Quetiapine Fumarate (Page 5 of 13)

5.13 Seizures

During clinical trials, seizures occurred in 0.5% (20/3,490) of patients treated with quetiapine fumarate compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs. 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 (T4 ) 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 T4 , 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 T4 , in addition to clinical assessment, should be measured at baseline and at follow-up.

In the mania adjunct studies, where quetiapine fumarate was added to lithium or divalproex, 12% (24/196) of quetiapine fumarate treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels. Of the quetiapine fumarate treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels (free T4 <0.8 LLN).

About 0.7% (26/3,489) of quetiapine fumarate patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.

In all quetiapine trials, the incidence of significant shifts in thyroid hormones and TSH were*: decrease in free T4 (free T4 <0.8 LLN), 2% (357/17,513); decrease in total T4, 4% (75/1,861); decrease in free T3 , 0.4% (53/13,766); decrease in total T3 , 2% (26/1,312), and increase in TSH, 4.9% (956/19,412). In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 8 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

Table 8: Incidence of shifts in thyroid hormone levels and TSH in short-term placebo-controlled clinical trials*, **

Total T4

Free T4

Total T3

Free T3

TSH

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

3.4 %

0.6%

0.7%

0.1%

0.5%

0%

0.2%

0%

3.2%

2.7%

(37/1097)

(4/651)

(52/7218)

(4/3668)

(2/369)

(0/113)

(11/5673)

(1/2679)

(240/7587)

(105/3912)

* Based on shifts from normal baseline to potentially clinically important value at any time post-baseline. Shifts in total T4 , free T4 , total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.
** Includes quetiapine fumarate and quetiapine fumarate extended-release data.

In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in T3 and TSH was 0% for both quetiapine (1/4,800) and placebo (0/2,190) and for T4 and TSH the shifts were 0.1% (7/6,154) for quetiapine versus 0% (1/3,007) for placebo.

Children and Adolescents

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 for thyroid function values at any time for quetiapine fumarate 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 treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.

5.15 Hyperprolactinemia

Adults

During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4,416) of patients treated with quetiapine compared to 2.6% (51/1,968) on placebo.

Children and Adolescents

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 mcg/L males: > 26 mcg/L females at any time) was 13.4% (18/134) for quetiapine fumarate compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine fumarate compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D2 receptors, quetiapine fumarate elevates 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)].

5.16 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse event reported in patients treated with quetiapine fumarate especially during the 3 to 5 day period of initial dose-titration. In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine fumarate compared to 11% (22/206) of placebo patients. In acute bipolar mania trials using quetiapine fumarate as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine fumarate compared to 4% of placebo patients. In acute bipolar mania trials using quetiapine fumarate as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine fumarate compared to 9% (19/203) of placebo patients. In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine fumarate compared to 15% (51/347) of placebo patients. Since quetiapine fumarate has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine fumarate therapy does not affect them adversely. Somnolence may lead to falls.

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