quetiapine 400 MG Oral Tablet [Seroquel]

INDICATIONS AND USAGE Quetiapine extended-release tablets are an atypical antipsychotic indicated for the treatment of: • Schizophrenia (1.1) • Bipolar I disorder, manic, or mixed episodes (1.2) • Bipolar disorder, depressive episodes (1.2) • Major depressive disorder, adjunctive therapy with antidepressants (1.3) 1.1 Schizophrenia Quetiapine extended-release tablets are indicated for the treatment of schizophrenia. The efficacy of quetiapine extended-release tablets in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13 to 17 years) treated with quetiapine tablets [see Clinical Studies (14.1) ]. 1.2 Bipolar Disorder Quetiapine extended-release tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of quetiapine extended-release tablets in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 to 17 years) with manic episodes associated with bipolar I disorder treated with quetiapine tablets [see Clinical Studies (14.2) ]. Quetiapine extended-release tablets are indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of quetiapine extended-release tablets was established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with quetiapine tablets [see Clinical Studies (14.2) ]. Quetiapine extended-release tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with quetiapine tablets. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials [see Clinical Studies (14.2) ]. 1.3 Adjunctive Treatment of Major Depressive Disorder (MDD) Quetiapine extended-release tablets are indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of quetiapine extended-release tablets as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment [see Clinical Studies (14.3) ]. 1.4 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.

DOSAGE AND ADMINISTRATION Swallow tablets whole and do not split, chew or crush ( 2.1 ) Take without food or with a light meal (approx. 300 calories) ( 2.1 ) Administer once daily, preferably in the evening ( 2.1 ) 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 (50 mg/day) and slower titration may be needed ( 2.4 , 8.7 , 12.3 ) Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia- Adults ( 2.2 ) 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia-Adolescents (13 to 17 years) ( 2.2 ) 50 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed-Acute monotherapy or adjunct to lithium or divalproex-Adults ( 2.2 ) 300 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic Acute monotherapy -Children and Adolescents (10 to 17 years) ( 2.2 ) 50 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes-Adults ( 2.2 ) 50 mg/day 300 mg/day 300 mg/day Major Depressive Disorder, Adjunctive Therapy with Antidepressants-Adults ( 2.2 ) 50 mg/day 150 to 300 mg/day 300 mg/day 2.1 Important Administration Instructions Quetiapine extended-release tablets USP should be swallowed whole and not split, chewed, or crushed. It is recommended that quetiapine extended-release tablet USP be taken without food or with a light meal (approximately 300 calories) [see CLINICAL PHARMACOLOGY ( 12.3 )]. Quetiapine extended-release tablet USP should be administered once daily, preferably in the evening. 2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum Quetiapine extended-release tablet USP dose for each approved indication is displayed in Table 1 below. 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 , 14.2 and 14.3 )]. Table 1: Recommended Dosing for Quetiapine extended-release tablet USP Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia-Adults Day 1: 300 mg/day Dose increases can be made at intervals as short as 1 day and in increments of up to 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia-Adolescents (13 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia Maintenance-Monotherapy-Adults Not applicable 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed-Acute monotherapy or adjunct to lithium or divalproex-Adults Day 1: 300 mg/day Day 2: 600 mg/day Day 3: between 400 and 800 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic -Acute monotherapy -Children and Adolescents (10 to 17 years) Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes-Adults Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day 300 mg/day 300 mg/day Bipolar I Disorder Maintenance-Adjunct to lithium or divalproex-Adults Not applicable 400 to 800 mg/day 800 mg/day Major Depressive Disorder- Adjunctive Therapy with Antidepressants-Adults Day 1: 50 mg/day Day 2: 50 mg/day Day 3: 150 mg/day 150 to 300 mg/day 300 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 ( 14.1 , 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 USE IN SPECIFIC POPULATIONS ( 8.5 , 8.7 ), and CLINICAL PHARMACOLOGY ( 12.3 )]. When indicated, dose escalation should be performed with caution in these patients. Elderly patients should be started on quetiapine extended-release tablet USP 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 quetiapine extended-release tablet USP 50 mg/day. The dose can be increased daily in increments of 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 extended-release tablet USP 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 extended-release tablet USP 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 extended-release tablet USP 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 tolerance of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine extended-release tablet 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 extended-release tablet USP for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine extended-release tablet USP for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated. 2.8 Switching Patients from SEROQUEL to Quetiapine Extended-Release Tablets USP Patients who are currently being treated with SEROQUEL (immediate release formulation) may be switched to quetiapine extended-release tablet USP at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary. 2.9 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients from other antipsychotics to quetiapine extended-release tablet USP, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, if medically appropriate, initiate quetiapine extended-release tablet USP therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.

WARNINGS AND PRECAUTIONS · Cerebrovascular Adverse Reactions: Increased incidence of cerebrovascular adverse reactions (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 ) · Anticholinergic (antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, or constipation ( 5.20 ) 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 dep

CONTRAINDICATIONS Hypersensitivity to quetiapine or to any excipients in the quetiapine extended-release tablets formulation. Anaphylactic reactions have been reported in patients treated with quetiapine extended-release tablets. Known hypersensitivity to quetiapine extended-release tablets or any components in the formulation. ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of quetiapine in the listed indications is unclear. However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D 2 , but greater activity at 5HT 2A receptors, than the parent drug (quetiapine). 12.2 Pharmacodynamics Quetiapine and its metabolite, norquetiapine, have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general. The K i values for quetiapine and norquetiapine at the dopamine D 1 are 428/99.8 nM, at D 2 626/489 nM, at serotonin 5HT 1A 1,040/191 nM at 5HT 2A 38/2.9 nM, at histamine H 1 4.4/1.1 nM, at muscarinic M 1 1,086/38.3 nM, and at adrenergic α 1 b 14.6/46.4 nM and, at α 2 receptors 617/1,290 nM, respectively. Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors. 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 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 (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C max of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C max were 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 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 max and AUC values increased by 25% and 15%, respectively. Distribution Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 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 14 C-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 (Clcr=10-30 mL/min/1.73 m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 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 max were 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 [s ee 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 100 mg three times daily 250 mg three times daily 5-fold increase in oral clearance Divalproex 500 mg twice daily 150 mg twice daily 17% increase mean max plasma concentration at steady state. No effect on absorption or mean oral clearance Thioridazine 200 mg twice daily 300 mg twice daily 65% increase in oral clearance Cimetidine 400 mg three times daily for 4 days 150 mg three times daily 20% decrease in mean oral clearance Ketoconazole (potent CYP 3A4 inhibitor) 200 mg once daily for 4 days 25 mg single dose 84% decrease in oral clearance resulting in a 6.2-fold increase in AUC of quetiapine Fluoxetine 60 mg once daily 300 mg twice daily No change in steady state PK Imipramine 75 mg twice daily 300 mg twice daily No change in steady state PK Haloperidol 7.5 mg twice daily 300 mg twice daily No change in steady state PK Risperidone 3 mg twice daily 300 mg twice daily No change in steady state PK 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) [s ee 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 2 mg, single dose 250 mg three times daily Oral clearance of lorazepam reduced by 20% Divalproex 500 mg twice daily 150 mg twice daily C max and AUC of free valproic acid at steady-state was decreased by 10-12% Lithium Up to 2,400 mg/day given in twice daily doses 250 mg three times daily No effect on steady-state pharmacokinetics of lithium Antipyrine 1 g, single dose 250 mg three times daily No effect on clearance of antipyrine or urinary recovery of its metabolites