Learn a Drug a Day - Quetiapine

Today's drug is quetiapine.
What is quetiapine indicated for?
INDICATIONS : 

• It is an antipsychotics drug.
• It is used to treat conditions such as:
• Schizophrenia, an illness with disturbances in thinking, feelings and behaviour. (精神分裂症）
• Bipolar disorder, an illness in which there are sustained mood swings either up (mania) or down(depression). During mania, patients experience episodes of overactivity, elation or irritability. During depression, patients may feel depressed or guilty, lack energy, lose their appetite andhave trouble sleeping.

How does quetipine work?

MECHANISMS OF ACTION : 

• The mechanism of action of quetipine, as with other drugs having efficacy in the treatment of schizophrenia and bipolar disorder, is unknown. However, it has been proposed that the efficacy of quetipine in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other effects of quetipine.
• Quetipine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug.
• Quetipine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.

How is quetipine being used?

ROUTE OF ADMINISTRATION : 

• It is taken orally as tablets.
• May be taken with or without food.
• For extended-release:  It should be taken on an empty stomach. (Take w/o food or w/ a light meal. Swallow whole, do not chew/crush. )

Is there any contraindication?

CONTRAINDICATIONS : 

• Severe CNS depression 
• Bone marrow suppression 
• Coma

Are there any possible side effects?

SIDE EFFECTS : 

(i) Common possible side effects : 

• Back pain 
• Constipation
• Dizziness 
• Drowsiness
• Dry mouth
• Headache 
• Increased appetite
• Light-headedness
• Nausea
• Runny or stuffy nose
• Sluggishness
• Sore throat
• Stomach pain or upset
• Tiredness
• Vomiting
• Weakness
• Weight gain.

(ii) Severe side effects : 

• Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue)
• confusion
• difficult or painful urination 
• fainting; fast, slow, or irregular heartbeat 
• fever, chills, or persistent sore throat
• hallucinations
• increased saliva production or drooling
• increased sweating
• memory loss
• menstrual changes
• muscle pain, stiffness, or weakness
• new or worsening mental or mood changes (eg, aggressiveness, agitation, anxiety, depression, exaggerated feeling of well-being, hostility, impulsiveness, inability to sit still, irritability, panic attacks, restlessness)
• numbness, burning, or tingling
• persistent, painful erection
• red, swollen, blistered, or peeling skin
• seizures
• severe or prolonged dizziness, light-headedness, or headache
• shortness of breath
• suicidal thoughts or actions
• swelling of the hands, legs, or feet
• symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness)
• tremor
• trouble concentrating, speaking, or swallowing
• trouble sleeping
• trouble walking or standing
• uncontrollable or involuntary muscle movements (eg, uncontrollable arm or leg movements, twitching of the face or tongue, loss of balance)
• vision changes

What precautions are necessary?

PRECAUTIONS : 

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine.

(i) Increased Mortality in Elderly Patients with Dementia-Related Psychosis

• Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. 
• Quetiapine is not approved for elderly patients with dementia-related psychosis.

(ii) Clinical Worsening and Suicide Risk

• Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. 
• Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. 
• Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. 

(iii) Neuroleptic Malignant Syndrome (NMS)

• Patients should be advised to report to their physician any signs or symptoms that may be related to NMS. 
• These may include hyperpyrexia (high fever), muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. 

(iv) Hyperglycemia and Diabetes Mellitus

• Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. 
• Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment.

(v) Hyperlipidemia

• Patients should be advised that elevations in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol may occur. 
• Patients should have their lipid profile monitored at the beginning of and periodically during treatment.

(vi) Weight Gain

• Patients should be advised that they may experience weight gain. 
• Patients should have their weight monitored regularly.

(vii) Orthostatic Hypotension

• Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls), especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose.

(viii) Increased Blood Pressure in Children and Adolescents

• Blood pressure should be measured at the beginning of, and periodically during, treatment.

(ix) Leukopenia/Neutropenia

• Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking quetiapine.

(x) Interference with Cognitive and Motor Performance

• Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration. 
• Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely. 
• Patients should limit consumption of alcohol during treatment with quetiapine.

(xi) Heat Exposure and Dehydration

• Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
• Although not reported with quetiapine, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

(xii) Need for Comprehensive Treatment Program

• Quetiapine is indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological, educational, and social). Effectiveness and safety of quetiapine have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania. 
• Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms.

DRUG INTERACTIONS : 

The risks of using quetiapine in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of  quetiapine, 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 avoided while taking quetiapine.

• Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive agents.

• Quetiapine may antagonize the effects of levodopa and dopamine agonists.

• Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QT interval.

• There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g. chromatographic methods) should be considered.

The Effect of Other Drugs on Quetiapine

Phenytoin

• Coadministration of quetiapine (250 mg three times daily) and phenytoin (100 mg three times daily) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of  quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate).

Divalproex 

• Coadministration of quetiapine (150 mg twice daily) and divalproex (500 mg twice daily) increased the mean maximum plasma concentration of quetiapine at steady state by 17% without affecting the extent of absorption or mean oral clearance.

Thioridazine

• Thioridazine (200 mg twice daily) increased the oral clearance of quetiapine (300 mg twice daily) by 65%.

Cimetidine 

• Administration of multiple daily doses of cimetidine (400 mg three times daily for 4 days) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg three times daily). Dosage adjustment for quetiapine is not required when it is given with cimetidine.

P450 3A Inhibitors 

• Coadministration of ketoconazole (200 mg once daily for 4 days), a potent inhibitor of cytochrome P450 3A, reduced oral clearance of quetiapine by 84%, resulting in a 335% increase in maximum plasma concentration of quetiapine. 
• Caution (reduced dosage) is indicated when quetiapine is administered with ketoconazole and other inhibitors of cytochrome P450 3A (e.g., itraconazole, fluconazole, erythromycin, and protease inhibitors).

Fluoxetine, Imipramine, Haloperidol, and Risperidone

• Coadministration of fluoxetine (60 mg once daily); imipramine (75 mg twice daily), haloperidol (7.5 mg twice daily), or risperidone (3 mg twice daily) with quetiapine (300 mg twice daily) did not alter the steady-state pharmacokinetics of quetiapine.

Effect of Quetiapine on Other Drugs

Lorazepam

• The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg three times daily dosing.

Divalproex

• The mean maximum concentration and extent of absorption of total and free valproic acid at steady state were decreased by 10 to 12% when divalproex (500 mg twice daily) was administered with quetiapine (150 mg twice daily). The mean oral clearance of total valproic acid (administered as divalproex 500 mg twice daily) was increased by 11% in the presence of quetiapine (150 mg twice daily). The changes were not significant.

Lithium

• Concomitant administration of quetiapine (250 mg three times daily) with lithium had no effect on any of the steady-state pharmacokinetic parameters of lithium.

Antipyrine

• Administration of multiple daily doses up to 750 mg/day (on a three times daily schedule) of quetiapine to subjects with selected psychotic disorders had no clinically relevant effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. These results indicate that quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine.

Drug Abuse And Dependence

Abuse

• Quetiapine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. 
• Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine, e.g., development of tolerance, increases in dose, drug-seeking behavior.

Pregnancy and breastfeeding:  

• There are no adequate and well-controlled studies in pregnant women and quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Quetiapine was excreted in milk of treated animals during lactation. It is not known if  quetiapine is excreted in human milk. It is recommended that women receiving quetiapine should not breast feed.

References : 

1. Quetiapine by AstraZeneca Pharmaceuticals LP.

2. Quetiapine by RxList.

3. Quetiapine by MIMS Malaysia.