Quetiapine (Page 10 of 13)


Quetiapine 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 C 42 H 50 N 6 O 4 S 2 •C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:

(click image for full-size original)

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

Quetiapine tablet, USP is supplied for oral administration as 25 mg (round, pink), 50 mg (round, white to off white), 100 mg (round, yellow), 200 mg (round, white to off white), 300 mg (capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets.

Inactive ingredients are povidone, dibasic calcium phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide.

The 25 mg tablets contain iron oxide red and iron oxide yellow and the 100 mg and 400 mg tablets contain only iron oxide yellow.

Each 25 mg tablet contains quetiapine fumarate, USP equivalent to 25 mg quetiapine.
Each 50 mg tablet contains quetiapine fumarate, USP equivalent to 50 mg quetiapine.
Each 100 mg tablet contains quetiapine fumarate, USP equivalent to 100 mg quetiapine.
Each 200 mg tablet contains quetiapine fumarate, USP equivalent to 200 mg quetiapine.
Each 300 mg tablet contains quetiapine fumarate, USP equivalent to 300 mg quetiapine. Each 400 mg tablet contains quetiapine fumarate, USP equivalent to 400 mg quetiapine.


12.1 Mechanism of Action

The mechanism of action of quetiapine in the listed indications is unclear. However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D 2 , but greater activity at 5HT 2A 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 K i values for quetiapine and norquetiapine at the dopamine D 1 are 428/99.8 nM, at D 2 626/489nM, at serotonin 5HT 1A 1040/191 nM at 5HT 2A 38/2.9 nM, at histamine H 1 4.4/1.1 nM, at muscarinic M 1 1086/38.3 nM, and at adrenergic α 1 b 14.6/46.4 nM and, at α 2 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


Quetiapine activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine 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)] .


Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C max and AUC values increased by 25% and 15%, respectively.


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.

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 N-desalkyl quetiapine.


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)] .


There is no gender effect on the pharmacokinetics of quetiapine.


There is no race effect on the pharmacokinetics of quetiapine.


Smoking has no effect on the oral clearance of quetiapine.

Renal Insufficiency

Patients with severe renal impairment (Clcr=10 to 30 mL/min/1.73 m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 80 mL/min/1.73 m 2 , 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 two 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 17 [see Dosage and Administration (2.5 and 2.6) and Drug Interactions (7.1)Drug Interactions (7.1) ] .

Table 17: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine

Coadministered Drug

Dose Schedules

Effect on Quetiapine Pharmacokinetics

Coadministered Drug



100 mg three times daily

250 mg three times daily

5 fold increase in oral clearance


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


200 mg twice daily

300 mg twice daily

65% increase in oral clearance


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


60 mg once daily

300 mg twice daily

No change in steady state PK


75 mg twice daily

300 mg twice daily

No change in steady state PK


7.5 mg twice daily

300 mg twice daily

No change in steady state PK


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 18) [see Drug Interactions (7.2)].

Table 18: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs

Coadministered drug

Dose schedules

Effect on other drugs pharmacokinetics

Coadministered drug



2 mg, single dose

250 mg three times daily

Oral clearance of lorazepam reduced by 20%


500 mg twice daily

150 mg twice daily

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


Up to 2400 mg/day given in twice daily doses

250 mg three times daily

No effect on steady-state pharmacokinetics of lithium


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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