Quetiapine Fumarate Extended Release (Page 10 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (MRHD) of 800 mg/day based on mg/m 2 body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m 2 body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD on mg/m 2 body surface area and in male rats at a dose of 3 times the MRHD on mg/m 2 body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD on mg/m 2 body surface area).

Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see Warnings and Precautions (5.15)].

Mutagenesis

The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose on mg/m 2 body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests.

Impairment of Fertility

Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day on mg/m 2 body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose on mg/m 2 body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day on mg/m 2 body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day on mg/m 2 body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day on mg/m 2 body surface area.

13.2 Animal Toxicology and/or Pharmacology

Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1-3, and 0.1-4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m 2 body surface area, respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.

In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day on mg/m 2 body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day on mg/m 2 body surface area.

14 CLINICAL STUDIES

14.1 Schizophrenia

Short-term Trials – Adults

The efficacy of quetiapine fumarate extended-release tablets in the treatment of schizophrenia was demonstrated in 1 short-term, 6-week, fixed-dose, placebo-controlled trial of inpatients and outpatients with schizophrenia (n=573) who met DSM-IV criteria for schizophrenia. Quetiapine fumarate extended-release tablets (once daily) was administered as 300 mg on Day 1, and the dose was increased to either 400 mg or 600 mg by Day 2, or 800 mg by Day 3. The primary endpoint was the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment (Day 42). Quetiapine fumarate extended-release tablets doses of 400 mg, 600 mg and 800 mg once daily were superior to placebo in the PANSS total score at Day 42 (study 1 in Table 27).

Short-term Trials –Adolescents (ages 13-17)

The efficacy of quetiapine fumarate extended-release tablets in the treatment of schizophrenia in adolescents (13-17 years of age) was supported by a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: quetiapine fumarate tablets 400 mg/day (n = 73), quetiapine fumarate tablets 800 mg/day (n = 74), or placebo (n = 75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS). Quetiapine fumarate tablets at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score (study 2 in Table 27).

Table 27: Schizophrenia Short-Term Trials
*
Difference (drug minus placebo) in least-squares mean change from baseline
Doses that are statistically significantly superior to placebo
Included in the trial for assay sensitivity

Study

Number

Treatment Group

Primary Efficacy Endpoint: PANSS Total

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Difference * (95% CI)

Study 1

Quetiapine fumarate extended-release tablets (400 mg/day)

95.8 (13.9)

-24.8 (2.5)

-6.1 (-11.5, -0.6)

Quetiapine fumarate extended-release tablets (600 mg/day)

96.8 (14.1)

-30.9 (2.5)

-12.1 (-17.6, -6.7)

Quetiapine fumarate extended-release tablets (800 mg/day)

97.3 (14.7)

-31.3 (2.5)

-12.5 (-17.9, -7.1)

Quetiapine fumarate tablets (400 mg/day) ,

96.5 (16.0)

-26.6 (2.4)

-7.8 (-13.1, -2.4)

Placebo

96.2 (13.3)

-18.8 (2.5)

Study 2

(adolescents)

Quetiapine fumarate tablets (400 mg/day)

96.2 (17.7)

-27.3 (2.6)

-8.2 (-16.1, -0.3)

Quetiapine fumarate tablets (800 mg/day)

96.9 (15.3)

-28.4 (1.8)

-9.3 (-16.2, -2.4)

Placebo

96.2 (17.7)

-19.2 (3.0)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

Maintenance Trials

In a longer-term trial (study 3), clinically stable adult outpatients (n=171) meeting DSM-IV criteria for schizophrenia who remained stable following 16 weeks of open-label treatment with flexible doses of quetiapine fumarate extended-release tablets (400 mg/day-800 mg/day) were randomized to placebo or to continue on their current quetiapine fumarate extended-release tablets (400 mg/day-800 mg/day) for observation for possible relapse during the double-blind continuation (maintenance) phase. Stabilization during the open-label phase was defined as receiving a stable dose of quetiapine fumarate extended-release tablets and having a CGI-S≤4 and a PANSS score ≤60 from beginning to end of this open-label phase (with no increase of ≥10 points in PANSS total score). Relapse during the double-blind phase was defined in terms of a ≥30% increase in the PANSS Total score, or CGI-Improvement score of ≥6, or hospitalization due to worsening of schizophrenia, or need for any other antipsychotic medication. Patients on quetiapine fumarate extended-release tablets experienced a statistically significant longer time to relapse than did patients on placebo (Figure 1).

Figure 1: Kaplan-Meier Curves of Time to Schizophrenic Relapse (study 3)

figure 1 kaplan-meier curves of time to schizophrenic relapse study 3.jpg
(click image for full-size original)

PLA Placebo. QTP Quetiapine. XR Extended-release.

Note: Results are from the interim analysis.

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