DRUG INTERACTIONS
7 Concomitant Use of Strong CYP3A4 Inhibitors: Reduce quetiapine dose to one sixth when coadministered with strong CYP3A4 inhibitors (e.g.
ketoconazole, ritonavir) ( 2.5 , 7.1 , 12.3 ) Concomitant Use of Strong CYP3A4 Inducers: Increase quetiapine dose up to 5 fold when used in combination with a chronic treatment (more than 7 to 14 days) of potent CYP3A4 inducers (e.g.
phenytoin, rifampin, St.
John’s wort) ( 2.6 , 7.1 , 12.3 ) Discontinuation of Strong CYP3A4 Inducers: Reduce quetiapine dose by 5 fold within 7 to 14 days of discontinuation of CYP3A4 inducers ( 2.6 , 7.1 , 12.3 ) 7.1 Effect of Other Drugs on Quetiapine 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 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 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.
CYP3A4 Inhibitors Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure.
The dose of quetiapine should be reduced to one sixth of the original dose if co-administered with a strong CYP3A4 inhibitor [see DOSAGE AND ADMINISTRATION ( 2.5 ) and CLINICAL PHARMACOLOGY ( 12.3 )].
CYP3A4 Inducers Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold.
Increased doses of quetiapine 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 should be reduced to the original level within 7 to 14 days [see DOSAGE AND ADMINISTRATION ( 2.6 )].
The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied [see CLINICAL PHARMACOLOGY ( 12.3 )].
7.2 Effect of Quetiapine on Other Drugs 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.
There are no clinically relevant pharmacokinetic interactions of quetiapine on other drugs based on the CYP pathway.
Quetiapine and its metabolites are non-inhibitors of major metabolizing CYP’s (1A2, 2C9, 2C19, 2D6 and 3A4).
OVERDOSAGE
10 10.1 Human Experience In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine.
Most patients who overdosed experienced no adverse reactions or recovered fully from the reported reactions.
Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone.
In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension.
Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see WARNINGS AND PRECAUTIONS ( 5.12 )].
One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first-degree heart block.
In post-marketing experience, there were cases reported of QT prolongation with overdose.
There were also very rare reports of overdose of quetiapine alone resulting in death or coma.
10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation.
Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of quetiapine.
Similarly it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.
There is no specific antidote to quetiapine.
Therefore, appropriate supportive measures should be instituted.
The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade).
In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Close medical supervision and monitoring should continue until the patient recovers.
DESCRIPTION
11 Quetiapine fumarate is a psychotropic agent belonging to a chemical class, the dibenzothiazepine derivatives.
The chemical designation is 2-[2-(4-dibenzo [b , f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt).
It is present in tablets as the fumarate salt.
All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt.
Its molecular formula is C 42 H 50 N 6 O 4 S 2 .
C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt).
The structural formula is: Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.
Quetiapine tablets USP are supplied for oral administration as 25 mg (quetiapine) round, pink tablets, 50 mg (quetiapine) round, white tablets, 100 mg (quetiapine) round, yellow tablets, 200 mg (quetiapine) round, white tablets, 300 mg (quetiapine) capsule-shaped, white tablets and 400 mg (quetiapine) capsule-shaped, yellow tablets.
Inactive ingredients are dibasic calcium phosphate dihydrate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide.
The 25 mg tablets contain iron oxide red and iron oxide black; and the 100 mg and 400 mg tablets contain iron oxide yellow.
CLINICAL STUDIES
14 14.1 Schizophrenia Short-term Trials-Adults The efficacy of quetiapine in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia.
Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of quetiapine and haloperidol.
Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.
A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
The results of the trials follow: In a 6-week, placebo-controlled trial (n=361) (study 1) involving 5 fixed doses of quetiapine (75 mg/day, 150 mg/day, 300 mg/day, 600 mg/day and 750 mg/day given in divided doses three times per day), the 4 highest doses of quetiapine were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 mg/day to 750 mg/day were generally indistinguishable.
In a 6-week, placebo-controlled trial (n=286) (study 2) involving titration of quetiapine in high (up to 750 mg/day given in divided doses three times per day) and low (up to 250 mg/day given in divided doses three times per day) doses, only the high dose quetiapine group (mean dose, 500 mg/day) was superior to placebo on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.
In a 6-week dose and dose regimen comparison trial (n=618) (study 3) involving two fixed doses of quetiapine (450 mg/day given in divided doses both twice daily and three times daily and 50 mg/day given in divided doses twice daily), only the 450 mg/day (225 mg given twice daily) dose group was superior to the 50 mg/day (25 mg given twice daily) quetiapine dose group on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.
The primary efficacy results of these three studies in the treatment of schizophrenia in adults is presented in Table 19.
Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 years compared to those older than 40.
The clinical significance of this finding is unknown.
Adolescents (Ages 13 to 17) The efficacy of quetiapine in the treatment of schizophrenia in adolescents (13 to 17 years of age) was demonstrated in a 6-week, double-blind, placebo-controlled trial (study 4).
Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: quetiapine 400 mg/day (n=73), quetiapine 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 at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score.
The primary efficacy results of this study in the treatment of schizophrenia in adolescents are presented in Table 19.
Table 19: Schizophrenia Short-Term Trials SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI:unadjusted confidence interval.
Study Number Treatment Group Primary Efficacy Endpoint : BPRS Total Mean Baseline Score ( SD ) LS Mean Change from Baseline ( SE ) Placebo – subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline.
( 95 % CI ) Quetiapine (75 mg/day) 45.7 (10.9) -2.2 (2.0) -4.0 (-11.2, 3.3) Quetiapine (150 mg/day) Doses that are statistically significant superior to placebo.
47.2 (10.1) -8.7 (2.1) -10.4 (-17.8, -3.0) Study 1 Quetiapine (300 mg/day) 45.3 (10.9) -8.6 (2.1) -10.3 (-17.6, -3.0) Quetiapine (600 mg/day) 43.5 (11.3) -7.7 (2.1) -9.4 (-16.7, -2.1) Quetiapine (750 mg/day) 45.7 (11.0) -6.3 (2.0) -8.0 (-15.2, -0.8) Placebo 45.3 (9.2) 1.7 (2.1) — Quetiapine (250 mg/day) 38.9 (9.8) -4.2 (1.6) -3.2 (-7.6, 1.2) Study 2 Quetiapine (750 mg/day) 41.0 (9.6) -8.7 (1.6) -7.8 (-12.2, -3.4) Placebo 38.4 (9.7) -1.0 (1.6) — Quetiapine (450 mg/day BID) 42.1 (10.7) -10.0 (1.3) -4.6 (-7.8, -1.4) Study 3 Quetiapine (450 mg/day TID) Doses that are statistically significant superior to quetiapine 50 mg BID.
42.7 (10.4) -8.6 (1.3) -3.2 (-6.4, 0.0) Quetiapine (50 mg BID) 41.7 (10.0) -5.4 (1.3) — Primary Efficacy Endpoint : PANSS Total Mean Baseline Score ( SD ) LS Mean Change from Baseline ( SE ) Placebo – subtracted Difference ( 95 % CI ) Quetiapine (400 mg/day) 96.2 (17.7) -27.3 (2.6) -8.2 (-16.1, -0.3) Study 4 Quetiapine (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) — 14.2 Bipolar Disorder Bipolar I Disorder , Manic or Mixed Episodes Adults: The efficacy of quetiapine in the acute treatment of manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes.
These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes.
Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex.
Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy.
Adjunct therapy is defined as the simultaneous initiation or subsequent administration of quetiapine with lithium or divalproex.
The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).
The results of the trials follow: Monotherapy The efficacy of quetiapine in the acute treatment of bipolar mania was established in 2 placebo-controlled trials.
In two 12-week trials (n=300, n=299) comparing quetiapine to placebo, quetiapine was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12.
The majority of patients in these trials taking quetiapine were dosed in a range between 400 mg/day and 800 mg per day (studies 1 and 2 in Table 20).
Adjunct Therapy In this 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥20) were randomized to receive quetiapine or placebo as adjunct treatment to lithium or divalproex.
Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization.
Quetiapine was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score (study 3 in Table 20).
The majority of patients in this trial taking quetiapine were dosed in a range between 400 mg/day and 800 mg per day.
In a similarly designed trial (n=200), quetiapine was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.
The primary efficacy results of these studies in the treatment of mania in adults is presented in Table 20.
Children and Adolescents (Ages 10 to 17): The efficacy of quetiapine in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial (study 4 in Table 20).
Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: quetiapine 400 mg/day (n=95), quetiapine 600 mg/day (n=98), or placebo (n=91).
Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily).
Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily.
The primary efficacy variable was the mean change from baseline in total YMRS score.
Quetiapine 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (Table 20).
Bipolar Disorder , Depressive Episodes Adults: The efficacy of quetiapine for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (N=1045) (studies 5 and 6 in Table 21).
These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course.
Patients randomized to quetiapine were administered fixed doses of either 300 mg or 600 mg once daily.
The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 to 60.
The primary endpoint in both studies was the change from baseline in MADRS score at week 8.
In both studies, quetiapine was superior to placebo in reduction of MADRS score.
Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1) and onwards.
In these studies, no additional benefit was seen with the 600 mg dose.
For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).
The primary efficacy results of these studies in the acute treatment of depressive episodes associated with bipolar disorder in adults is presented in Table 21.
Table 21: Depressive Episodes Associated with Bipolar Disorder SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
Study Number Treatment Group Primary Efficacy Measure : MADRS Total Mean Baseline Score ( SD ) LS Mean Change from Baseline ( SE ) Placebo – subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline.
( 95 % CI ) Quetiapine (300 mg/day) Doses that are statistically significantly superior to placebo.
30.3 (5.0) -16.4 (0.9) -6.1 (-8.3, -3.9) Study 5 Quetiapine (600 mg/day) 30.3 (5.3) -16.7 (0.9) -6.5 (-8.7, -4.3) Placebo 30.6 (5.3) -10.3 (0.9) — Quetiapine (300 mg/day) 31.1 (5.7) -16.9 (1.0) -5.0 (-7.3, -2.7) Study 6 Quetiapine (600 mg/day) 29.9 (5.6) -16.0 (1.0) -4.1 (-6.4, -1.8) Placebo 29.6 (5.4) -11.9 (1.0) — Maintenance Treatment as an Adjunct to Lithium or Divalproex The efficacy of quetiapine in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 7 and 8 in Figures 1 and 2).
The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features.
In the open-label phase, patients were required to be stable on quetiapine plus lithium or divalproex for at least 12 weeks in order to be randomized.
On average, patients were stabilized for 15 weeks.
In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either quetiapine (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo.
Approximately 50% of the patients had discontinued from the quetiapine group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment.
The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode).
A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥20 or MADRS score ≥20 at 2 consecutive assessments; or study discontinuation due to a mood event.
(Figure 1 and Figure 2) In both studies, quetiapine was superior to placebo in increasing the time to recurrence of any mood event.
The treatment effect was present for increasing time to recurrence of both manic and depressed episodes.
The effect of quetiapine was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).
Figure 1: Kaplan-Meier Curves of Time to Recurrence of A Mood Event (Study 7) Figure 2: Kaplan-Meier Curves of Time to Recurrence of A Mood Event (Study 8) Table 20: Mania Trials Mood stabilizer: lithium or divalproex; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
Study Number Treatment Group Primary Efficacy Measure : YMRS Total Mean Baseline Score ( SD ) Adult data mean baseline score is based on patients included in the primary analysis; pediatric mean baseline score is based on all patients in the ITT population.
LS Mean Change from Baseline ( SE ) Placebo – Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline.
( 95 % CI ) Quetiapine (200 to 800 mg/day) Doses that are statistically significantly superior to placebo.
Included in the trial as an active comparator.
34.0 (6.1) -12.3 (1.3) -4.0 (-7.0, -1.0) Study 1 Haloperidol 32.3 (6.0) -15.7 (1.3) -7.4 (-10.4, -4.4) Placebo 33.1 (6.6) -8.3 (1.3) — Quetiapine (200 to 800 mg/day) 32.7 (6.5) -14.6 (1.5) -7.9 (-10.9, -5.0) Study 2 Lithium 33.3 (7.1) -15.2 (1.6) -8.5 (-11.5, -5.5) Placebo 34.0 (6.9) -6.7 (1.6) — Study 3 Quetiapine (200 to 800 mg/day) + mood stabilizer 31.5 (5.8) -13.8 (1.6) -3.8 (-7.1, -0.6) Placebo + mood stabilizer 31.1 (5.5) -10 (1.5) — Quetiapine (400 mg/day) 29.4 (5.9) -14.3 (0.96) -5.2 (-8.1, -2.3) Study 4 Quetiapine (600 mg/day) 29.6 (6.4) -15.6 (0.97) -6.6 (-9.5, -3.7) Placebo 30.7 (5.9) -9.0 (1.1) —
HOW SUPPLIED
16 /STORAGE AND HANDLING Quetiapine tablets USP , 25 mg (as quetiapine) are pink colored, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y15” on the other side, which are supplied as follows: NDC 68180-445-01 Bottle of 100s NDC 68180-445-03 Bottle of 1000s NDC 68180-445-13 Unit Dose Blisters of 10 x 10s Quetiapine tablets USP , 50 mg (as quetiapine) are white, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y16” on the other side, which are supplied as follows: NDC 68180-446-01 Bottle of 100s NDC 68180-446-03 Bottle of 1000s NDC 68180-446-13 Unit Dose Blisters of 10 x 10s Quetiapine tablets USP, 100 mg (as quetiapine) are yellow colored, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y17” on the other side, which are supplied as follows: NDC 68180-447-01 Bottle of 100s NDC 68180-447-03 Bottle of 1000s NDC 68180-447-13 Unit Dose Blisters of 10 x 10s Quetiapine tablets USP, 200 mg (as quetiapine) are white, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y18” on the other side, which are supplied as follows: NDC 68180-448-01 Bottle of 100s NDC 68180-448-02 Bottle of 500s NDC 68180-448-03 Bottle of 1000s NDC 68180-448-13 Unit Dose Blisters of 10 x 10s Quetiapine tablets USP, 300 mg (as quetiapine) are white, capsule shape, biconvex, film-coated tablets, debossed “LU” on one side and “Y19” on the other side, which are supplied as follows: NDC 68180-449-07 Bottle of 60s NDC 68180-449-01 Bottle of 100s NDC 68180-449-02 Bottle of 500s NDC 68180-449-03 Bottle of 1000s NDC 68180-449-13 Unit Dose Blisters of 10 x 10s Quetiapine tablets USP, 400 mg (as quetiapine) are yellow colored, capsule shape, biconvex, film-coated tablets, debossed “LU” on one side and “Y20” on the other side, which are supplied as follows: NDC 68180-450-01 Bottle of 100s NDC 68180-450-02 Bottle of 500s NDC 68180-450-03 Bottle of 1000s NDC 68180-450-13 Unit Dose Blisters of 10 x 10s Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Warnings and Precautions, Falls ( 5.8 ) 02/2017
GERIATRIC USE
8.5 Geriatric Use Of the approximately 3700 patients in clinical studies with quetiapine, 7% (232) were 65 years of age or over.
In general, there was no indication of any different tolerability of quetiapine in the elderly compared to younger adults.
Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly.
The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see CLINICAL PHARMACOLOGY ( 12.3 ) and DOSAGE AND ADMINISTRATION ( 2.3 )].
DOSAGE FORMS AND STRENGTHS
3 Tablets: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg ( 3 ) Quetiapine tablets, 25 mg (as quetiapine) are pink colored, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y15” on the other side.
Quetiapine tablets, 50 mg (as quetiapine) are white, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y16” on the other side.
Quetiapine tablets, 100 mg (as quetiapine) are yellow colored, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y17” on the other side.
Quetiapine tablets, 200 mg (as quetiapine) are white, round, biconvex, film-coated tablets, debossed “LU” on one side and “Y18” on the other side.
Quetiapine tablets, 300 mg (as quetiapine) are white, capsule shape, biconvex, film-coated tablets, debossed “LU” on one side and “Y19” on the other side.
Quetiapine tablets, 400 mg (as quetiapine) are yellow colored, capsule shape, biconvex, film-coated tablets, debossed “LU” on one side and “Y20” on the other side.
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of quetiapine is unknown.
However, it has been proposed that the efficacy of quetiapine in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism.
Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other effects of quetiapine.
Quetiapine’s antagonism of histamine H 1 receptors may explain the somnolence observed with this drug.
Quetiapine’s antagonism of adrenergic α 1 receptors may explain the orthostatic hypotension observed with this drug.
INDICATIONS AND USAGE
1 Quetiapine fumarate tablet USP is an atypical antipsychotic indicated for the treatment of: Schizophrenia ( 1.1 ) Bipolar I disorder manic episodes ( 1.2 ) Bipolar disorder, depressive episodes ( 1.2 ) 1.1 Schizophrenia Quetiapine tablets USP are indicated for the treatment of schizophrenia.
The efficacy of quetiapine tablets USP in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (13 to 17 years).
The effectiveness of quetiapine tablets USP for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see CLINICAL STUDIES ( 14.1 )].
1.2 Bipolar Disorder Quetiapine tablets USP are indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex.
Efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10 to 17 years) [see CLINICAL STUDIES ( 14.2 )].
Quetiapine tablets USP are indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder.
Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [see CLINICAL STUDIES ( 14.2 )].
Quetiapine tablets USP are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex.
Efficacy was established in two maintenance trials in adults.
The effectiveness of quetiapine tablets USP as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see CLINICAL STUDIES ( 14.2 )].
1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder 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 risks associated with medication treatment.
Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.
PEDIATRIC USE
8.4 Pediatric Use In general, the adverse reactions observed in children and adolescents during the clinical trials 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 to 7%) compared to children and adolescents (<1%) [see WARNINGS AND PRECAUTIONS ( 5.7 ) and ADVERSE REACTIONS ( 6.1 )].
Schizophrenia The efficacy and safety of quetiapine in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [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 in pediatric patients less than 13 years of age with schizophrenia have not been established.
Maintenance The safety and effectiveness of quetiapine in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age.
The safety and effectiveness of quetiapine in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.
Bipolar Mania The efficacy and safety of quetiapine in the treatment of mania in children and adolescents ages 10 to 17 years with Bipolar I disorder was demonstrated in a 3-week, double-blind, placebo controlled, multicenter trial [see INDICATIONS AND USAGE ( 1.2 ), DOSAGE AND ADMINISTRATION ( 2.3 ), ADVERSE REACTIONS ( 6.1 ), and CLINICAL STUDIES ( 14.2 )].
Safety and effectiveness of quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.
Bipolar Depression Safety and effectiveness of quetiapine in pediatric patients less than 18 years of age with bipolar depression have not been established.
A clinical trial with quetiapine extended-release was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established.
Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 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 )].
PREGNANCY
8.1 Pregnancy Pregnancy Category C Risk Summary: There are no adequate and well-controlled studies of quetiapine 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Human Data: 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), 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.
Animal Data: When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect 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, which included delays in skeletal ossification occurring at approximately 1 and 2 times the MRHD of 800 mg/day 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 approximately 1 to 2 times the MRHD (all doses tested) 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, 0.12, and 0.24 times the MRHD of 800 mg/day based 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.
NUSRING MOTHERS
8.3 Nursing Mothers Quetiapine was excreted into human milk.
Because of the potential for serious adverse reactions in nursing infants from quetiapine, 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 mcg/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).
BOXED WARNING
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Quetiapine is not approved for elderly patients with dementia-related psychosis ( 5.1 ) Suicidal Thoughts and Behaviors Increased risk of suicidal thoughts and behavior in children, adolescents and young adults taking antidepressants ( 5.2 ) Monitor for worsening and emergence of suicidal thoughts and behaviors ( 5.2 ) Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see WARNINGS AND PRECAUTIONS ( 5.1 )].
Quetiapine is not approved for the treatment of patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS ( 5.1 )].
Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies.
These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS ( 5.2 )].
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors.
Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS ( 5.2 )].
Quetiapine is not approved for use in pediatric patients under ten years of age [see USE IN SPECIFIC POPULATIONS ( 8.4 )].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions: Increased incidence of cerebrovascular adverse events (e.g.
stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs ( 5.3 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring ( 5.4 ) Metabolic Changes: Atypical antipsychotics have been associated with metabolic changes.
These metabolic changes include hyperglycemia, dyslipidemia, and weight gain ( 5.5 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.
Monitor glucose regularly in patients with diabetes or at risk for diabetes Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.
Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically, during treatment Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.6 ) Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease ( 5.7 ) Increased Blood Pressure in Children and Adolescents: Monitor blood pressure at the beginning of, and periodically during treatment in children and adolescents ( 5.9 ) Leukopenia, Neutropenia and Agranulocytosis: Monitor complete blood count frequently during the first few months of treatment in patients with a pre-existing low white cell count or a history of leukopenia/neutropenia and discontinue quetiapine at the first sign of a decline in WBC in absence of other causative factors ( 5.10 ) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment.
Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.
Over the course of a typical 10-week controlled trial, 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.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
Quetiapine is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING ].
5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Age Range Drug – Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for quetiapine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.
Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, including quetiapine, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects.
Quetiapine is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5.1 )].
5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine.
Rare cases of NMS have been reported with quetiapine.
Clinical manifestations of NMS are hyperpyrexia, 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 creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated.
In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.
There is no general agreement about specific pharmacological treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored since recurrences of NMS have been reported.
5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain.
While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies.
Changes in these metabolic profiles should be managed as clinically appropriate.
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 reactions is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
Precise risk estimates for hyperglycemia-related adverse reactions 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 of 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.
Adults: Table 3: Fasting Glucose-Proportion of Patients Shifting to ≥126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled Studies * * Includes quetiapine and quetiapine extended-release data Laboratory Analyte Category Change ( At Least Once ) from Baseline Treatment Arm N Patients n (%) Normal to High (<100 mg/dL to ≥126 mg/dL) Quetiapine 2907 71 (2.4%) Placebo 1346 19 (1.4%) Fasting Glucose Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) In a 24-week trial (active-controlled, 115 patients treated with quetiapine) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥126 mg/dL was 2.6%.
The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2-hour glucose from baseline was -1.8 mg/dL for quetiapine.
In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for quetiapine (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and -0.05 mg/dL for placebo.
The exposure-adjusted rate of any increased blood glucose level (≥126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).
Children and Adolescents: In a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was -0.75 mg/dL versus -1.70 mg/dL.
In a placebo-controlled quetiapine monotherapy study of children and adolescent patients (10 to 17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dL versus -1.17 mg/dL.
No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.
In a placebo-controlled quetiapine extended-release monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for quetiapine extended-release (n=60) compared to placebo (n=62) was 1.8 mg/dL versus 1.6 mg/dL.
In this study, there were no patients in the quetiapine extended-release or placebo-treated groups with a baseline normal fasting glucose level (126 mg/dL.
There was one patient in the quetiapine extended-release group with a baseline borderline fasting glucose level (>100 mg/dL and 126 mg/dL compared to zero patients in the placebo group.
Dyslipidemia Adults: Table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with quetiapine.
Table 4: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%) Schizophrenia 6 weeks duration Quetiapine 137 24 (18%) Placebo 92 6 (7%) Total Cholesterol ≥240 mg/dL Bipolar Depression 8 weeks duration Quetiapine 463 41 (9%) Placebo 250 15 (6%) Schizophrenia Quetiapine 120 26 (22%) Placebo 70 11 (16%) Triglycerides ≥200 mg/dL Bipolar Depression Quetiapine 436 59 (14%) Placebo 232 20 (9%) Schizophrenia Quetiapine na Parameters not measured in the quetiapine registration studies for schizophrenia.
Lipid parameters also were not measured in the bipolar mania registration studies.
na Placebo na na LDL- Cholesterol ≥160 mg/dL Bipolar Depression Quetiapine 465 29 (6%) Placebo 256 12 (5%) Schizophrenia Quetiapine na na Placebo na na HDL-Cholesterol ≤40 mg/dL Bipolar Depression Quetiapine 393 56 (14%) Placebo 214 29 (14%) Children and Adolescents: Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine.
Table 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels Laboratory Analyte Indication Treatment Arm N Patients n (%) Schizophrenia 13 to 17 years, 6 weeks duration Quetiapine 107 13 (12%) Placebo 56 1 (2%) Total Cholesterol ≥200 mg/dL Bipolar Mania 10 to 17 years, 3 weeks duration Quetiapine 159 16 (10%) Placebo 66 2 (3%) Schizophrenia Quetiapine 103 17 (17%) Placebo 51 4 (8%) Triglycerides ≥150 mg/dL Bipolar Mania Quetiapine 149 32 (22%) Placebo 60 8 (13%) Schizophrenia Quetiapine 112 4 (4%) Placebo 60 1 (2%) LDL-Cholesterol ≥130 mg/dL Bipolar Mania Quetiapine 169 13 (8%) Placebo 74 4 (5%) Schizophrenia Quetiapine 104 16 (15%) Placebo 54 10 (19%) HDL-Cholesterol ≤40 mg/dL Bipolar Mania Quetiapine 154 16 (10%) Placebo 61 4 (7%) In a placebo-controlled quetiapine extended-release monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥130 mg/dL) and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for quetiapine extended-release vs.
6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine extended-release vs.
9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for quetiapine extended-release vs.
4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for quetiapine extended-release vs.
15% (11/74) for placebo.
Weight Gain Increases in weight have been observed in clinical trials.
Patients receiving quetiapine should receive regular monitoring of weight.
Adults: In clinical trials with quetiapine the following increases in weight have been reported.
Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults) Vital Sign Indication Treatment Arm N Patients n (%) Schizophrenia up to 6 weeks duration Quetiapine 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) up to 12 weeks duration Quetiapine 209 44 (21%) Weight Gain ≥ 7 % of Body Weight Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) up to 3 weeks duration Quetiapine 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression up to 8 weeks duration Quetiapine 554 47 (8%) Placebo 295 7 (2%) Children and Adolescents: In two clinical trials with quetiapine, one in bipolar mania and one in schizophrenia, reported increases in weight are included in table 7.
Table 7: Proportion of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents) Vital Sign Indication Treatment Arm N Patients n (%) Schizophrenia 6 weeks duration Quetiapine 111 23 (21%) Placebo 44 3 (7%) Weight Gain ≥ 7 % of Body Weight Bipolar Mania 3 weeks duration Quetiapine 157 18 (12%) Placebo 68 0 (0%) The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine group and 0.4 kg in the placebo group.
In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine.
After 26 weeks of treatment, the mean increase in body weight was 4.4 kg.
Forty-five percent of the patients gained ≥7% of their body weight, not adjusted for normal growth.
In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on quetiapine met this criterion after 26 weeks of treatment.
In a clinical trial for quetiapine extended-release in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for quetiapine extended-release vs.
10% (10/100) for placebo.
The mean change in body weight was 1.4 kg in the quetiapine extended-release group vs.
0.6 kg in the placebo group.
When treating pediatric patients with quetiapine for any indication, weight gain should be assessed against that expected for normal growth.
5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine.
Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.
Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.
The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.
Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) 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 clinical response should be sought.
The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine, drug discontinuation should be considered.
However, some patients may require treatment with quetiapine despite the presence of the syndrome.
5.7 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 α 1 -adrenergic antagonist properties.
Syncope was reported in 1% (28/3265) of the patients treated with quetiapine, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs.
Orthostatic hypotension, dizziness, and syncope may lead to falls.
Quetiapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications).
The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see DOSAGE AND ADMINISTRATION ( 2.2 )].
If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.
5.8 Falls Atypical antipsychotic drugs, including quetiapine, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.
For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
5.9 Increases in Blood Pressure (Children and Adolescents) In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine and 24.5% (40/163) for placebo.
In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis.
Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.
In a placebo-controlled quetiapine extended-release clinical trial (8 weeks duration) in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for quetiapine extended-release and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for quetiapine extended-release and 36.0% (36/100) for placebo.
5.10 Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine.
Agranulocytosis (including fatal cases) has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia.
Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine at the first sign of a decline in WBC in absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.
Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue quetiapine and have their WBC followed until recovery.
5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see NONCLINICAL TOXICOLOGY ( 13.2 )].
Lens changes have also been observed in adults, children and adolescents during long-term quetiapine treatment, but a causal relationship to quetiapine use has not been established.
Nevertheless, the possibility of lenticular changes cannot be excluded at this time.
Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.
5.12 QT Prolongation In clinical trials, quetiapine was not associated with a persistent increase in QT intervals.
However, the QT effect was not systematically evaluated in a thorough QT study.
In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see OVERDOSAGE ( 10.1 )], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see DRUG INTERACTIONS ( 7.1 )].
The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g.
cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).
5.13 Seizures During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs.
As with other antipsychotics, quetiapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.
Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
5.14 Hypothyroidism Adults Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels.
The reduction in total and free thyroxine (T 4 ) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy.
In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4 , irrespective of the duration of treatment.
The mechanism by which quetiapine effects the thyroid axis is unclear.
If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status.
Therefore, both TSH and free T 4 , in addition to clinical assessment, should be measured at baseline and at follow-up.
In the mania adjunct studies, where quetiapine was added to lithium or divalproex, 12% (24/196) of quetiapine treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels.
Of the quetiapine treated patients with elevated TSH levels, 3 had simultaneous low free T 4 levels (free T 4 <0.8 LLN).
About 0.7% (26/3489) of quetiapine patients did experience TSH increases in monotherapy studies.
Some patients with TSH increases needed replacement thyroid treatment.
In all quetiapine trials, the incidence of significant shifts in thyroid hormones and TSH were 1 : decrease in free T 4 (free T 4 <0.8 LLN), 2.0% (357/17513); decrease in total T 4 , 4.0% (75/1861); decrease in free T 3 , 0.4% (53/13766); decrease in total T 3 , 2.0% (26/1312), and increase in TSH, 4.9% (956/19412).
In eight patients, where TBG was measured, levels of TBG were unchanged.
1 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline.
Shifts in total T 4 , free T 4 , total T 3 and free T 3 are defined as 5 mIU/L at any time.
Table 8 shows the incidence of these shifts in short-term placebo-controlled clinical trials.
Table 8: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short-Term Placebo-Controlled Clinical Trials 1 , 2 1 Based on shifts from normal baseline to potentially clinically important value at any time post-baseline.
Shifts in total T 4 , free T 4 , total T 3 and free T 3 are defined as 5 mIU/L at any time.
2 Includes quetiapine and quetiapine extended-release data.
Total T 4 Free T 4 Total T 3 Free T 3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4% (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.
Children and Adolescents In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts for thyroid function values at any time for quetiapine treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs.
0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs.
0% (0/145, respectively).
Of the quetiapine treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment.
5.15 Hyperprolactinemia Adults During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.
Children and Adolescents In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 mcg/L males; >26 mcg/L females at any time) was 13.4% (18/134) for quetiapine compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine compared to 0% (0/39) for placebo in females.
Like other drugs that antagonize dopamine D 2 receptors, quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration.
Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.
This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.
Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer.
As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats.
Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [see NONCLINICAL TOXICOLOGY ( 13.1 )].
5.16 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with quetiapine especially during the 3 to 5 day period of initial dose-titration.
In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine compared to 11% (22/206) of placebo patients.
In acute bipolar mania trials using quetiapine as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine compared to 4% of placebo patients.
In acute bipolar mania trials using quetiapine as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine compared to 9% (19/203) of placebo patients.
In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine compared to 15% (51/347) of placebo patients.
Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely.
Somnolence may lead to falls.
5.17 Body Temperature Regulation 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.
5.18 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.
Quetiapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
5.19 Discontinuation Syndrome Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine.
In short-term placebo-controlled, monotherapy clinical trials with quetiapine extended-release that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine extended-release and 6.7% (71/1065) for placebo.
The incidence of the individual adverse events (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation.
Gradual withdrawal is advised.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( MEDICATION GUIDE ) Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with quetiapine and should counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for quetiapine.
The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine.
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 [see WARNINGS AND PRECAUTIONS ( 5.1 )].
Suicidal Thoughts and Behaviors 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 [see WARNINGS AND PRECAUTIONS ( 5.2 )].
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 muscle stiffness and high fever [see WARNINGS AND PRECAUTIONS ( 5.4 )].
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 [see WARNINGS AND PRECAUTIONS ( 5.5 )].
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 [see WARNINGS AND PRECAUTIONS ( 5.5 )].
Weight Gain Patients should be advised that they may experience weight gain.
Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS ( 5.5 )].
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 [see WARNINGS AND PRECAUTIONS ( 5.7 )].
Increased Blood Pressure in Children and Adolescents Children and adolescent patients should have their blood pressure measured at the beginning of, and periodically during, treatment [see WARNINGS AND PRECAUTIONS ( 5.9 )].
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 [see WARNINGS AND PRECAUTIONS ( 5.10 )].
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 [see WARNINGS AND PRECAUTIONS ( 5.16 )].
Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS ( 5.17 )].
Concomitant Medication As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs [see DRUG INTERACTIONS ( 7.1 )].
Pregnancy and Nursing Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with quetiapine [see USE IN SPECIFIC POPULATIONS ( 8.1 ) and ( 8.3 )].
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 [see INDICATIONS AND USAGE ( 1.3 )].
Manufactured for: Lupin Pharmaceuticals , Inc.
Baltimore, Maryland 21202 United States.
MADE IN INDIA.
Rev: October 2017 ID#: 253002
DOSAGE AND ADMINISTRATION
2 Quetiapine fumarate tablets USP can be taken with or without food ( 2.1 ).
Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia-Adults ( 2.2 ) 25 mg twice daily 150 to 750 mg/day 750 mg/day Schizophrenia-Adolescents (13 to 17 years) ( 2.2 ) 25 mg twice daily 400 to 800 mg/day 800 mg/day Bipolar Mania- Adults Monotherapy or as an adjunct to lithium or divalproex ( 2.2 ) 50 mg twice daily 400 to 800 mg/day 800 mg/day Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy ( 2.2 ) 25 mg twice daily 400 to 600 mg/day 600 mg/day Bipolar Depression-Adults ( 2.2 ) 50 mg once daily at bedtime 300 mg/day 300 mg/day Geriatric Use : Consider a lower starting dose (50 mg/day), slower titration and careful monitoring during the initial dosing period in the elderly ( 2.3 , 8.5 ) Hepatic Impairment : Lower starting dose (25 mg/day) and slower titration may be needed ( 2.4 , 8.7 , 12.3 ) 2.1 Important Administration Instructions Quetiapine tablets USP can be taken with or without food.
2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1.
After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see CLINICAL STUDIES ( 14.1 and 14.2 )].
Table 1: Recommended Dosing for Quetiapine Tablets USP Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia-Adults Day 1: 25 mg twice daily.
Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4.
Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days.
150 to 750 mg/day 750 mg/day Schizophrenia-Adolescents (13 to 17 years) Day 1: 25 mg twice daily.
Day 2: Twice daily dosing totaling 100 mg.
Day 3: Twice daily dosing totaling 200 mg.
Day 4: Twice daily dosing totaling 300 mg.
Day 5: Twice daily dosing totaling 400 mg.
Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 800 mg/day.
Based on response and tolerability, may be administered three times daily.
400 to 800 mg/day 800 mg/day Schizophrenia-Maintenance N/A N/A Not applicable 400 to 800 mg/day 800 mg/day Bipolar Mania- Adults Monotherapy or as an adjunct to lithium or divalproex Day 1: Twice daily dosing totaling 100 mg.
Day 2: Twice daily dosing totaling 200 mg.
Day 3: Twice daily dosing totaling 300 mg.
Day 4: Twice daily dosing totaling 400 mg.
Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.
400 to 800 mg/day 800 mg/day Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy Day 1: 25 mg twice daily.
Day 2: Twice daily dosing totaling 100 mg.
Day 3: Twice daily dosing totaling 200 mg.
Day 4: Twice daily dosing totaling 300 mg.
Day 5: Twice daily dosing totaling 400 mg.
Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day.
Based on response and tolerability, may be administered three times daily.
400 to 600 mg/day 600 mg/day Bipolar Depression-Adults Administer once daily at bedtime.
Day 1: 50 mg Day 2: 100 mg Day 3: 200 mg Day 4: 300 mg 300 mg/day 300 mg/day Bipolar I Disorder Maintenance Therapy-Adults Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex.
Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized.
400 to 800 mg/day 800 mg/day Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ( 14.2 )].
2.3 Dose Modifications in Elderly Patients Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see CLINICAL PHARMACOLOGY ( 12.3 )].
When indicated, dose escalation should be performed with caution in these patients.
Elderly patients should be started on quetiapine 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.
2.4 Dose Modifications in Hepatically Impaired Patients Patients with hepatic impairment should be started on 25 mg/day.
The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
2.5 Dose Modifications when used with CYP3A4 Inhibitors Quetiapine dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g.
ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.).
When the CYP3A4 inhibitor is discontinued, the dose of quetiapine should be increased by 6 fold [see CLINICAL PHARMACOLOGY ( 12.3 ) and DRUG INTERACTIONS ( 7.1 )].
2.6 Dose Modifications when used with CYP3A4 Inducers Quetiapine dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g.
phenytoin, carbamazepine, rifampin, avasimibe, St.
John’s wort etc.).
The dose should be titrated based on the clinical response and tolerability of the individual patient.
When the CYP3A4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7 to 14 days [see CLINICAL PHARMACOLOGY ( 12.3 ) and DRUG INTERACTIONS ( 7.1 )].
2.7 Re-initiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine for more than one week, the initial dosing schedule should be followed.
When restarting patients who have been off quetiapine for less than one week, gradual dose escalation may not be required and the maintenance dose may be re-initiated.
2.8 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine, or concerning concomitant administration with antipsychotics.
While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others.
In all cases, the period of overlapping antipsychotic administration should be minimized.
When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine therapy in place of the next scheduled injection.
The need for continuing existing EPS medication should be re-evaluated periodically.