QUETIL

Brand Name: QUETIL

Strength: 25 mg, 100 mg, 150 mg, 200 mg and 300 mg

Generic Name: Quetiapine fumarate

QUETIL is indicated for:

Bipolar Disorder

Adults

Maintenance treatment of bipolar I disorder, as monotherapy or in combination

with lithium or sodium valproate, for the prevention of relapse/recurrence of manic, depressive or mixed episodes.

Treatment of depressive episodes associated with bipolar disorder.

Treatment of acute mania is associated with bipolar I disorder as monotherapy or in combination with lithium or sodium valproate.

Children/Adolescents Aged 10 To 17 Years

Monotherapy treatment of acute mania associated with bipolar I disorder

Schizophrenia (adults and adolescents aged 13 to 17 years)

Treatment of Schizophrenia

Dose And Method of Administration

Chronic antipsychotic treatment should generally be reserved for patients who appear to

suffer from a chronic illness that is known to respond to antipsychotic drugs, and

for whom alternative equally effective but potentially less harmful treatments are not

available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory response should be sought.

The need for continued treatment should be reassessed periodically.

Quetiapine can be administered with or without food.

Adults

Bipolar Disorder

Maintenance Treatment

Quetiapine should be administered twice daily.

Patients who have responded to quetiapine for acute treatment of bipolar disorder should

continue therapy at the same dose. It is generally recommended that responding patients

be continued beyond the acute response, but at the lowest possible dose needed to

maintain remission.

For prevention of relapse/recurrence of manic, depressive and mixed episodes in bipolar

disorder, the usual effective dose is within the range of 300 to 800 mg/day.

The dose of quetiapine can be re-adjusted depending on the clinical response and

tolerability of the individual patient. Patients should be periodically reassessed to

determine the need for maintenance treatment.

Bipolar Depression

When treating depressive episodes in bipolar disorder, treatment should be initiated either

by the treating psychiatrist or by the general practitioner after consultation with the

psychiatrist.

Quetiapine should be administered once daily at bedtime.

Quetiapine should be titrated as follows: 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3)

and 300 mg (Day 4). The dose may be adjusted up to 600 mg/day in increments of

100 mg/day depending on the clinical response and tolerability of the individual patient.

Acute Mania

Quetiapine should be administered twice daily. The total daily dose for the first four days

of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4), alone

or in combination with a mood stabilizer. Further dosage adjustments up to 800 mg/day by

day 6 should be in increments of no greater than 200 mg/day.

The dose may be adjusted depending on clinical response and tolerability of the individual

patient, within the range of 200 to 800 mg/day. The usual effective dose is in the range of

400 to 800 mg/day.

Schizophrenia

Quetiapine should be administered twice daily. The total daily dose for the first four days

of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4).

From Day 4 onwards, the dose should be titrated to the usual effective dose of 300 to

450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.

Children And Adolescents

The safety and efficacy of quetiapine immediate release tablets have been evaluated in

children and adolescents 10 to 17 years of age with bipolar mania (as monotherapy), and

13 to 17 years of age with schizophrenia.

Quetiapine should be administered twice daily. However, quetiapine may be administered

three times daily based on response and tolerability.

Acute mania - monotherapy (10 to 17 years of age)

The total daily dose for the first five days of therapy is 50 mg (Day 1), 100 mg (Day 2),

200 mg (Day 3), 300 mg (Day 4) and 400 mg (Day 5). After Day 5, the dose should be

adjusted within the effective dose range of 400 to 600 mg/day depending upon the clinical

response and tolerability of the patient. Patients should be administered the lowest

effective dose. Dosage adjustments should be in increments of no greater than

100 mg/day.

Schizophrenia (13 to 17 years of age)

The total daily dose for the first five days of therapy is 50 mg (Day 1), 100 mg (Day 2),

200 mg (Day 3), 300 mg (Day 4) and 400 mg (Day 5). After Day 5, the dose should be

adjusted within the effective dose range of 400 to 800 mg/day depending upon the clinical

response and tolerability of the patient. Patients should be administered the lowest

effective dose. Dosage adjustments should be in increments of no greater than

100 mg/day.

Use in the elderly

As with other antipsychotics, quetiapine should be used with caution in the elderly,

especially during the initial dosing period. The rate of dose titration may need to be

slower, and the daily therapeutic dose lower than that used in younger patients, depending

on the clinical response and tolerability of the individual patient. The mean plasma

clearance of quetiapine was reduced by 30% to 50% in elderly subjects when compared

with younger patients.

Use In Renal Impairment

Dosage adjustment is not necessary.

Use In Hepatic Impairment

Quetiapine is extensively metabolized by the liver. Therefore, quetiapine should be used

with caution in patients with known hepatic impairment, especially during the initial

dosing period. Patients with hepatic impairment should start on 25 mg/day. The

dose should be increased in increments of 25 to 50 mg/day to an effective dose, depending

on the clinical response and tolerability of the individual patient.

Quetiapine is contraindicated in patients who are hypersensitive to any component of this

product.

Concomitant Cardiovascular Illness

Quetiapine should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or other conditions predisposing to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications).

Quetiapine has not been evaluated or used to any appreciable extent in patients with a

recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical studies. Because of the risk of orthostatic hypotension with quetiapine, caution should be observed in cardiac patients.

Orthostatic Hypotension

Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and,

in some patients, syncope especially during the initial dose titration period, probably

reflecting its α1-adrenergic antagonist properties. Syncope has been commonly reported. Orthostatic hypotension, dizziness and syncope may lead to falls.

If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

QT Interval

In clinical trials, quetiapine was not associated with a persistent increase in QTc intervals.

However, in post marketing experience there were cases reported of QT prolongation

with overdose, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.

As with other antipsychotics, caution should be exercised when quetiapine is prescribed in

patients, including children and adolescents, with cardiovascular disease or family history

of QT prolongation. Particularly in the elderly, the use of quetiapine should be avoided in

combination with neuroleptics and drugs that are known to prolong QTc including Class Ia

antiarrhythmics (e.g. Disopyramide) or Class III antiarrhythmics (e.g. amiodarone, sotalol),

antipsychotic medications (e.g. ziprasidone, chlorpromazine, haloperidol), antibiotics (e.g.

moxifloxacin, erythromycin), or any other class of medications known to prolong the QTc

interval (e.g. citalopram, pentamidine, methadone). Quetiapine should also be avoided in

circumstances that may increase the risk of occurrence of torsade de pointes and/or

sudden death, including a history of cardiac arrhythmias such as bradycardia;

hypokalemia or hypomagnesemia; concomitant use of other drugs that prolong the QTc

interval; and presence of congenital prolongation of the QT interval.

Cardiomyopathy And Myocarditis

Cardiomyopathy and myocarditis have been reported in clinical trials and during the postmarketing experience. In patients with suspected cardiomyopathy or myocarditis discontinuation of quetiapine should be considered.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS),

toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life-threatening adverse drug reactions that have been

reported during quetiapine exposure. SCARs are commonly present as a combination of the

following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever,

lymphadenopathy and possible eosinophilia. Discontinue quetiapine if severe cutaneous

adverse reactions occur.

Seizures

In controlled clinical trials there was no difference in the incidence of seizures in patients

treated with quetiapine or placebo. As with other antipsychotics, caution is recommended

when treating patients with a history of seizures or with conditions that are potentially lower

the seizure threshold. Conditions that lower the seizure threshold may be more prevalent

in a population of 65 years or older.

Clinical worsening and suicide risk associated with psychiatric disorders

The risk of suicide attempts is inherent in depression and may persist until significant

remission occurs. The risk must be considered in all depressed patients.

Patients with depression may experience worsening of their depressive symptoms and/or

the emergence of suicidal ideation and behavior (suicidality), whether they are

taking antidepressant medications, and this risk may persist until significant remission

occurs. As improvement may not occur during the first few weeks or more of treatment,

patients should be closely monitored for clinical worsening and suicidality, especially at

the beginning of a course of treatment or at the time of dose changes, either increases or

decreases. Consideration should be given to changing the therapeutic regimen, including

possibly discontinuing the medication, in patients whose depression is persistently worse

or whose emergent suicidality is severe, abrupt in onset or was not part of the patient’s

presenting symptoms.

Patients (and caregivers of patients) should be alerted about the need to monitor any

worsening of their condition and/or the emergence of suicidal ideation/behavior or

thoughts of harming themselves and to seek medical advice immediately if these

symptoms present. Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical

worsening and suicidality.

Pooled analysis of 24 short-term (4 to 16 weeks) placebo-controlled trials of nine

antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major

depressant disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric

disorders (4 trials) have revealed a greater risk of adverse events representing suicidal

behavior or thinking (suicidality) during the first few months of treatment in those

receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients taking a placebo. There was

considerable variation in risk among the antidepressants but there was a tendency towards

an increase for almost all antidepressants studied. This meta-analysis did not include trials

involving quetiapine.

The risk of suicidality was most consistently observed in the major depressive disorder

trials but there were signals of risk arising from the trials in other psychiatric indications

(obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred

in these trials. It is unknown whether suicidality is risk in children and adolescents

patients extend to use beyond several months. The nine antidepressant medicines in the

pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine,

sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).

Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility

(aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania

have been reported in adults, adolescents and children being treated with antidepressants

for major depressive disorder as well as for other indications, both psychiatric and

nonpsychiatric. Although there is a causal link between the emergence of such symptoms and

either worsening of depression and/or emergence of suicidal impulses has not been

established there is concern that such symptoms may be precursors of emerging

suicidality.

Families and caregivers of patients being treated with antidepressants for major depressive

disorder or for any other condition (psychiatric or nonpsychiatric) should be informed

about the need to monitor these patients for the emergence of agitation, irritability, unusual

changes in behaviors and other symptoms described above, as well as emergence of

suicidality, and to report such symptoms immediately to health care providers. It is

particularly important that monitoring be undertaken during the initial few months of

antidepressant treatment or at times of dose increase or decrease.

The possibility of a suicide attempt is inherent in schizophrenia; close supervision of high

risk patients should accompany drug therapy.

Prescriptions for quetiapine should be written for the smallest quantity of tablets consistent

with good patient management, to reduce the risk of overdose.

Venous Thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs.

Since patients treated with antipsychotics often present with acquired risk factors for VTE,

all possible risk factors for VTE should be identified before and during treatment with

quetiapine, and preventative measures undertaken.

Extrapyramidal Symptoms (EPS)

In placebo controlled clinical trials of adult patients with schizophrenia, bipolar mania and

maintenance treatment of bipolar disorder, the incidence of EPS was no different from that

of placebo across the recommended therapeutic dose range. In short-term, placebo-

controlled clinical trials of adult patients with bipolar depression, the incidence of EPS

was higher in quetiapine treated patients than in placebo treated patients.

Class Effect: Akathisia has been reported in patients treated with quetiapine. The

presentation of akathisia may be variable and comprises subjective complaints of

restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapses.

Tardive Dyskinesia

Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence

of tardive dyskinesia.

The risk of developing tardive dyskinesia and the likelihood that it will become

irreversible are believed to increase as the duration of treatment and total cumulative dose

of antipsychotic medicines administered to the patient increase. However, tardive

dyskinesia can develop, although much less commonly after relatively brief treatment

periods at low doses.

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

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.

Body Temperature Regulation

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.

Neutropenia And Agranulocytosis

Severe neutropenia (<0.5 x 109 /L) without infection has been uncommonly reported in short term placebo-controlled monotherapy clinical trials with quetiapine. There have been reports of agranulocytosis (severe neutropenia with infection) among all patients treated with quetiapine during clinical trials (rare) as well as post-marketing reports (including fatal cases). Most of these cases of severe neutropenia have occurred within the first two months of starting therapy with quetiapine. There was no apparent dose relationship.

Possible risk factors for neutropenia include pre-existing low white cell count (WBC), a

history of drug induced neutropenia and concomitant use of other medicines that have

been associated with neutropenia.

There have been cases of agranulocytosis in patients without pre-existing risk factors.

Neutropenia should be considered in patients presenting with infection, particularly in the

absence of obvious predisposing factor(s), or in patients with unexplained fever, and

should be managed as clinically appropriate.

Quetiapine should be discontinued in patients with a neutrophil count <1.0 x 109

/L. These patients should be observed for signs and symptoms of infection and neutrophil counts

followed (until they exceed 1.5 x 109 /L).

Hepatic Enzyme Inducers

Concomitant use of quetiapine with hepatic enzyme inducers such as carbamazepine may

substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher doses of quetiapine may need to be considered if quetiapine is used concomitantly with a hepatic enzyme inducer.

CYP3A4 Inhibitors

During concomitant administration of medicines which are potent CYP3A4 inhibitors

(such as azole antifungals, macrolide antibiotics and protease inhibitors), plasma

concentrations of quetiapine can be significantly higher than observed in patients in

clinical trials. Because of this, lower doses of quetiapine should be used.

Special consideration should be given in elderly and debilitated patients. The risk-benefit

ratio needs to be considered on an individual basis in all patients.

Hyperglycemia And Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar

coma or death, has been reported in patients treated with atypical antipsychotics including

quetiapine.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in

the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening glucose control. Patients

with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who

are starting treatment with atypical antipsychotics should undergo fasting blood

glucose testing at the beginning of treatment and periodically during treatment. Any

patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia and weakness. Patients who

develop symptoms of hyperglycemia during treatment with atypical antipsychotics

should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved

when the atypical antipsychotic was discontinued; however, some patients required

continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Lipids

Increases in triglycerides and cholesterol, and decreases in fasting HDL cholesterol have

been observed in clinical trials with quetiapine. Monitoring is recommended at baseline and periodically during treatment for all patients. Lipid changes should be managed as clinically appropriate.

Metabolic Factors

In some patients, a worsening of more than one of the metabolic factors of weight, blood

glucose and lipids were observed in clinical studies. All patients taking antipsychotic

medications such as quetiapine should be monitored for metabolic factors at the start of

treatment and at intervals during treatment in accordance with current local guidelines.

The results of monitoring should be managed as clinically appropriate.

Pancreatitis

Pancreatitis has been reported in clinical trials and during post marketing experience.

Among the post marketing reports, many patients had factors which are known to be

associated with pancreatitis such as increased triglycerides, gallstones and alcohol consumption.

Hepatic

Hepatic failure, including fatalities, has been reported very rarely during the postmarketing period. There have been rare reports of hepatitis in clinical studies. Rare postmarketing reports of hepatitis (with or without jaundice), in patients with or without prior

history, have been received. Very rare cases of hepatic steatosis, cholestatic or mixed liver injury have also been reported in the post-marketing period.

For patients who have known or suspected abnormal hepatic function prior to starting

quetiapine, standard clinical assessment, including measurement of transaminase levels is

recommended. Periodic clinical reassessment with transaminase levels is recommended

for such patients, as well as for patients who develop any signs and symptoms suggestive

of a new onset liver disorder during quetiapine therapy.

Increased Risk of Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with atypical anti-psychotics are

at an increased risk of death compared to placebo. A meta-analysis of seventeen placebo

controlled trials with dementia related behavioral disorders showed a risk of death in the

drug-treated patients of approximately 1.6 to 1.7 times that seen in placebo-treated

patients. The clinical trials included in the meta-analysis were undertaken with olanzapine,

aripiprazole, risperidone, and quetiapine. Over the course of these trials averaging about

10 weeks in duration, the rate of death in drug-treated patients was about 4.5%, compared

to a rate of about 2.6% in the placebo group. Although the causes of death were varied,

most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)

or infectious (e.g., pneumonia) in nature. Quetiapine is not approved for the treatment of

elderly patients with dementia-related psychosis or behavioral disorders.

Withdrawal

Acute withdrawal symptoms such as nausea, vomiting and insomnia have been described

after abrupt cessation of antipsychotic medicines including quetiapine. Gradually withdrawal over a period of at least one to two weeks is advisable.

Dependence/Tolerance

There have been reports of quetiapine misuse, abuse, tolerance, and/or physical

dependence. These cases include adult and adolescent patients using quetiapine alone or

with other substances of abuse. Caution is needed when prescribing quetiapine to patients

with a history of alcohol or drug abuse. Patients should be observed closely for signs of

quetiapine misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behaviors), particularly if they have a history of alcohol or drug abuse.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Quetiapine and other antipsychotic medicines should be used cautiously in patients at risk

for aspiration pneumonia (e.g. elderly patients).

Constipation And Intestinal Obstruction

Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal

obstruction has been reported with quetiapine. This includes fatal reports in patients who are at higher

risk of intestinal obstruction, including those that are receiving multiple concomitants

medications that decrease intestinal motility and/or may not report symptoms of

constipation.

Lactose Monohydrate

QUETIL tablets contain lactose monohydrate. Patients with rare hereditary

problems of galactose intolerance, the lapp lactase deficiency, or glucose-galactose

malabsorption should not take this medicine.

Sleep Apnea

In patients who have a history of or are at risk for sleep apnea, and are receiving

concomitant central nervous system (CNS) depressants, quetiapine should be used with

caution.

Anti-Cholinergic (Muscarinic) Effects

Nor quetiapine, an active metabolite of quetiapine, has moderate to strong affinity for

several muscarinic receptor subtypes. This contributes to adverse drug reactions reflecting

anti-cholinergic effects when quetiapine is used at recommended doses, when used

concomitantly with other medications having anti-cholinergic effects, and in the setting of

overdose. Quetiapine should be used with caution in patients receiving medications having

anti-cholinergic (muscarinic) effects. Quetiapine should be used with caution in patients

with a current diagnosis or prior history of urinary retention, clinically significant prostatic

hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or

narrow angle glaucoma.

Use In the Elderly

Pediatric Use

Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic

evaluation has been performed and careful consideration given to the potential benefits

and risks associated with medication treatment. Medication treatment for both pediatrics

schizophrenia and bipolar I disorder is indicated as part of a total treatment program that

often includes psychological, educational and social interventions.

Efficacy and safety of quetiapine have been demonstrated for adolescents aged from

13 years with schizophrenia and for children/adolescents aged from 10 years with bipolar I

disorder experiencing acute mania in two clinical trials of 6- and 3-weeks duration,

respectively. Safety data was provided for up to 26 weeks in a third open-label safety and

tolerability trial. The safety and efficacy of quetiapine in children and

adolescents have not been assessed beyond these time periods.

Although not all adverse reactions that have been identified in adult patients have been

observed in clinical trials with quetiapine in children and adolescent patients, the same

precautions that appear above for adults should be considered for children and adolescents.

As seen in adults, increases in Thyroid stimulating hormone (TSH), serum cholesterol, triglycerides, and weight have been observed.

The following events were reported more frequently in the short-term studies in children

and adolescents than in studies in adults: EPS, increases in appetite and serum prolactin.

Increased blood pressure has not been identified in the adult population but was seen in

children and adolescents. Blood pressure should be monitored at the beginning of, and

periodically during treatment in children and adolescents.

Long-term safety data including growth, maturation and behavioral development, beyond

26 weeks of treatment with quetiapine are not available for children and adolescents (10 to 17 years of age).

Effects On Laboratory Tests

Leukopenia And/or Neutropenia

As with other antipsychotics, transient leukopenia and/or neutropenia have been observed

in patients administered quetiapine. Possible risk factors for leukopenia and/or

neutropenia includes pre-existing low white cell count and history of drug induced

leukopenia and/or neutropenia. Occasionally, eosinophilia has been observed.

Serum Transaminase

Asymptomatic elevations in serum transaminase (ALT, AST) or γ-GT levels have been

observed in some patients administered quetiapine. These elevations were usually

reversible on continued quetiapine treatment.

Lipids

Increases in triglyceride levels and total cholesterol (predominantly LDL cholesterol) have

been observed during treatment with quetiapine. Decreases in fasting HDL cholesterol

have also been observed.

Thyroid Hormone Levels

Quetiapine treatment was associated with dose-related decreases in thyroid hormone

levels. In short term placebo-controlled clinical trials the incidence of potentially

clinically significant shifts in thyroid hormone levels were total T4 -3.4% for quetiapine

versus 0.6% for placebo; free T4 - 0.7% for quetiapine versus 0.1% for placebo; total T3 -

0.54% for quetiapine versus 0.0% for placebo and free T3 - 0.2% for quetiapine versus

0.0% for placebo. The incidence of shifts in TSH was 3.2 % for quetiapine versus 2.7%

for placebo. In short term placebo- controlled monotherapy trials, the incidence of

reciprocal, potentially clinically significant shifts in T3 and TSH were 0.0% for both

quetiapine and placebo and 0.1% for quetiapine versus 0.0% for placebo for shifts in T4

and TSH. According to the literature, these changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in

total and free T4 was maximal within the first 6 weeks of quetiapine treatment, with no

further reduction during long-term treatment. 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.

Methadone And Tricyclic Antidepressant Enzyme Immunoassays

There have been reports of false positive results in enzyme immunoassays for methadone

and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of

questionable immunoassay screening results by an appropriate chromatographic technique

is recommended.

INTERACTIONS

Antipsychotic And Other Centrally Acting Medicines

Given the primary central nervous system effects of quetiapine, it should be used with

caution in combination with other centrally acting medicines and alcohol.

Thioridazine

Thioridazine (200 mg twice a day) increased the oral clearance of quetiapine (300 mg

twice a day) by 65%.

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 a day dosing. Dosage

adjustment is not required.

Levodopa And Dopamine Agonists

As it exhibits in vitro dopamine antagonism, quetiapine may antagonize the effects of

levodopa and dopamine agonists.

Carbamazepine And Phenytoin

Antipsychotics

The pharmacokinetics of quetiapine were not significantly altered following

co-administration with the antipsychotic’s risperidone (3 mg twice a day) or haloperidol

(7.5 mg twice a day). The pharmacokinetics of lithium were not altered when

co-administered with quetiapine (250 mg three times a day). The pharmacokinetics of

sodium valproate and quetiapine were not altered to a clinically relevant extent when

co-administered.

Imipramine And Fluoxetine

CYP Inhibitors

CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of

quetiapine (see section 5.2 PHARMACOKINETIC PROPERTIES, Metabolism

section). CYP2D6 and CYP2C9 are also involved.

CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics and protease inhibitors)

During concomitant administration of medicines which are potent CYP3A4 inhibitors

(such as azole antifungals, macrolide antibiotics and protease inhibitors), plasma

concentrations of quetiapine can be significantly higher than observed in patients in

clinical trials (refer ketoconazole below). Because of this lower dose of

quetiapine should be used. Special consideration should be given in elderly or debilitated

patients. The risk-benefit ratio needs to be considered on an individual basis.

It is also not recommended to take quetiapine together with grapefruit juice.

Ketoconazole

In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine

given before and during treatment with ketoconazole, co-administration of ketoconazole

(200 mg once daily for 4 days) resulted in an increase in mean Cmax and AUC of

quetiapine of 335% and 522%, respectively, with a corresponding decrease in mean oral

clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours, but the mean tmax was unchanged.

Cimetidine

The pharmacokinetics of quetiapine (150 mg three times a day) were not significant

altered (20% decrease in clearance) following co-administration with cimetidine (400 mg

three times a day for 4 days) a known P450 enzyme inhibitor. Dosage adjustment for

quetiapine is not required when it is given with cimetidine.

Imipramine And Fluoxetine

The pharmacokinetics of quetiapine were not significantly altered following coadministration with the antidepressant’s imipramine (75 mg twice a day; a known CYP2D6

inhibitor) or fluoxetine (60 mg once daily; a known CYP3A4 and CYP2D6 inhibitor).

Hepatic enzyme inducers (e.g. carbamazepine and phenytoin)

Quetiapine (administration of multiple daily doses up to 750 mg/day, on a three times a

day dosing schedule) did not induce the hepatic enzyme systems involved in the

metabolism of antipyrine. However, concomitant use of quetiapine with hepatic enzyme

inducers such as carbamazepine or phenytoin may substantially decrease systemic

exposure to quetiapine (see Carbamazepine and phenytoin below). Depending on

clinical response, increased doses of quetiapine may be required to maintain control of

psychotic symptoms in patients co-administered quetiapine and hepatic enzyme inducers

(e.g. carbamazepine, phenytoin, barbiturates, rifampicin, glucocorticoids). The safety of

doses above 800 mg/day have not been established in the clinical trials. Continued

treatment at higher doses should only be considered because of careful consideration of

the benefit risk assessment for an individual patient.

The dose of quetiapine may need to be reduced if phenytoin, carbamazepine or other

hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g. sodium

valproate).

Carbamazepine And Phenytoin

In a multiple dose trial in patients assessing the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), coadministration 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. Because of this interaction, lower

plasma concentrations can occur, and hence, in each patient, consideration for a higher

dose of quetiapine, depending on clinical response, should be considered.

Co-administration of quetiapine (250 mg three times a day) and phenytoin (100 mg three

times a day; another microsomal enzyme inducer) also caused increases in clearance of

quetiapine by 5-fold.

Cardiovascular Medicines

Caution should be used when quetiapine is used concomitantly with medicines known to

cause electrolyte imbalance or to increase QTc interval.

Because of its potential for inducing hypotension, quetiapine may enhance the effects of

certain anti-hypertensive medicines.

Medications to manage attention deficit hyperactivity disorder (ADHD)

The data regarding safety and efficacy of quetiapine for the treatment of bipolar mania in

children and adolescents receiving psychostimulants for co-morbid ADHD are limited.

Therefore, concomitant use of ADHD medication and quetiapine is not recommended. If concomitant therapy is considered necessary, patients should be carefully monitored for

the effect of the combination of treatments on the signs and symptoms of both ADHD and

acute mania. Effects on blood pressure may be cumulative and blood pressure should be

carefully monitored.

Anti-Cholinergic (Muscarinic) Effects

Caution should be exercised by treating patients receiving other medications that have anticholinergic (muscarinic).

Effects on Fertility

Effects related to elevated prolactin levels (marginal reduction in male fertility and

pseudopregnancy, protracted periods of dioestrus, increased precoital interval and reduced

pregnancy rate) were seen in rats, although these are not directly relevant to humans

because of species differences in hormonal control of reproduction

Use in Pregnancy (Category C)

The safety and efficacy of quetiapine during human pregnancy have not been established.

Non-teratogenic class effect: Neonates exposed to antipsychotic medicines (including

quetiapine) during the third trimester of pregnancy are at risk of experiencing

extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery.

There have been post-market reports of agitation, hypertonia, hypotonia, tremors,

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 additional medical treatment or monitoring.

Quetiapine should be used during pregnancy only if the anticipated benefit outweighs the

risk and the administered dose and duration of treatment should be as low and as short as

possible.

Teratogenic effects were not observed following administration of quetiapine at oral doses

up to 200 mg/kg in rats (less than the exposure to quetiapine at the maximum

recommended clinical dose based on AUC) and 100 mg/kg in rabbits (approximately

twice the maximum clinical exposure based on BSA).

Use In Lactation

There have been published reports of quetiapine excretion into human breast milk, however the degree of excretion was not consistent in a study in lactating rats the

concentration of quetiapine and/or its metabolites was higher in milk than in plasma.

Women who are breast-feeding should therefore be advised to avoid breast-feeding while

taking quetiapine.

Somnolence has been very commonly reported in patients treated with quetiapine. Given

its primary central nervous system effects, quetiapine has the potential to impair

judgement, thinking or motor skills. Patients are likely to drive or operate other machines

should therefore be cautioned appropriately.

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

Frequency System Organ Class Reaction

Very common (≥10%) Nervous system disorders Extrapyramidal symptoms

Common (≥1% to <10%)

Cardiac Disorders: Palpitations

Eye Disorders: Vision blurred

Gastrointestinal Disorders: Vomiting

General Disorders And Administration Site Conditions:

Peripheral oedema;

Irritability; Pyrexia

Metabolism & Nutritional

Disorders: Increased appetite

Nervous System Disorders: Dysarthria

Psychiatric Disorders: Abnormal dreams and nightmares

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Blood Disorder: Leukopenia

Cardiac Disorders: Bradycardia

Gastrointestinal Disorders: Dysphagia

Immune System Disorders: Hypersensitivity

Nervous System Disorders: Syncope; Seizure; Restless legs syndrome; Tardive dyskinesia

Pharmacodynamic Properties

Mechanism of Action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the human plasma

metabolite, nor quetiapine, interact with a broad range of neurotransmitter receptors.

Quetiapine and nor quetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1

and D2 receptors; this combination of receptor antagonism with a higher selectivity for

5HT2 relative to D2 receptors is believed to contribute to the clinical antipsychotic

properties and low extrapyramidal side effects (EPS) liability of quetiapine compared to

typical antipsychotics. Quetiapine has no affinity for the norepinephrine transporter (NET)

and low affinity for the serotonin 5HT1A receptor, whereas nor quetiapine has high affinity

for both. Inhibition of NET and partial agonist action at 5HT1A sites by nor quetiapine may

contribute to Quetiapine therapeutic efficacy as an antidepressant. Quetiapine and

nor quetiapine have high affinity at histaminergic and adrenergic alpha1 receptors and

moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity

for muscarinic receptor, while nor quetiapine has moderate to high affinity for several

muscarinic receptor subtypes, which may explain anti-cholinergic (muscarinic) effects.

Nor quetiapine metabolite 7-hydroxy nor quetiapine also have affinity for histaminergic

H1 and 5HT2B and 2C receptors at clinically relevant concentrations.

Absorption

Quetiapine is well absorbed and the bioavailability of quetiapine is not significantly

affected by administration with food.

Distribution

The elimination half-lives of quetiapine and nor quetiapine are approximately 7 and

12 hours respectively. Quetiapine is approximately 83% bound to plasma proteins. Steady

state peak molar concentrations of the active metabolite nor quetiapine are 35% of that

observed for quetiapine.

The pharmacokinetics of quetiapine and nor quetiapine are linear across the approved

dosage range. The kinetics of quetiapine do not differ between men and women.

Metabolism

Quetiapine is extensively metabolized by the liver following oral administration, with

parent compound accounting for less than 5% of unchanged drug related material in the

urine or faces, following the administration of radiolabeled quetiapine. The average molar does fraction of free quetiapine and the active human plasma metabolite

nor quetiapine is <5% excreted in the urine.

In Vitro investigations established that CYP3A4 is likely to be the primary enzyme

responsible for cytochrome P450 mediated metabolism of quetiapine. Nor quetiapine is

primarily formed and eliminated via CYP3A4. CYP2D6 and CYP2C9 are also involved

in quetiapine metabolism.

Quetiapine and several of its metabolites (including nor quetiapine) were found to be weak

to modest inhibitors of human cytochrome P450 3A4, 2C19, 2D6, 1A2 and 2C9 activities

in vitro. In Vitro CYP inhibition is observed only at concentrations approximately 5 to 50-

fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on

these in vitro results, it is unlikely that coadministration of quetiapine with other

medicines will result in clinically significant drug inhibition of cytochrome P450 mediated

metabolism of the other drug. From animal studies it appears that quetiapine can induce

cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.

Excretion

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faces.

Special Patient Populations

Use in the Elderly

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than

that seen in adults aged 18 to 65 years.

Use In Renal Impairment

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects

with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m2), but the

individual clearance values are within the range for normal subjects.

Use In Hepatic Impairment

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects

with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values

are within the range for normal subjects. Since quetiapine is extensively metabolized by

the liver, higher plasma levels are expected in the hepatically impaired population, and

dosage adjustment may be needed in these patients.

Pediatric use (10 to 17 years of age)

At steady-state the pharmacokinetics of the parent compound in children and adolescents

(10-17 years of age) were like adults, while AUC and Cmax of the active metabolite,

nor quetiapine, were higher in children and adolescents than in adults, 45% and 31%,

respectively. However, when adjusted for weight AUC and Cmax of the parent compound

in children and adolescents were lower than in adults, 41% and 39%, respectively, while the pharmacokinetics of the metabolite, nor quetiapine, were similar.

Store below 25°C