Quetiapine fumarate tablet

Recent major changes

Warnings and Precautions, Falls ( 5.8) 02/2017

Spl unclassified section

Boxed warning section

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)

Spl unclassified section

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)].

1 indications and usage

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)

2 dosage and administration

  • Quetiapine fumarate tablets USP can be taken with or without food ( 2.1).
Indication
Initial Dose
Recommended Dose
Maximum Dose
Schizophrenia-Adults( 2.2) 25mgtwicedaily
150to750mg/day
750mg/day
Schizophrenia-Adolescents (13to17years)( 2.2) 25mgtwicedaily
400to800mg/day
800mg/day
BipolarMania-AdultsMonotherapy orasanadjuncttolithiumor divalproex( 2.2) 50mgtwicedaily
400to800mg/day
800mg/day
BipolarMania-ChildrenandAdolescents(10to17years),Monotherapy( 2.2) 25mgtwicedaily
400to600mg/day
600mg/day
BipolarDepression-Adults( 2.2) 50mgoncedailyatbedtime
300mg/day
300mg/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)

3 dosage forms and strengths

Tablets: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg ( 3)

Spl unclassified section

  • 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.

4 contraindications

Known hypersensitivity to quetiapine or any components in the formulation. ( 4)

Spl unclassified section

Hypersensitivity to quetiapine or to any excipients in the quetiapine tablets formulation. Anaphylactic reactions have been reported in patients treated with quetiapine tablets.

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)

6 adverse reactions

  • Most common adverse reactions (incidence 5% and twice placebo):

Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia. ( 6.1)

  • Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Spl unclassified section

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Increased mortality in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS( 5.1 )]
  • Suicidal thoughts and behaviors in adolescents and young adults [see WARNINGS AND PRECAUTIONS( 5.2 )]
  • Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS( 5.3 )]
  • Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS( 5.4 )]
  • Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see WARNINGS AND PRECAUTIONS( 5.5 )]
  • Tardive dyskinesia [see WARNINGS AND PRECAUTIONS( 5.6 )]
  • Hypotension [see WARNINGS AND PRECAUTIONS( 5.7 )]
  • Falls [see WARNINGS AND PRECAUTIONS ( 5.8)]
  • Increases in blood pressure (children and adolescents) [see WARNINGS AND PRECAUTIONS( 5.9 )]
  • Leukopenia, neutropenia and agranulocytosis [see WARNINGS AND PRECAUTIONS( 5.10 )]
  • Cataracts [see WARNINGS AND PRECAUTIONS( 5.11 )]
  • QT Prolongation [see WARNINGS AND PRECAUTIONS( 5.12 )]
  • Seizures [see WARNINGS AND PRECAUTIONS( 5.13 )]
  • Hypothyroidism [see WARNINGS AND PRECAUTIONS( 5.14 )]
  • Hyperprolactinemia [see WARNINGS AND PRECAUTIONS( 5.15 )]
  • Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS( 5.16 )]
  • Body temperature regulation [see WARNINGS AND PRECAUTIONS( 5.17 )]
  • Dysphagia [see WARNINGS AND PRECAUTIONS( 5.18 )]
  • Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS( 5.19 )]

Spl unclassified section

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term , Placebo-Controlled Trials

Schizophrenia:

The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).

Bipolar I Mania:

The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse reactions leading to discontinuation in 2% or more of patients on quetiapine and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0).

Commonly Observed Adverse Reactions in Short-Term , Placebo-Controlled Trials

In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%).

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).

In an acute (8-week) quetiapine extended-release trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of quetiapine extended-release (incidence of 5% or greater and at least twice that for placebo) were dizziness 7%, diarrhea 5%, fatigue 5% and nausea 5%.

Adverse Reactions Occurring at an Incidence of 2% among Quetiapine Treated Patients in Short-Term, Placebo-Controlled Trials

Schizophrenia (Adolescents, 13 to 17 years old):

The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.

Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with quetiapine (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine was at least twice the incidence in placebo-treated patients.

Adverse events that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%).

Table 13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients
Preferred Term
Quetiapine
400 mg
( n = 73 )
Quetiapine
800 mg
( n = 74 )
Placebo
( n = 75 )
Somnolence 33%
35%
11%
Dizziness
8% 15%
5%
DryMouth
4%
10%
1%
Tachycardia 6%
11%
0%
Irritability
3%
5%
0%
Arthralgia
1%
3%
0%
Asthenia
1%
3%
1%
BackPain
1%
3%
0%
Dyspnea
0%
3%
0%
AbdominalPain
3%
1%
0%
Anorexia
3%
1%
0%
ToothAbscess
3%
1%
0%
Dyskinesia
3%
0%
0%
Epistaxis
3%
0%
1%
MuscleRigidity
3%
0%
0%

Bipolar I Mania (Children and Adolescents 10 to 17 years old):

The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.

Commonly Observed Adverse Reactions

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with quetiapine (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Adverse events that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%).

Table 14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients
Preferred Term
Quetiapine
400 mg
( n = 95 )
Quetiapine
600 mg
( n = 98 )
Placebo ( n = 90 )
Somnolence 50%
57%
14%
Dizziness
19% 17%
2%
Nausea
6%
10%
4%
Fatigue 14%
9%
4%
IncreasedAppetite
10%
9%
1%
Tachycardia
6%
9%
1%
DryMouth
7%
7%
0%
Vomiting
8%
7%
3%
NasalCongestion
3%
6%
2%
WeightIncreased
6%
6%
0%
Irritability
3%
5%
1%
Pyrexia
1%
4%
1%
Aggression
1%
3%
0%
MusculoskeletalStiffness
1%
3%
1%
AccidentalOverdose
0%
2%
0%
Acne
3%
2%
0%
Arthralgia
4%
2%
1%
Lethargy
2%
2%
0%
Pallor
1%
2%
0%
StomachDiscomfort
4%
2%
1%
Syncope
2%
2%
0%
VisionBlurred
3%
2%
0%
Constipation
4%
2%
0%
EarPain
2%
0%
0%
Paraesthesia
2%
0%
0%
SinusCongestion
3%
0%
0%
Thirst
2%
0%
0%

Extrapyramidal Symptoms

In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine and 5.3% (4/75) for placebo, though the incidence of the individual adverse events (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) or quetiapine and 1.1% (1/90) for placebo.

Table 15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).

In Tables 15 and 16 dystonic event included nuchal rigidity, hypertonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia, and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder.

Table 15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-Controlled Trial in Adolescent Patients with Schizophrenia (6-week duration)
Preferred Term
Quetiapine 400 mg / day ( N = 73 )
Quetiapine 800 mg / day ( N = 74 )
All
Quetiapine
( N = 147 )
Placebo
( N = 75 )

n
%
n
%
n
%
n
%
Dystonicevent
2
2.7

0.0
2
1.4

0.0
Parkinsonism
4
5.5
4
5.4
8
5.4
2
2.7
Akathisia
3
4.1
4
5.4
7
4.8
3
4.0
Dyskineticevent
2
2.7

0.0
2
1.4

0.0
OtherExtrapyramidal
event
2
2.7
2
2.7
4
2.7

0.0

Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration)
Preferred Term
Quetiapine
400 mg / day ( N = 95 )
Quetiapine
600 mg / day ( N = 98 )
All Quetiapine ( N = 193 )
Placebo ( N = 90 )

n
%
n
%
n
%
n
%
Parkinsonism
2
2.1
1
1.0
3
1.6
1
1.1
Akathisia 1
1.0
1
1.0
2
1.0

0.0
OtherExtrapyramidalevent 1
1.1
1
1.0
2
1.0

0.0

Other Adverse Reactions Observed During the Pre-Marketing Evaluation of Quetiapine

Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with quetiapine at multiple doses 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients treated for schizophrenia. All reported reactions are included except those already listed in the tables or elsewhere in labeling, those reactions for which a drug cause was remote, and those reaction terms which were so general as to be uninformative. It is important to emphasize that, although the reactions reported occurred during treatment with quetiapine, they were not necessarily caused by it.

Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Nervous System:

Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased *, urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia;

Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased *, neuralgia, stuttering, subdural hematoma.

Body as a Whole :

Frequent: flu syndrome;

Infrequent: neck pain, pelvic pain *, suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis;

Rare: abdomen enlarged.

Digestive System:

Frequent: anorexia;

Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema;

Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis.

Cardiovascular System:

Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion;

Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration.

Respiratory System:

Frequent: cough increased, dyspnea;

Infrequent: pneumonia, epistaxis, asthma;

Rare: hiccup, hyperventilation.

Metabolic and Nutritional System:

Infrequent: weight loss, alkaline phosphatase increased, hyperlipidemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia;

Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication.

Skin and Appendages System:

Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer;

Rare: exfoliative dermatitis, psoriasis, skin discoloration.

Urogenital System:

Infrequent: dysmenorrhea *, vaginitis *, urinary incontinence, metrorrhagia *, impotence *, dysuria, vaginal moniliasis *, abnormal ejaculation *, cystitis, urinary frequency, amenorrhea *, female lactation *, leukorrhea *, vaginal hemorrhage *, vulvovaginitis *orchitis *;

Rare: gynecomastia *, nocturia, polyuria, acute kidney failure.

Special Senses:

Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain;

Rare: abnormality of accommodation, deafness, glaucoma.

Musculoskeletal System:

Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain.

Hemic and Lymphatic System:

Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis;

Rare: hemolysis, thrombocytopenia.

Endocrine System:

Infrequent: hypothyroidism, diabetes mellitus;

Rare: hyperthyroidism.

*Adjusted for gender.

Spl unclassified section

Laboratory, ECG and Vital Sign Changes Observed in Clinical Studies

Laboratory Changes:

Neutrophil Counts

Adults:

In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 10 9/L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine fumarate, compared to 0.1% (2/1349) in patients treated with placebo [see WARNINGS AND PRECAUTIONS( 5.10 )].

Transaminase Elevations

Adults:

Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for quetiapine compared to 1% (3/194) for placebo. In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 12-week placebo-controlled trials were approximately 1% for both quetiapine (3/560) and placebo (3/294). These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine. In bipolar depression trials, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1% (5/698) for quetiapine and 2% (6/347) for placebo.

Decreased Hemoglobin

Adults:

In short-term placebo-controlled trials, decreases in hemoglobin to 13 g/dL males, 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to 13 g/dL males, 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.

Interference with Urine Drug Screens

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

Spl unclassified section

ECG Changes:

Adults

Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for quetiapine compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to >120 beats per minute. Quetiapine use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia in adults may be related to quetiapine's potential for inducing orthostatic changes [see WARNINGS AND PRECAUTIONS( 5.7 )].

Children and Adolescents

In the acute (6 week) schizophrenia trial in adolescents, increases in heart rate (>110 bpm) occurred in 5.2% (3/73) of patients receiving quetiapine 400 mg and 8.5% (5/74) of patients receiving quetiapine 800 mg compared to 0% (0/75) of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group [see WARNINGS AND PRECAUTIONS( 5.7 )].

In the acute (3 week) bipolar mania trial in children and adolescents, increases in heart rate (>110 bpm) occurred in 1.1% (1/89) of patients receiving quetiapine 400 mg and 4.7% (4/85) of patients receiving quetiapine 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group [see WARNINGS AND PRECAUTIONS( 5.7 )].

In an acute (8-week) quetiapine extended-release trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10 to 12 years and 13 to 17 years) occurred in 0% of patients receiving quetiapine extended-release and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine extended-release, compared to 0.3 bpm in the placebo group [see WARNINGS AND PRECAUTIONS( 5.7 )].

7 drug interactions

  • 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)

8 use in specific populations

  • Pregnancy:Limited human data. Based on animal data, may cause fetal harm. Quetiapine should be used only if the potential benefit justifies the potential risk. ( 8.1)
  • Nursing Mothers:Discontinue drug or nursing, taking into consideration importance of drug to mother's health ( 8.3)

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 2body 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 2body 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.

8.2 labor and delivery

The effect of quetiapine on labor and delivery in humans is unknown.

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).

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 maxof 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 )].

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 )].

9 drug abuse and dependence

9.1 controlled substance

Quetiapine fumarate is not a controlled substance.

9.2 abuse

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

10 overdosage

11 description

Spl unclassified section

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 42H 50N 6O 4S 2 .C 4H 4O 4and 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.

12 clinical pharmacology

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 2with similar receptor affinities may explain some of the other effects of quetiapine.

Quetiapine's antagonism of histamine H 1receptors may explain the somnolence observed with this drug.

Quetiapine's antagonism of adrenergic 1receptors may explain the orthostatic hypotension observed with this drug.

12.2 pharmacodynamics

Quetiapine is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT 1Aand 5HT 2(IC 50s=717 and 148 nM, respectively), dopamine D 1and D 2(IC 50s=1268 and 329 nM, respectively), histamine H 1(IC 50=30 nM), and adrenergic 1and 2receptors (IC 50s=94 and 271 nM, respectively). Quetiapine has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC 50s>5000 nM).

Effect on QT Interval

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.

12.3 pharmacokinetics

Adults

Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

Children and Adolescents

At steady state the pharmacokinetics of the parent compound, in children and adolescents (10 to 17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C maxof the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C maxwere 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see USE IN SPECIFIC POPULATIONS( 8.4 )].

Absorption

Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C maxand AUC values increased by 25% and 15%, respectively.

Distribution

Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 104 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.

Metabolism and Elimination

Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively.

Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite N-desalkyl quetiapine.

Age

Oral clearance of quetiapine was reduced by 40% in elderly patients (65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary [see DOSAGE AND ADMINISTRATION( 2.3 )].

Gender

There is no gender effect on the pharmacokinetics of quetiapine.

Race

There is no race effect on the pharmacokinetics of quetiapine.

Smoking

Smoking has no effect on the oral clearance of quetiapine.

Renal Insufficiency

Patients with severe renal impairment (Cl cr=10 to 30 mL/min/1.73 m 2, n=8) had a 25% lower mean oral clearance than normal subjects (Cl cr>80 mL/min/1.73 m 2, n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients [see USE IN SPECIFIC POPULATIONS( 8.6 )].

Hepatic Insufficiency

Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In two of the 8 hepatically impaired patients, AUC and C maxwere 3 times higher than those observed typically in healthy 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 [see DOSAGE AND ADMINISTRATION( 2.4 ) and USE IN SPECIFIC POPULATIONS( 8.7 )].

Drug-Drug Interaction Studies

The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 17 [see DOSAGE AND ADMINISTRATION( 2.5 and 2.6 ) and DRUG INTERACTIONS( 7.1 )].

Table 17: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine
Coadministered Drug
Dose Schedules
Effect on Quetiapine Pharmacokinetics

Coadministered Drug
Quetiapine

Phenytoin
100mgthreetimes
daily
250mgthreetimes
daily
5foldIncreaseinoralclearance
Divalproex
500mgtwicedaily
150mgtwicedaily
17%increasemeanmax
plasmaconcentrationatsteadystate.



Noeffectonabsorptionor
meanoralclearance
Thioridazine
200mgtwicedaily
300mgtwicedaily
65%increaseinoralclearance
Cimetidine
400mgthreetimesdailyfor4days
150mgthreetimes
daily
20%decreaseinmean
oralclearance
Ketoconazole(PotentCYP3A4Inhibitor)
200mgoncedaily
for4days
25mgsingledose
84%decreaseinoral
clearanceresultingina6.2
foldincreaseinAUCofquetiapine
Fluoxetine
60mgoncedaily
300mgtwicedaily
NochangeinsteadystatePK
Imipramine
75mgtwicedaily
300mgtwicedaily
NochangeinsteadystatePK
Haloperidol
7.5mgtwicedaily
300mgtwicedaily
NochangeinsteadystatePK
Risperidone
3mgtwicedaily
300mgtwicedaily
NochangeinsteadystatePK

In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table 18) [see DRUG INTERACTIONS( 7.2 )].

Table 18: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs
Coadministered Drug
Dose Schedules
Effect on Other Drugs Pharmacokinetics

Coadministered Drug
Quetiapine

Lorazepam
2mg,singledose
250mgthreetimesdaily
Oralclearanceoflorazepamreducedby20%
Divalproex
500mgtwicedaily
150mgtwicedaily
C m a xandAUCoffreevalproicacidatsteady-statewasdecreasedby10to12%
Lithium
Upto2400
mg/daygivenintwicedailydoses
250mgthreetimesdaily
Noeffectonsteady-state
pharmacokineticsoflithium
Antipyrine
1g,singledose
250mgthreetimesdaily
Noeffectonclearanceofantipyrineorurinaryrecoveryofitsmetabolites

13 nonclinical toxicology

14 clinical studies

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 ( 95 %

CI )
Quetiapine (300 mg/day) 30.3 (5.0) -16.4 (0.9) -6.1 (-8.3, -3.9)
Study 5 Quetiapine (600 mg/day) id1572_2 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) id1572_2 31.1 (5.7) -16.9 (1.0) -5.0 (-7.3, -2.7)
Study 6 Quetiapine (600 mg/day) id1572_2 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 )
LS Mean Change from Baseline ( SE ) Placebo - Subtracted

Difference ( 95 %

CI )
Quetiapine (200 to 800 mg/day) 34.0 (6.1) -12.3 (1.3) -4.0 (-7.0, -1.0)
Study 1 Haloperidol id1570_3 id1570_4 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) id1570_3 32.7 (6.5) -14.6 (1.5) -7.9 (-10.9, -5.0)
Study 2 Lithium id1570_3 id1570_4 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) id1570_3+ 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) id1570_3 29.4 (5.9) -14.3 (0.96) -5.2 (-8.1, -2.3)
Study 4 Quetiapine (600 mg/day) id1570_3 29.6 (6.4) -15.6 (0.97) -6.6 (-9.5, -3.7)
Placebo 30.7 (5.9) -9.0 (1.1) --

16 how supplied/storage and handling

Spl unclassified section

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 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

17 patient counseling information

Spl unclassified section

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 )].

Spl unclassified section

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

Spl medguide section

Spl unclassified section

MEDICATION GUIDE

Quetiapine (kwe-TYE-a-peen) Tablets USP

Read this Medication Guide before you start taking quetiapine tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about quetiapine tablets?

Quetiapine tablets may cause serious side effects, including:

  1. risk of death in the elderly with dementia. Medicines like quetiapine can increase the risk of death in elderly people who have memory loss (dementia). Quetiapine tablets are not for treating psychosis in the elderly with dementia.
  2. risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions).
  • Talk to your or your family member's healthcare provider about:
    • all risks and benefits of treatment with antidepressant medicines.
    • all treatment choices for depression or other serious mental illness.
  • Antidepressant medications may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
  • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions.These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or suicidal thoughts or actions.
  • How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
    • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
    • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
    • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Spl unclassified section

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling very agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

  • Never stop an antidepressant medicine without first talking to your healthcare provider.Stopping an antidepressant medicine suddenly can cause other symptoms.
  • Antidepressants are medicines used to treat depression and other illnesses.It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
  • Antidepressant medicines have other side effects.Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
  • Antidepressant medicines can interact with other medicines.Know all of the medicines that you or your family member take. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
  • Not all antidepressant medicines prescribed for children are FDA approved for use in children.Talk to your child's healthcare provider for more information.

What is quetiapine tablet?

Quetiapine tablet is a prescription medicine used to treat:

  • schizophrenia in people 13 years of age or older
  • bipolar disorder in adults, including:
    • depressive episodes associated with bipolar disorder
    • manic episodes associated with bipolar I disorder alone or with lithium or divalproex
    • long-term treatment of bipolar I disorder with lithium or divalproex
  • manic episodes associated with bipolar I disorder in children ages 10 to 17 years old

It is not known if quetiapine tablet is safe and effective in children under 10 years of age.

What should I tell my healthcare provider before taking quetiapine tablets?

Before you take quetiapine tablets, tell your healthcare provider if you have or have had:

  • diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start quetiapine tablets and also during therapy
  • high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
  • low or high blood pressure
  • low white blood cell count
  • cataracts
  • seizures
  • abnormal thyroid tests
  • high prolactin levels
  • heart problems
  • liver problems
  • any other medical condition
  • pregnancy or plans to become pregnant. It is not known if quetiapine tablets will harm your unborn baby.
  • Breast-feeding or plans to breast-feed. Quetiapine can pass into your breast milk. You and your healthcare provider should decide if you will take quetiapine tablets or breast-feed. You should not do both.

Spl unclassified section

Tell the healthcare provider about all the medicines that you take or recently have takenincluding prescription medicines, over-the-counter medicines, herbal supplements and vitamins.

Quetiapine tablets and other medicines may affect each other causing serious side effects. Quetiapine tablets may affect the way other medicines work, and other medicines may affect how quetiapine tablet works.

Tell your healthcare provider if you are having a urine drug screen because quetiapine may affect your test results. Tell those giving the test that you are taking quetiapine tablets.

How should I take quetiapine tablets?

  • Take quetiapine tablets exactly as your healthcare provider tells you to take it. Do not change the dose yourself.
  • Take quetiapine tablets by mouth, with or without food.
  • If you feel you need to stop quetiapine tablets, talk with your healthcare provider first.If you suddenly stop taking quetiapine tablets, you may have side effects such as trouble sleeping or trouble staying asleep (insomnia), nausea, and vomiting.
  • If you miss a dose of quetiapine tablets, take it as soon as you remember. If you are close to your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.

What should I avoid while taking quetiapine tablets?

  • Do not drive, operate machinery, or do other dangerous activities until you know how quetiapine tablet affects you. Quetiapine tablets may make you drowsy.
  • Avoid getting overheated or dehydrated.
    • Do not over-exercise.
    • In hot weather, stay inside in a cool place if possible.
    • Stay out of the sun. Do not wear too much or heavy clothing.
    • Drink plenty of water.
  • Do not drink alcohol while taking quetiapine tablets. It may make some side effects of quetiapine tablets worse.

What are possible side effects of quetiapine tablets?

Quetiapine tablets can cause serious side effects, including:

  • See "What is the most important information I should know about quetiapine tablets?"
  • stroke that can lead to death can happen in elderly people with dementia who take medicines like quetiapine tablets
  • neuroleptic malignant syndrome (NMS).NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including quetiapine tablets. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms:
    • high fever
    • excessive sweating
    • rigid muscles
    • confusion
    • changes in your breathing, heartbeat, and blood pressure
  • fallscan happen in some people who take quetiapine tablets. These falls may cause serious injuries.
  • high blood sugar (hyperglycemia).High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:
    • build up of acid in your blood due to ketones (ketoacidosis)
    • coma
    • death

Increases in blood sugar can happen in some people who take quetiapine tablets. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start quetiapine tablets and during therapy.

Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking quetiapine tablets:

  • feel very thirsty
  • need to urinate more than usual
  • feel very hungry
  • feel weak or tired
  • feel sick to your stomach
  • feel confused, or your breath smells fruity

Spl unclassified section

  • high fat levels in your blood (increased cholesterol and triglycerides).High fat levels may happen in people treated with quetiapine tablets. You may not have any symptoms, so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with quetiapine tablets.
  • increase in weight (weight gain).Weight gain is common in people who take quetiapine tablets so you and your healthcare provider should check your weight regularly. Talk to your healthcare provider about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.
  • movements you cannot control in your face, tongue, or other body parts (tardive dyskinesia).These may be signs of a serious condition. Tardive dyskinesia may not go away, even if you stop taking quetiapine tablets. Tardive dyskinesia may also start after you stop taking quetiapine tablets.
  • decreased blood pressure (orthostatic hypotension),including lightheadedness or fainting caused by a sudden change in heart rate and blood pressure when rising too quickly from a sitting or lying position.
  • increases in blood pressure in children and teenagers.Your healthcare provider should check blood pressure in children and adolescents before starting quetiapine tablets and during therapy.
  • low white blood cell count
  • cataracts
  • seizures
  • abnormal thyroid tests.Your healthcare provider may do blood tests to check your thyroid hormone level.
  • increases in prolactin levels.Your healthcare provider may do blood tests to check your prolactin levels.
  • sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities
  • increased body temperature
  • difficulty swallowing
  • trouble sleeping or trouble staying asleep (insomnia), nausea, or vomiting if you suddenly stop taking quetiapine tablets.These symptoms usually get better 1 week after you start having them.

The most common side effects of quetiapine tablets include:

In Adults:

  • dry mouth
  • dizziness
  • weakness
  • abdominal pain
  • constipation
  • sore throat
  • difficulty moving

In Children and Adolescents:

  • nausea
  • dry mouth
  • weight gain
  • increased appetite
  • vomiting
  • rapid heart beat

These are not all the possible side effects of quetiapine tablets. For more information, ask your healthcare provider or pharmacist.

Spl unclassified section

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

How should I store quetiapine tablets?

  • Store quetiapine tablets at room temperature, between 68F to 77F (20C to 25C).
  • Keep quetiapine tablets and all medicines out of the reach of children.

General information about the safe and effective use of quetiapine tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use quetiapine tablets for a condition for which it was not prescribed. Do not give quetiapine tablets to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about quetiapine tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about quetiapine tablets that is written for health professionals.

For more information, go to www.lupinpharmaceuticals.com, or call 1-800-399-2561.

What are the ingredients in quetiapine tablets?

Active ingredient:quetiapine fumarate

Inactive ingredients: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 only iron oxide yellow.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States.

MADE IN INDIA.

Rev: April 2017 ID#: 251262

Ingredients and appearance - Product information

Quetiapine fumarate tablet- Quetiapine fumarate

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 61786-064
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Quetiapine fumarate ( UNII: 2S3PL1B6UJ)( Quetiapine - UNII: BGL0JSY5SI ) 100 mgin 1

Inactive Ingredients

Ingredient Name Code
Dibasic calcium phosphate dihydrate ( UNII: O7TSZ97GEP)
Ferric oxide yellow ( UNII: EX438O2MRT)
Hypromellose 2910 (6 mpa.s) ( UNII: 0WZ8WG20P6)
Povidone k30 ( UNII: U725QWY32X)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Polyethylene glycol 400 ( UNII: B697894SGQ)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Color yellow (Yellow) Shape ROUND (Round)
Size 9 mm Score 1
Imprint Code LU;Y17

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 61786-064-02 30 in 1 BLISTER PACK 2014/10/13

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA201109 USA 2014/10/13

Labeler - REMEDYREPACK INC.( 829572556)

Somnolence combines adverse reaction terms somnolence and sedation.
Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.
Somnolence combines adverse reactions terms somnolence and sedation.
Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.
There were no adverse experiences with the preferred term of dystonic or dyskinetic events.
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are statistically significantly superior to placebo.
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.
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are statistically significantly superior to placebo.
Included in the trial as an active comparator.