Chemical formula: C₂₁H₂₅N₃O₂S Molecular mass: 383.507 g/mol PubChem compound: 5002
Quetiapine interacts in the following cases:
Caution should be exercised when quetiapine is used concomitantly with medicinal products known to cause electrolyte imbalance or to increase QT interval.
Quetiapine is extensively metabolized by the liver. Therefore, Atrolak XL 50 mg should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.
The effects of quetiapine on human fertility have not been assessed. Effects related to elevated prolactin levels were seen in rats, although these are not directly relevant to humans.
In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, which could affect the efficacy of quetiapine therapy.
In a 6-week, randomised, study of lithium and quetiapine prolonged-release tablets versus placebo and quetiapine prolonged-release tablets in adult patients with acute mania, a higher incidence of extrapyramidal related events (in particular tremor), somnolence, and weight gain were observed in the lithium add-on group compared to the placebo addon group.
Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when coadministered. A retrospective study of children and adolescents who received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the monotherapy groups.
Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%.
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment.
Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.
Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. In clinical trials for treatment of patients with bipolar depression and major depressive disorder, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity.
Patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.
Quetiapine treatment has been associated with orthostatic hypotension and related dizziness which, like somnolence has onset usually during the initial dose-titration period. This could increase the occurrence of accidental injury (fall), especially in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.
In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder.
The use of quetiapine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Sleep apnoea syndrome has been reported in patients using quetiapine. In patients receiving concomitant central nervous system depressants and who have a history of or are at risk for sleep apnoea, such as those who are overweight/obese or are male, quetiapine should be used with caution.
The moderate amount of published data from exposed pregnancies (i.e. between 300-1000 pregnancy outcomes), including individual reports and some observational studies do not suggest an increased risk of malformations due to treatment. However, based on all available data, a definite conclusion cannot be drawn. Animal studies have shown reproductive toxicity. Therefore, quetiapine should only be used during pregnancy if the benefits justify the potential risks.
Neonates exposed to antipsychotics (including quetiapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Based on very limited data from published reports on quetiapine excretion into human breast milk, excretion of quetiapine at therapeutic doses appears to be inconsistent. Due to lack robust data, a decision must be made whether to discontinue breast-feeding or to discontinue quetiapine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effects of quetiapine on human fertility have not been assessed. Effects related to elevated prolactin levels were seen in rats, although these are not directly relevant to humans.
Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility to this is known.
The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine (≥10%) are somnolence, dizziness, headache, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms.
The incidences of ADRs associated with quetiapine therapy, are listed below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group 1995).
The frequencies of adverse events are ranked according to the following: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100, rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available data).
Very Common: Decreased haemoglobin22
Common: Leucopenia28, decreased neutrophil count, eosinophils increased27
Uncommon: Neutropenia, Thrombo-cytopenia, Anaemia, platelet count decreased13
Rare: Agranulo-cytosis26
Uncommon: Hypersensitivity (including allergic skin reactions)
Very Rare: Anaphylactic reaction5
Common: Hyper-prolactinaemia15, decreases in total T424, decreases in free T424, decreases in total T324, increases in TSH24
Uncommon: Decreases in free T324, Hypo-thyroidism
Very Rare: Inappropriate antidiuretic hormone secretion
Very Common: Elevations in serum triglyceride levels10,30, Elevations in total cholesterol (predominantly LDL cholesterol)11,30, Decreases in HDL cholesterol17,30, Weight gain8,30
Common: Increased appetite, blood glucose increased to hyperglycaemic levels6,30
Uncommon: Hyponatraemia19, Diabetes Mellitus5, Exacerbation of pre-existing diabetes
Rare: Metabolic syndrome29
Common: Abnormal dreams and nightmares, Suicidal ideation and suicidal behaviour20
Rare: Somnambulism and related reactions such as sleep talking and sleep related eating disorder
Very Common: Dizziness4,16, Somnolence2,16, Headache, Extrapyramidal symptoms
Common: Dysarthria
Uncommon: Seizure, Restless legs syndrome, Tardive dyskinesia5, Syncope4,16
Common: Tachycardia4, Palpitations23
Uncommon: QT prolongation12,18, Bradycardia32
Common: Vision blurred
Common: Orthostatic hypotension4,16
Rare: Venous thrombo-embolism
Common: Dyspnoea23
Uncommon: Rhinitis
Very Common: Dry mouth
Common: Constipation, dyspepsia, vomiting25
Uncommon: Dysphagia7
Rare: Pancreatitis, Intestinal obstruction/Ileus
Common: Elevations in serum alanine amino-transferase (ALT)3, Elevations in gamma-GT levels3
Uncommon: Elevations in serum aspartate amino-transferase (AST)3
Rare: Jaundice5, Hepatitis
Very Rare: Angioedema5, Stevens-Johnson syndrome5
Not known: Toxic Epidermal Necrolysis, Erythema Multiforme, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)33
Very Rare: Rhabdomyolysis
Uncommon: Urinary retention
Not known: Drug withdrawal syndrome neonatal
Uncommon: Sexual dysfunction
Rare: Priapism, galactorrhoea, breast swelling, menstrual disorder
Very Common: Withdrawal (discontinuation) symptoms9
Common: Mild asthenia, peripheral oedema, irritability, pyrexia
Rare: Neuroleptic malignant syndrome, hypothermia
Rare: Elevations in blood creatine phosphokinase14
2 Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of quetiapine.
3 Asymptomatic elevations (shift from normal to >3 X ULN at any time) in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment.
4 As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period.
5 Calculation of Frequency for these ADR’s have only been taken from postmarketing data with the immediate-release formulation of quetiapine.
6 Fasting blood glucose ≥7.0 mmol/L (≥126 mg/dL) or a non fasting blood glucose ≥11.1 mmol/L (≥200 mg/dL) on at least one occasion.
7 An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.
8 Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.
9 The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.
10 Triglycerides ≥2.258 mmol/L (≥200 mg/dL) (patients ≥18 years of age) or ≥1.694 mmol/L (≥150 mg/dL) (patients <18 years of age) on at least one occasion.
11 Cholesterol ≥6.2064 mmol/L (≥240 mg/dL) (patients ≥18 years of age) or ≥5.172 mmol/L (≥200 mg/dL) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥0.769 mmol/L (≥30 mg/dL) has been very commonly observed. Mean change among patients who had this increase was ≥1.07 mmol/L (41.7 mg/dL).
12 See text below.
13 Platelets ≤100 × 109/L on at least one occasion.
14 Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.
15 Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34 pmol/L) females at any time.
16 May lead to falls.
17 HDL cholesterol: ≤1.025 mmol/L (<40 mg/dL) males; ≤1.282 mmol/L (<50 mg/dL) females at any time.
18 Incidence of patient who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec increase. In placebo-controlled trials with quetiapine, the mean change and the incidence of patient who have a shift to a clinically significant level is similar between quetiapine and placebo
19 Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.
20 Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation.
22 Decreased haemoglobin to 8.07 mmol/L (≤13 g/l) males, 7.45 mmol/L (≤12 g/l) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in hemoglobin at any time was 1.50 g/l..
23 These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.
24 Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. 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.
25 Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
26 Based on shift in neutrophils from ≥=1.5 × 109/L at baseline to <0.5 × 109/L at any time during treatment and based on patients with severe neutropenia (<0.5 × 109/L) and infection during all quetiapine clinical trials.
27 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in eosinophils are defined as >1 × 109 cells/L at any time.
28 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in WBCs are defined as ≤3 × 109 cells/L at any time.
29 Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine.
30 In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies.
32 May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with quetiapine.
33 Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with quetiapine treatment
Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.
The same ADRs described above for adults should be considered for children and adolescents. The following list summarises ADRs that occur in a higher frequency category in children and adolescents patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population.
ADRs in children and adolescents associated with quetiapine therapy that occur in a higher frequency than adults, or not identified in the adult population:
The frequencies of adverse events are ranked according to the following: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000).
Very Common: Elevations in prolactin1
Very Common: Increased appetite
Very Common: Extrapyramidal symptoms3
Common: Syncope
Very Common: Increases in blood pressure2
Common: Rhinitis
Very Common: Vomiting
Common: Irritability3
1 Prolactin levels (patients <18 years of age): >20 ug/L (>869.56 pmol/L) males; >26 ug/L (>1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level >100 ug/L.
2 Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases >20mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.
3 Note: The frequency is consistent to that observed in adults, but irritability might be associated with different clinical implications in children and adolescents as compared to adults.
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