Quetiapine Fumarate Extended Release (Page 8 of 12)

8.5 Geriatric Use

Sixty-eight patients in clinical studies with quetiapine fumarate extended-release tablets were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate extended-release tablets in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine fumarate extended-release tablets, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Clinical experience with quetiapine fumarate extended-release tablets in patients with renal impairment is limited [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. In this population, a low starting dose of 50 mg/day is recommended and the dose may be increased in increments of 50 mg/day [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Quetiapine fumarate extended-release tablets are not a controlled substance.

9.2 Abuse

Quetiapine fumarate extended-release tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine fumarate extended-release tablets (e.g., development of tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE

10.1 Human Experience

In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and anticholinergic toxicity including coma and delirium. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see Warnings and Precautions (5.12)]. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there were cases reported of QT prolongation with overdose.

10.2 Management of Overdosage

Establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

Appropriate supportive measures are the mainstay of management. For the most up-to-date information on the management of quetiapine fumarate extended-release tablets overdosage, contact a certified Regional Poison Control Center (1-800-222-1222).

11 DESCRIPTION

Quetiapine fumarate extended-release tablets are 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:

structural formula
(click image for full-size original)

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

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

Inactive ingredients for quetiapine fumarate extended-release tablets are lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, and magnesium stearate. The film coating for all quetiapine fumarate extended-release tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, yellow iron oxide (50, 200 and 300 mg tablets) and red iron oxide (50 mg tablets) are included in the film coating of specific strengths.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of quetiapine fumarate extended-release tablets in the treatment of schizophrenia, bipolar disorder and major depressive disorder (MDD), is unknown. However, its efficacy in schizophrenia could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2A (5HT 2A ) 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). Quetiapine’s efficacy in bipolar depression and MDD may partly be explained by the high affinity and potent inhibitory effects that norquetiapine exhibits for the norepinephrine transporter.

Antagonism at receptors other than dopamine and serotonin with similar or greater affinities may explain some of the other effects of quetiapine and norquetiapine: antagonism at histamine H 1 receptors may explain the somnolence, antagonism at adrenergic α 1 b receptors may explain the orthostatic hypotension, and antagonism at muscarinic M 1 receptors may explain the anticholinergic effects.

12.2 Pharmacodynamics

Quetiapine and norquetiapine have affinity for multiple neurotransmitter receptors including dopamine D 1 and D 2 , serotonin 5HT 1A and 5HT 2A , histamine H 1 , muscarinic M 1 , and adrenergic α 1 b and α 2 receptors. Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M 1 receptors whereas norquetiapine has high affinity. Quetiapine and norquetiapine lack appreciable affinity for benzodiazepine receptors.

Table 24: Receptor Affinities (Ki, nM) for Quetiapine and Norquetiapine
Receptor Quetiapine Norquetiapine

Dopamine D 1

428

99.8

Dopamine D 2

626

489

Serotonin 5HT 1A

1040

191

Serotonin 5HT 2A

38

2.9

Norepinephrine transporter

>10000

34.8

Histamine H 1

4.41

1.15

Adrenergic α 1 b

14.6

46.4

Adrenergic α 2

617

1290

Muscarinic M 1

1086

38.3

Benzodiazepine

>10000

> 10000

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.

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