Quetiapine Fumarate (Page 9 of 14)

11 DESCRIPTION

Quetiapine fumarate is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [b,f ] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C42 H50 N6 O4 S2 . C4 H4 O4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:

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Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.

Quetiapine extended-release tablets are supplied for oral administration as 50 mg (peach to red), 150 mg (white), 200 mg (yellow), 300 mg (yellow to pale yellow), and 400 mg (white). All tablets are capsule shaped and film coated.

Inactive ingredients for quetiapine extended-release tablets are hypromellose, hypromellose 2208, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate dihydrate. The film coating for all quetiapine extended-release tablets contain hypromellose 2910, macrogol and titanium dioxide. In addition, red iron oxide (for 50 mg) and yellow iron oxide (for 50 mg, 200 mg and 300 mg) are included in the film coating of specific strengths.

Each 50 mg film-coated tablet contains 58 mg of quetiapine fumarate USP equivalent to 50 mg quetiapine. Each 150 mg film-coated tablet contains 173 mg of quetiapine fumarate USP equivalent to 150 mg quetiapine. Each 200 mg film-coated tablet contains 230 mg of quetiapine fumarate equivalent to 200 mg quetiapine. Each 300 mg film-coated tablet contains 345 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400 mg film-coated tablet contains 461 mg of quetiapine fumarate equivalent to 400 mg quetiapine.

USP Dissolution Test Pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of quetiapine extended-release tablet in the listed indications is unclear. However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D2 ) and serotonin type 2A (5HT2A ) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D2 , but greater activity at 5HT2A receptors, than the parent drug (quetiapine).

12.2 Pharmacodynamics

Quetiapine and its metabolite norquetiapine have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general. The Ki values for quetiapine and norquetiapine at the dopamine D1 are 428/99.8 nM, at D2 626/489nM, at serotonin 5HT1A 1040/191 nM at 5HT2A 38/2.9 nM, at histamine H1 4.4/1.1 nM, at muscarinic M1 1086/38.3 nM, and at adrenergic α1b 14.6/46.4 nM and, at α2 receptors 617/1290 nM, respectively. Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors.

Effect on QT Interval

In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see OVERDOSAGE (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.

12.3 Pharmacokinetics

Adults

Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of norquetiapine are about 21 to 27% and 46 to 56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. quetiapine extended-release tablet is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

Children and Adolescents

At steady state, the pharmacokinetics of the parent compound, in children and adolescents (10 to 17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and Cmax of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmax were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see USE IN SPECIFIC POPULATIONS (8.4)].

Absorption

Quetiapine reaches peak plasma concentrations approximately 6 hours following administration. quetiapine extended-release tablet dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of quetiapine tablet administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the quetiapine extended-release tablet Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmax or AUC of quetiapine. It is recommended that quetiapine extended-release tablet be taken without food or with a light meal [see DOSAGE AND ADMINISTRATION (2.1)].

Distribution

Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.

Metabolism and Elimination

Following a single oral dose of 14 C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine.

Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine.

Age

Oral clearance of quetiapine was reduced by 40% in elderly patients (≥65 years, n = 9) compared to young patients (n=12), and dosing adjustment may be necessary [see DOSAGE AND ADMINISTRATION (2.3)].

Gender

There is no gender effect on the pharmacokinetics of quetiapine.

Race

There is no race effect on the pharmacokinetics of quetiapine.

Smoking

Smoking has no effect on the oral clearance of quetiapine.

Renal Insufficiency

Patients with severe renal impairment (CLcr =10 to 30 mL/min/1.73m2 , n=8) had a 25% lower mean oral clearance than normal subjects (CLcr >80 mL/min/1.73m2 , n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients [see USE IN SPECIFIC POPULATIONS (8.6)].

Hepatic Insufficiency

Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and Cmax were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [see DOSAGE AND ADMINISTRATION (2.4) and USE IN SPECIFIC POPULATIONS (8.7)].

Drug-Drug Interaction Studies

The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 24 [see DOSAGE AND ADMINISTRATION (2.5 and 2.6) and DRUG INTERACTIONS (7.1)].

Table 24: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine

Coadministered Drug

Dose Schedules

Effect on Quetiapine Pharmacokinetics

Coadministered Drug

Quetiapine

Phenytoin

100 mg three times daily

250 mg three times daily

5 fold Increase in oral clearance

Divalproex

500 mg twice daily

150 mg twice daily

17% increase mean max plasma concentration at steady state. No effect on absorption or mean oral clearance

Thioridazine

200 mg twice daily

300 mg twice daily

65% increase in oral clearance

Cimetidine

400 mg three times daily for 4 days

150 mg three times daily

20% decrease in mean oral clearance

Ketoconazole (potent CYP 3A4 inhibitor)

200 mg once daily for 4 days

25 mg single dose

84% decrease in oral clearance resulting in a 6.2 fold increase in AUC of quetiapine

Fluoxetine

60 mg once daily

300 mg twice daily

No change in steady state PK

Imipramine

75 mg twice daily

300 mg twice daily

No change in steady state PK

Haloperidol

7.5 mg twice daily

300 mg twice daily

No change in steady state PK

Risperidone

3 mg twice daily

300 mg twice daily

No change in steady state PK

In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table 25) [see DRUG INTERACTIONS (7.2)].

Table 25: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs

Coadministered Drug

Dose Schedules

Effect On Other Drugs Pharmacokinetics

Coadministered drug

Quetiapine

Lorazepam

2 mg, single dose

250 mg three times daily

Oral clearance of lorazepam reduced by 20%

Divalproex

500 mg twice daily

150 mg twice daily

Cmax and AUC of free valproic acid at steady-state was decreased by 10 to 12%

Lithium

Up to 2400 mg/day given in twice daily doses

250 mg three times daily

No effect on steady-state pharmacokinetics of lithium

Antipyrine

1 g, single dose

250 mg three times daily

No effect on clearance of antipyrine or urinary recovery of its metabolites

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