Quetiapine Fumarate Extended Release (Page 5 of 12)

5.13 Seizures

During short-term clinical trials with quetiapine fumarate extended-release tablets, seizures occurred in 0.05% (1/1866) of patients treated with quetiapine fumarate extended-release tablets across all indications compared to 0.3% (3/928) on placebo. During clinical trials with quetiapine fumarate, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine fumarate tablets compared to 0.2% (2/954) on placebo. As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism

Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T 4 ) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4 , irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status. Therefore, both TSH and free T 4 , in addition to clinical assessment, should be measured at baseline and at follow-up.

In quetiapine fumarate extended-release tablets clinical trials across all indications 1.8% (24/1336) of patients on quetiapine fumarate extended-release tablets versus 0.6% (3/530) on placebo experienced decreased free thyroxine (<0.8 LLN) and 1.6% (21/1346) on quetiapine fumarate extended-release tablets vs 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (TSH). About 0.7% (26/3489) of quetiapine fumarate tablets patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.

In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were 1: decrease in free T 4 (<0.8 LLN), 2.0% (357/17513); decrease in total T 4 (<0.8 LLN), 4.0% (75/1861); decrease in free T 3 (<0.8 LLN), 0.4% (53/13766); decrease in total T 3 (<0.8 LLN), 2.0% (26/1312), and increase in TSH (>5 mIU/L), 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 11 shows the incidence of these shifts in short term placebo-controlled clinical trials.

Table 11: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short term Placebo-controlled Clinical Trials *
*
Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T 4, free T 4, total T 3 and free T 3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.
Includes quetiapine fumarate tablets and quetiapine fumarate extended-release tablets data

Total T 4

Free T 4

Total T 3

Free T 3

TSH

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

3.4%

(37/1097)

0.6%

(4/651)

0.7%

(52/7218)

0.1%

(4/3668)

0.5%

(2/369)

0.0%

(0/113)

0.2%

(11/5673)

0.0%

(1/2679)

3.2%

(240/7587)

2.7%

(105/3912)

In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo.

Children and Adolescents: Safety and effectiveness of quetiapine fumarate extended-release tablets are supported by studies of quetiapine fumarate tablets in children and adolescent patients 10 — 17 years of age [see Clinical Studies ( 14.1 and 14.2)].

In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts at any time for quetiapine fumarate tablets treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the quetiapine fumarate tablets treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment.


1
Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T 4, free T 4, total T 3 and free T 3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.

5.15 Hyperprolactinemia

Adults: During clinical trials with quetiapine across all indications, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents: Safety and effectiveness of quetiapine fumarate extended-release tablets are supported by studies of quetiapine fumarate tablets in children and adolescent patients 10 — 17 years of age [see Clinical Studies ( 14.1 and 14.2)]. In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for quetiapine fumarate tablets compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine fumarate tablets compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D 2 receptors, quetiapine fumarate extended-release tablets elevate prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [see Nonclinical Toxicology (13.1)].

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