Active ingredient: Quetiapine - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

• Antipsychotics

Dosage Forms

• Tablet

Brands / Synonyms

Quetiapin hemifumarate; Quetiapine fumarate; Quetiapine hemifumarate; Seroquel; Seroquel ; Seroquel XR

Indications

For the treatment of schizophrenia and acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex.

Pharmacology

Quetiapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Quetiapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT₂), and dopamine type 2 (D2) receptors. Quetiapine is an antagonist at serotonin 5-HT_1A and 5HT₂, dopamine D1 and D2, histamine H1, and adrenergic alpha 1 and alpha 2 receptors. Quetiapine has no significant affinity for cholinergic muscarinic or benzodiazepine receptors. Drowsiness and orthostatic hypotension associated with use of quetiapine may be explained by its antagonism of histamine H1 and adrenergic alpha 1 receptors, respectively. Quetiapine's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.

Mechanism of Action

The mechanism of action of quetiapine, as with other drugs used to treat schizophrenia, is unknown. However, it is thought that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT₂) receptor antagonism. Although quetiapine is known to bind other receptors with similar affinity, only the dopamine D2 and serotonin 5HT₂ receptor binding is responsible for quetiapine's therapeutic activity in schizophrenia.

Absorption

Rapidly and well absorbed.

Toxicity

Symptoms of overdose include drowsiness and sedation, tachycardia, and hypotension.

Biotrnasformation / Drug Metabolism

Hepatic. The major metabolic pathways are sulfoxidation, mediated by cytochrome P450 3A4 (CYP3A4), and oxidation. The major metabolites of quetiapine are inactive.

Contraindications

SEROQUEL is contraindicated in individuals with a known hypersensitivity to this medication or any of its ingredients.

Drug Interactions

The risks of using SEROQUEL in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of SEROQUEL, caution should be used when it is taken in combination with other centrally acting drugs. SEROQUEL potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be avoided while taking SEROQUEL.

Because of its potential for inducing hypotension, SEROQUEL may enhance the effects of certain antihypertensive agents. SEROQUEL may antagonize the effects of levodopa and dopamine agonists.

The Effect of Other Drugs on Quetiapine

Phenytoin: Coadministration of quetiapine (250 mg tid) and phenytoin (100 mg tid) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of SEROQUEL may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate).

Divalproex: Coadministration of quetiapine (150 mg bid) and divalproex (500 mg bid) increased the mean maximum plasma concentration of quetiapine at steady state by 17% without affecting the extent of absorption or mean oral clearance.

Thioridazine: Thioridazine (200 mg bid) increased the oral clearance of quetiapine (300 mg bid) by 65%.

Cimetidine: Administration of multiple daily doses of cimetidine (400 mg tid for 4 days) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg tid). Dosage adjustment for quetiapine is not required when it is given with cimetidine.

P450 3A Inhibitors: Coadministration of ketoconazole (200 mg once daily for 4 days), a potent inhibitor of cytochrome P4503A, reduced oral clearance of quetiapine by 84%, resulting in a 335% increase in maximum plasma concentration of quetiapine. Caution is indicated when SEROQUEL is administered with ketoconazole and other inhibitors of cytochrome P450 3A (e.g., itraconazole, fluconazole, and erythromycin).

Fluoxetine, Imipramine, Haloperidol, and Risperidone: Coadministration of fluoxetine (60 mg once daily); imipramine (75 mg bid), haloperidol (7.5 mg bid), or risperidone (3 mg bid) with quetiapine (300 mg bid) did not alter the steady-state pharmacokinetics of quetiapine.

Effect of Quetiapine on Other Drugs

Lorazepam: The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg tid dosing.

Divalproex: The mean maximum concentration and extent of absorption of total and free valproic acid at steady state were decreased by 10 to 12% when divalproex (500 mg bid) was administered with quetiapine (150 mg bid). The mean oral clearance of total valproic acid (administered as divalproex 500 mg bid) was increased by 11% in the presence of quetiapine (150 mg bid). The changes were not significant

Lithium: Concomitant administration of quetiapine (250 mg tid) with lithium had no effect on any of the steady-state pharmacokinetic parameters of lithium.

Antipyrine: Administration of multiple daily doses up to 750 mg/day (on a tid schedule) of quetiapine to subjects with selected psychotic disorders had no clinically relevant effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. These results indicate that quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine.