled trial (n = 286) involving titration of quetiapine fumarate in high (up to 750 mg/day on a t.i.d. schedule) and low (up to 250 mg/day on a t.i.d. schedule) doses, only the high dose quetiapine fumarate group (mean dose, 500 mg/day) was generally superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the SANS.
3. In a 6-week dose and dose regimen comparison trial (n = 618) involving two fixed doses of quetiapine fumarate (450 mg/day on both b.i.d. and t.i.d. schedules and 50 mg/day on a b.i.d. schedule), only the 450 mg/day (225 mg b.i.d. schedule) dose group was generally superior to the 50 mg/day (25 mg b.i.d.) quetiapine fumarate dose group on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and on the SANS.
Clinical trials have demonstrated that quetiapine fumarate is effective when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study which identified that for quetiapine, 5HT2 and D2 receptor occupancy is maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.
Bipolar Disorder: Bipolar Mania: The efficacy of quetiapine fumarate in the treatment of manic episodes was established in two 12-week placebo-controlled monotherapy trials in patients who met DSM-IV criteria for Bipolar I disorder. These trials included patients with or without psychotic features and excluded patients with rapid-cycling and mixed episodes. There were from 95 to 107 patients per treatment group in each study.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), and these studies included patients with a wide range of baseline YMRS scores (i.e. 18 to 58). The primary outcome in these trials was change from baseline in the YMRS total score at Day 21.
In the two 12-week trials comparing quetiapine fumarate to placebo, quetiapine fumarate was significantly superior to placebo in reducing manic symptoms. Of those patients with a clinical response, 87% received doses of quetiapine fumarate between 400 and 800 mg per day; in the two individual studies, 52% and 81% of responders received doses between 600 and 800 mg per day (b.i.d. dosing).
Bipolar Depression: The efficacy of quetiapine fumarate for the management of depressive episodes associated with bipolar disorder was established in four 8-week placebo-controlled trials (n = 2,593). These clinical trials included patients with either bipolar I or bipolar II disorder with or without a rapid cycling course.
The primary endpoint was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 8. In all four trials, quetiapine fumarate at 300 mg/day and 600 mg/day was demonstrated to be statistically significant versus placebo in reducing depressive symptoms. The antidepressant effect of quetiapine fumarate was statistically significant at Week 1 (for three of the studies), Week 2 (for all four studies) and maintained throughout 8 weeks of treatment.
Sixty-four percent (64%) of quetiapine fumarate treated patients had at least a 50% improvement in MADRS total score compared to 46% of the placebo-treated patients (p< 0.001). The proportion of patients showing a MADRS total score ≤ 12 (remitters) was 62% for quetiapine fumarate compared to 42% for placebo (p< 0.001).
There were fewer episodes of treatment-emergent mania with either dose of quetiapine fumarate (3.0%) than with placebo (5.0%).
Detailed Pharmacology: Quetiapine is a multiple receptor antagonist. It exhibits affinity for brain serotonin 5HT1A and 5HT2 receptors (IC50s = 717 and 148 nM, respectively), and dopamine D1 and D2 receptors (IC50s = 1,268 and 329 nM, respectively). Quetiapine has lower affinity for dopamine D2 receptors, than serotonin 5HT2 receptors. Quetiapine also has high affinity at histamine H1 receptors (IC50 = 30 nM) and adrenergic α1 receptors (IC50 = 94 nM), with a lower affinity at adrenergic α2 receptors (IC50 = 271 nM), but no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC50s > 5,000 nM). Norquetiapine is an active human plasma metabolite. Norquetiapine, similar to quetiapine, exhibits affinity for brain serotonin 5HT2 and dopamine D1 and D2 receptors. Norquetiapine also has high affinity at histaminergic and adrenergic α1 receptors, with a lower affinity at adrenergic α2 receptors and serotonin 5HT1A receptors. Additionally, norquetiapine has high affinity for the norepinephrine transporter (NET). Quetiapine differs from norquetiapine in having low or no appreciable affinity for muscarinic receptors whereas norquetiapine has moderate to high affinity for several muscarinic receptor subtypes which may explain anticholinergic (muscarinic) effects (see Mechanism of Action as previously mentioned; Neurologic: Anticholinergic (Muscarinic) Effects under Precautions; Drug-Drug Interactions: Urinary Hesitation and Retention under Interactions).
Quetiapine is active in pharmacologic tests for antipsychotic activity, such as conditioned avoidance in primates. It also reverses the actions of dopamine agonists measured either behaviourally or electrophysiologically in mice, rats, cats and monkeys. Quetiapine also elevates levels of the dopamine metabolites homovanillic acid (HVA) and 3,4 dihydroxyphenylalanine (DOPAC) in brain, which are considered to be neurochemical indices of dopamine D2 receptor blockade. The extent to which the norquetiapine metabolite contributes to the pharmacological activity of quetiapine fumarate in humans is not known.
In preclinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2 receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2 receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarization blockade of the A10 mesolimbic but not the A9 nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration.
Pharmacology of Metabolites: Quetiapine and several of its metabolites (including norquetiapine) have been tested in vitro for their affinity for 5HT2, D1 and D2 receptors, and in vivo animal models. The major metabolites, parent acid and sulfoxide, are pharmacologically inactive in plasma. The 7-hydroxy and 7-hydroxy N-dealkylated metabolites are pharmacologically active with in vitro binding comparable to or greater than that for parent compound. The peak plasma concentrations for the 7-hydroxy and 7-hydroxy N-dealkylated metabolites account for approximately only 5% and 2% of that of quetiapine at steady state, respectively.
Pharmacokinetics: The pharmacokinetics of quetiapine and norquetiapine are linear within the clinical dose range. The kinetics of quetiapine are similar in men and women, and smokers and non-smokers.
Absorption: Quetiapine is well-absorbed following oral administration. In studies with radiolabelled drug, approximately 73% of the total radioactivity is recovered in the urine and 21% in the feces over a period of one week. The bioavailability of quetiapine is marginally affected by administration with food, with Cmax and AUC values increased by 25% and 15%, respectively. Peak plasma concentrations of quetiapine generally occur within 2 hours after oral administration. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.
Distribution: Quetiapine has a mean apparent volume of distribution of 10±4 L/kg, and is approximately 83% bound to plasma proteins.
Elimination and Metabolism: The elimination half-life of quetiapine is approximately 6-7 hours upon multiple dosing within the proposed clinical dosage range. The elimination half-life of norquetiapine is approximately 12 hours. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is < 5% excreted in the urine.
Quetiapine is extensively metabolized by the liver, with parent compound accounting for less than 5% of the dose in the urine and feces, one week following the administration of radiolabelled quetiapine. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed in these patients.
Major routes of metabolism of quetiapine involve oxidation of the alkyl side chain, hydroxylation of the dibenzothiazepine ring, sulphoxidation, and phase 2 conjugation. The principal human plasma metabolites are the sulfoxide, and the parent acid metabolite, neither of which are pharmacologically active.
In vitro investigations established that CYP 3A4 is the primary enzyme responsible for cytochrome P450-mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans.
Special Populations and Conditions: Geriatrics (≥ 65 years of age): The mean clearance of quetiapine in the elderly is approximately 30 to 50% of that seen in adults aged 18-65 years (see Dosing Considerations in Special Populations: Elderly under Dosage & Administration; Use in the Elderly under Precautions).
Hepatic Impairment: In 8 cirrhotic subjects with mild hepatic impairment, administration of a single 25 mg (sub-clinical) oral dose of quetiapine resulted in a 40% increase in both AUC and Cmax. Clearance of the drug decreased by 25% whereas t½ was elevated by nearly 45%. Therefore, pms-QUETIAPINE should be used with caution in patients with mild hepatic impairment, especially during the initial dosing period. No pharmacokinetic data are available for any dose of quetiapine in patients with moderate or severe hepatic impairment (see Dosing Considerations in Special Populations: Hepatic Impairment under Dosage & Administration; Hepatic/Pancreatic: Hepatic Impairment under Precautions).
Renal Impairment: At single low (sub-clinical) doses, the mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2). However, the individual clearance values remained within the range observed for healthy subjects (see Dosing Considerations in Special Populations: Renal Impairment under Dosage & Administration; Renal under Precautions).
Toxicology: Thyroid: Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10-250 mg/kg in rats, 75-750 mg/kg in mice; these doses are 0.1-3.0, and 0.1-4.5 times the maximum recommended human dose (on a mg/m2 basis), respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.
Cataracts: In dogs receiving quetiapine for 6 or 12 months, but not for 1-month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the maximum recommended human dose on a mg/m2 basis. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta-8-cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the maximum recommended human dose on a mg/m2 basis.
Acute Toxicity: Single dose studies were conducted in mice and rats by the oral and intraperitoneal routes and in dogs by the oral route. The principal clinical signs in mice, rats and dogs of decreased motor activity, ptosis, loss of righting reflex, tremors, ataxia, prostration and convulsions were consistent with the pharmacological activity of the drug. The lowest oral doses causing lethality were 250 mg/kg in mouse and 500 mg/kg in rat; no deaths occurred at the highest oral dose tested (750 mg/kg) in dogs. The highest parenteral non-lethal doses were 100 mg/kg in both mouse and rat.
Subacute/Chronic Toxicity: In multiple dose studies in rats, dogs and monkeys (refer to Table 3 for individual study details) anticipated central nervous system effects of an antipsychotic drug were observed with quetiapine (e.g., sedation at lower doses and tremor, convulsions or prostration at higher exposures). (See Table 3.)
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Hyperprolactinemia, induced through the dopamine D2 receptor antagonist activity of quetiapine or its metabolites, varied between species, but was most marked in the rat. A range of effects consequent to this were seen in the 12-month study including mammary hyperplasia, increased pituitary weight, decreased uterine weight and enhanced growth of females.
Reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction, were seen in mouse, rat and monkey.
Thyroid follicular cell hypertrophy and concomitant changes in plasma thyroid hormone levels occurred in rat and monkey.
Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.
Transient increases in heart rate, unaccompanied by an effect on blood pressure, occurred in dogs.
Posterior triangular cataracts seen after 6 months in dogs at 100 mg/kg/day were consistent with inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in cynomolgus monkeys dosed up to 225 mg/kg/day, or in rodents. Monitoring in clinical studies did not reveal drug-related corneal opacities in man.
No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.
Carcinogenicity: Results from the 2-year carcinogenicity studies performed in mice and rats (and mouse sighting studies) are summarized in Table 4. (See Table 4.)
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In the rat study (doses 0, 20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinemia.
In male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.
Reproduction and Teratology: Results from the individual reproduction and teratology studies, performed with quetiapine in rats and rabbits, are summarized in Table 5. (See Table 5.)
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Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
Quetiapine had no teratogenic effects.
Mutagenicity: Genetic toxicity studies with quetiapine show that it is not a mutagen or a clastogen. There was no evidence of mutagenic potential in reverse (Salmonella typhimurium and E. coli) or forward point mutation (CHO-HGPRT) assays or in two assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenesis assay and the rat bone marrow erythrocyte micronucleus assay).