- Somnolence combines adverse reaction terms somnolence and sedation
The following adverse reactions were identified during post approval use of quetiapine fumarate tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, sleep apnea, and urinary retention.
The risks of using quetiapine fumarate extended-release tablets in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine fumarate extended-release tablets, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.
Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype of CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors.
Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose should be reduced to one sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine fumarate extended-release tablets up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate extended-release tablets should be reduced to the original level within 7-14 days [see Dosage and Administration (2.6)].
The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied.
Because of its potential for inducing hypotension, quetiapine fumarate extended-release tablets may enhance the effects of certain antihypertensive agents.
Quetiapine fumarate extended-release tablets may antagonize the effects of levodopa and dopamine agonists.
There are no clinically relevant pharmacokinetic interactions of quetiapine fumarate tablets on other drugs based on the CYP pathway. Quetiapine fumarate tablets and its metabolites are non-inhibitors of major metabolizing CYP’s (1A2, 2C9, 2C19, 2D6 and 3A4).
Pregnancy Category C:
There are no adequate and well-controlled studies of quetiapine fumarate extended-release tablet use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine fumarate extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including quetiapine fumarate extended-release tablets), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses at doses up to 2.4 times the maximum recommended human dose (MRHD), for schizophrenia of 800 mg/day based on mg/m 2 body surface area. However, there was evidence of embryo-fetal toxicity. These included delays in skeletal ossification occurred at approximately 1 and 2 times the MRHD of 800 mg/day and in both rats and rabbits and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity observed as decreased body weights and/or death occurred at 2 times the MRHD in rats and at approximately 1-2 times the MRHD (all doses) in rabbits.
In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day on mg/m 2 body surface area. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.
The effect of quetiapine fumarate extended-release tablets on labor and delivery in humans is unknown.
Quetiapine fumarate was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from quetiapine fumarate extended-release tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother’s health.
In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).
Safety and effectiveness of quetiapine fumarate extended-release tablets is supported by studies of quetiapine fumarate tablets for schizophrenia in adolescent patients 13 — 17 years of age and in bipolar mania in children and adolescent patients 10 — 17 years of age [see Clinical Studies ( 14.1 and 14.2)].
In general, the adverse reactions observed in children and adolescents during the clinical trials with quetiapine fumarate tablets 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 (4-7%) compared to children and adolescents (< 1%) [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].
The effectiveness of quetiapine fumarate extended-release tablets for the treatment of bipolar depression in patients under the age of 18 years has not been established. One 8-week trial was conducted to evaluate the safety and efficacy of quetiapine fumarate extended-release tablets in the treatment of bipolar depression in pediatric patients 10 — 17 years of age. The primary objective of the study was to evaluate whether quetiapine fumarate extended-release tablets at a dose of 150 to 300 mg/day demonstrated superior efficacy (as measured by change in CDRS-R total score from baseline to end of 8 weeks) compared to placebo in children and adolescents 10 — 17 years of age with bipolar depression. A total of 193 patients with bipolar depression were randomized to placebo or quetiapine fumarate extended-release tablets. The primary results of this study did not show a difference between quetiapine fumarate extended-release tablets and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with quetiapine fumarate extended-release tablets exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate [see Warnings and Precautions ( 5.5, 5.9) and Adverse Reactions (6.1)].
Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 — 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)].
The efficacy and safety of quetiapine fumarate extended-release tablets in the treatment of schizophrenia in adolescents aged 13 — 17 years is supported by one 6-week, double-blind, placebo-controlled trial with quetiapine fumarate tablets [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 extended-release tablets in pediatric patients less than 13 years of age with schizophrenia have not been established.
The safety and effectiveness of quetiapine fumarate extended-release tablets in the maintenance treatment of schizophrenia has not been established in patients less than 18 years of age.
The efficacy and safety of quetiapine fumarate extended-release tablets in the treatment of bipolar mania in children and adolescents ages 10 — 17 years is supported by one 3-week, double-blind, placebo controlled trial with quetiapine fumarate tablets [see Indications and Usage (1.2), Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Studies (14.2)] .
Safety and effectiveness of quetiapine fumarate extended-release tablets in pediatric patients less than 10 years of age with bipolar mania have not been established.
The safety and effectiveness of quetiapine fumarate extended-release tablets in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age.
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