QUETIAPINE FUMARATE (Page 8 of 13)

8.2 Lactation

Risk Summary

Limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of <1% of the maternal weight-adjusted dosage. There are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk. There is no information on the effects of quetiapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for quetiapine and any potential adverse effects on the breastfed child from quetiapine or from the mother’s underlying condition.

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of quetiapine (D2 antagonism), treatment with quetiapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.15)].

8.4 Pediatric Use

In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%) [see Warnings and Precautions ( 5.7) and Adverse Reactions ( 6.1)].

Schizophrenia

The efficacy and safety of quetiapine fumarate in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [see Indications and Usage ( 1.1), Dosage and Administration ( 2.2), Adverse Reactions ( 6.1), and Clinical Studies ( 14.1)].

Safety and effectiveness of quetiapine fumarate in pediatric patients less than 13 years of age with schizophrenia have not been established.

Maintenance

The safety and effectiveness of quetiapine fumarate in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age. The safety and effectiveness of quetiapine fumarate in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.

Bipolar Mania

The efficacy and safety of quetiapine fumarate in the treatment of mania in children and adolescents ages 10 to 17 years with bipolar I disorder was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial [see Indications and Usage ( 1.2), Dosage and Administration ( 2.3), Adverse Reactions ( 6.1), and Clinical Studies ( 14.2)] . Safety and effectiveness of quetiapine fumarate in pediatric patients less than 10 years of age with bipolar mania have not been established.

Bipolar Depression

Safety and effectiveness of quetiapine fumarate in pediatric patients less than 18 years of age with bipolar depression have not been established. A clinical trial with quetiapine fumarate extended-release tablets was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established.

Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and C max of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [see Clinical Pharmacology ( 12.3)] .

8.5 Geriatric Use

Of the approximately 3,700 patients in clinical studies with quetiapine fumarate, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine fumarate, 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 fumarate was reduced by 30% to 50% in elderly patients when compared to younger patients [ see Clinical Pharmacology ( 12.3) and Dosage and Administration ( 2.3) ].

8.6 Renal Impairment

Clinical experience with quetiapine fumarate 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 25 mg/day is recommended and the dose may be increased in increments of 25 mg/day to 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 is not a controlled substance.

9.2 Abuse

Quetiapine fumarate has 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, 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 reactions. 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 9,600 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 overdosage, contact a certified Regional Poison Control Center (1-800-222-1222).

11 DESCRIPTION

Quetiapine fumarate USP 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:

Structural Formula
(click image for full-size original)

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

Quetiapine tablets USP are supplied for oral administration as 25 mg (round, brownish red),
50 mg (round, white to off-white), 100 mg (round, white to off-white), 200 mg (round, white to off-white), 300 mg (capsule shaped, white to off-white), and 400 mg (round, white to off-white) tablets.

Inactive ingredients are colloidal silicon dioxide, dibasic calcium phosphate dihydrate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-30), sodium starch glycolate and titanium dioxide.

Additionally, the 25 mg tablets contain ferric oxide red and ferric oxide yellow.

Each 25 mg tablet contains 28.78 mg of quetiapine fumarate equivalent to 25 mg quetiapine. Each 50 mg tablet contains 57.56 mg of quetiapine equivalent to 50 mg quetiapine. Each 100 mg tablet contains 115.13 mg of quetiapine equivalent to 100 mg quetiapine. Each 200 mg tablet contains 230.26 mg fumarate equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345.39 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400 mg tablet contains 460.51 mg of fumarate equivalent to 400 mg quetiapine.

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