Apo-Quetiapine

Apo-Quetiapine

quetiapine

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Quetiapine fumarate.
Description
Each film-coated tablet contains 25 mg, 100 mg and 200 mg quetiapine as quetiapine fumarate.
Excipients/Inactive Ingredients: Croscarmellose Sodium NF, Colloidal Silicon Dioxide NF, Fumaric Acid NF, Ethyl Cellulose N7 FP NF, Magnesium Stearate NF, Hydroxypropyl Methylcellulose 2910 USP E5 (Film-coating), Hydroxypropyl Cellulose NF Type LF0 (Film-coating), Polyethylene Glycol 8000 NF (Film-coating), Titanium Dioxide USP (Film-coating), Yellow Ferric Oxide NF (Film-coating), Red Ferric Oxide NF (Film-coating).
Action
Pharmacotherapeutic Group: Antipsychotic.
Pharmacology: Pharmacodynamics: Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviorally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of dopamine D2 receptor blockade.
The results of animal studies predictive of EPS liability revealed that quetiapine causes only weak catalepsy at effective dopamine D2 receptor blocking doses, that quetiapine causes selective reduction in the firing of mesolimbic A10 dopaminergic neurones versus the A9 nigrostriatal neurones involved in motor function, and that quetiapine exhibits minimal dystonic liability in neuroleptic-sensitised monkeys.
Clinical efficacy: Clinical trials have demonstrated that quetiapine is effective when given twice a day. This is further supported by data from a positron emission tomography (PET) study which identified that 5HT2 and D2 receptor occupancy are maintained for up to 12 hours after dosing with quetiapine.
Schizophrenia: In clinical trials, quetiapine has been shown to be effective in the treatment of both positive and negative symptoms of schizophrenia. In one trial against chlorpromazine, and two against haloperidol, quetiapine showed similar short-term efficacy.
The results of three placebo-controlled clinical trials, including one that used a dose range of quetiapine of 75 to 750 mg/day, identified no difference between quetiapine and placebo in the incidence of EPS or use of concomitant anticholinergics.
Bipolar Mania: In clinical trials, quetiapine has been shown to be effective as monotherapy or as adjunct therapy in reducing manic symptoms in patients with bipolar mania. The mean last week median dose of quetiapine in responders, was approximately 600 mg and approximately 85% of the responders were in the dose range of 400 to 800 mg per day.
In four placebo-controlled trials, evaluating doses of quetiapine up to 800mg for the treatment of bipolar mania, two each in monotherapy and as adjunct therapy to lithium or valproate semisodium, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.
Mechanism of Action: Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interacts with a broad range of neurotransmitter receptors.
Quetiapine and norquetiapine exhibit affinity for serotonin (5HT2) and dopamine D1 and D2 receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to dopamine D2 receptors which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of quetiapine.
Additionally, norquetiapine has high affinity for the norepinenephrine transporter (NET).
Quetiapine and norquetiapine also have high affinity at histaminergic and adrenergic α1 receptors, with a lower affinity at adrenergic α2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.
Pharmacokinetics: Quetiapine is well absorbed and extensively metabolised following oral administration.
The bioavailability of quetiapine is not significantly affected by administration with food.
Quetiapine is approximately 83% bound to plasma proteins. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine. The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively.
The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range. The kinetics of quetiapine does not differ between men and women.
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2) and in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
Quetiapine is extensively metabolised, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug.
Toxicology: Pre-clinical Safety Data: Acute toxicity studies: Quetiapine has low acute toxicity. Findings in mice and rats after oral (500 mg/kg) or intraperitoneal (100 mg/kg) dosing were typical of an effective neuroleptic agent and included decreased motor activity, ptosis, loss of righting reflex, fluid around the mouth and convulsions.
Repeat-dose toxicity studies: In multiple-dose studies in rats, dogs and monkeys, anticipated central nervous system effects of an antipsychotic drug were observed with quetiapine (eg, sedation at lower doses and tremor, convulsions or prostration at higher exposures).
Hyperprolactinaemia, induced through the dopamine D2 receptor antagonist activity of quetiapine or its metabolites, varied between species but was most marked in the rat, and a range of effects consequent to this were seen in the 12-month study, including mammary hyperplasia, increased pituitary weight, decreased uterine weight and enhanced growth of females.
Reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction, were seen in mouse, rat and monkey.
Thyroid follicular cell hypertrophy and concomitant changes in plasma thyroid hormone levels occurred in rat and monkey.
Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.
Transient increases in heart rate, unaccompanied by an effect on blood pressure, occurred in dogs.
Posterior triangular cataracts seen after 6 months in dogs at 100 mg/kg/day were consistent with inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in Cynomolgus monkeys dosed up to 225 mg/kg/day, nor in rodents.
Monitoring in clinical studies did not reveal drug-related corneal opacities in man.
No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.
Carcinogenicity studies: In the rat study (doses 0, 20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia.
In male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.
Reproduction studies: Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
Quetiapine had no teratogenic effects.
Mutagenicity studies: Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen.
Indications/Uses
Quetiapine is indicated for the treatment of: Schizophrenia, Acute manic episodes associated with bipolar I disorder, Depressive episodes associated with bipolar disorder, Preventing recurrence in maintenance treatment of bipolar I disorder (manic, mixed or depressive episode) as monotherapy or in combination with lithium or valproate.
Dosage/Direction for Use
Adults: For the treatment of schizophrenia: Quetiapine should be administered twice daily, with or without food.
For the treatment of schizophrenia: the total daily dose for the first 4 days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4).
From Day 4 onwards, the dose should be titrated to the usual effective dose range of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.
For the treatment of manic episodes associated with bipolar disorder: Quetiapine should be administered twice daily, with or without food.
As monotherapy or as adjunct therapy to mood stabilizers, the total daily dose for the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800 mg per day by Day 6 should be in increments of no greater than 200 mg per day.
The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg per day. The usual effective dose is in the range of 400 to 800 mg per day.
The safety of doses above 800 mg/day has not been evaluated in clinical trials.
Effectiveness for more than 12 weeks has not been systematically evaluated in clinical trials for monotherapy. Therefore, the physician who elects to use quetiapine for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
For the treatment of depressive episodes associated with bipolar disorder: Quetiapine should be administered once daily at bedtime, with or without food.
Quetiapine should be titrated as follows: 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). Quetiapine can be titrated to 400 mg on Day 5 and up to 600 mg by Day 8. Antidepressant efficacy was demonstrated with Quetiapine at 300 mg and 600 mg however no additional benefit was seen in the 600 mg group, Effectiveness has not been systematically evaluated in clinical trials for more than 8 weeks (see Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Efficacy under Actions).
For preventing recurrence in maintenance treatment of bipolar disorder: Patients who have responded to Quetiapine in combination therapy with lithium or valproate for acute treatment of bipolar disorder should continue on Quetiapine therapy at the same dose. The Quetiapine dose can be re-adjusted depending on clinical response and tolerability of the individual patient within the dose range of 400 mg to 800 mg/day. Patients who have responded to Quetiapine for acute treatment of bipolar disorder should continue on Quetiapine therapy at the same dosing regimen. The Quetiapine dose can be re-adjusted depending on clinical response and tolerability of the individual patient within the dose range of 300 mg to 800 mg/day.
Elderly: As with other antipsychotics, quetiapine should be used with caution in the elderly, especially during the initial dosing period. Elderly patients should be started on quetiapine 25 mg/day. The dose should be increased daily, in increments of 25 to 50 mg, to an effective dose, which is likely to be lower than that in younger patients.
Children and adolescents: The safety and efficacy of quetiapine have not been evaluated in children and adolescents.
Renal and hepatic impairment: The oral clearance of quetiapine is reduced by approximately 25% in patients with renal or hepatic impairment. Quetiapine is extensively metabolised by the liver, and therefore should be used with caution in patients with known hepatic impairment.
Patients with renal or hepatic impairment should be started on quetiapine 25 mg/day.
The dose should be increased daily, in increments of 25 to 50 mg, to an effective dose.
Overdosage
In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed reported no adverse events or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone.
In postmarketing experience, there have been very rare reports of overdose of quetiapine alone resulting in death or coma.
Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. (See Precautions.)
In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension.
There is no specific antidote to quetiapine. In cases of severe intoxication, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.
Close medical supervision and monitoring should be continued until the patient recovers.
Contraindications
APO-QUETIAPINE is contraindicated in patients who are hypersensitive to any component of this product.
Special Precautions
Elderly patients with dementia: Quetiapine is not approved for the treatment of patients with dementia-related psychosis.
In a meta-analysis of atypical antipsychotic drugs, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. In two 10-week placebo controlled quetiapine studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died from a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.
Suicide/suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which quetiapine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in approximately 4400 children and adolescents and 77000 adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in children, adolescents, and young adult patients less than 25 years old. This meta-analysis did not include trials involving quetiapine (see Pharmacology: Pharmacodynamics under Actions).
Severe Neutropenia: Severe neutropenia (<0.5 x 109/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within the first two months of starting therapy with quetiapine. There was no apparent dose relationship. Possible risk factors for neutropenia include pre-existing low white cell count (WBC) and history of drug induced neutropenia. Quetiapine should be discontinued in patients with a neutrophil count <1.0 x 109/L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 109/L). (See Adverse Reactions.)
Increases in Blood Glucose and Hyperglycemia: Increases in blood glucose and hyperglycaemia, and occasional reports of diabetes, have been observed in clinical trials with quetiapine. Although a causal relationship with diabetes has not been established, patients who are at risk for developing diabetes are advised to have appropriate clinical monitoring. Similarly, patients with existing diabetes should be monitored for possible exacerbation. (See Adverse Reactions.)
Hyperglycemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with atypical antipsychotics, including quetiapine. Assessment of the association between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia, and the increasing incidence of diabetes mellitus in the general population.
Some epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus should be monitored regularly for worsening of glucose control. Appropriate clinical monitoring is advised for patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) and those who develop symptoms of hyperglycemia during treatment with atypical antipsychotics.
Patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.
Lipids: Increases in triglycerides and cholesterol have been observed in clinical trials with quetiapine (see Adverse Reactions). Lipid increases should be managed as clinically appropriate.
Seizures: In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. As with other antipsychotics, caution is recommended when treating patients with a history of seizures. (See Adverse Reactions.)
Cardiovascular disease: Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension.
Quetiapine may induce orthostatic hypotension, especially during the initial dose-titration period; this is more common in elderly patients than in younger patients.
In clinical trials, quetiapine was not associated with a persistent increase in QTc intervals. However, in post marketing experience there were cases reported of QT prolongation with overdose (see Overdosage). As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also caution should be exercised when quetiapine is prescribed either with medicines known to increase QTc interval, and concomitant neuroleptics, especially for patients with increased risk of QT prolongation, i.e., the elderly, patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia, or hypomagnesemia (see Interactions).
Extrapyramidal symptoms (EPS) and Tardive dyskinesia: In placebo-controlled clinical trials of adult patients with schizophrenia and bipolar mania the incidence of extrapyramidal symptoms was no different from that of placebo across the recommended therapeutic dose range. This predicts that quetiapine has less potential than standard antipsychotic agents to induce tardive dyskinesia in schizophrenia and bipolar mania patients. In short-term placebo-controlled clinical trials of adult patients with bipolar depression, the incidence of EPS was higher in quetiapine treated patients than in placebo treated patients. (See Adverse Reactions for rates of EPS observed in all indications and ages). If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered.
Neuroleptic malignant syndrome: Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see Adverse Reactions). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.
Acute withdrawal reactions: Acute withdrawal symptoms such as insomnia, nausea and vomiting have been described after abrupt cessation of antipsychotic drugs including quetiapine. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Gradual withdrawal over a period of at least one to two weeks is advisable (see Adverse Reactions).
Venous thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures undertaken.
Dysphagia:
Dysphagia (see Adverse Reactions) and aspiration pneumonia have been reported with quetiapine. Although a causal relationship with aspiration pneumonia has not been established, quetiapine should be used with caution in patients at risk of aspiration pneumonia.
Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life threatening adverse drug reactions that have been reported during quetiapine exposure. SCARs commonly present as a combination of the following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. Discontinue quetiapine if severe cutaneous adverse reactions occur.
Effects on Ability to Drive and Use Machines: Because quetiapine may cause somnolence, patients should be cautioned about operating hazardous machines, including motor vehicles.
Use In Pregnancy & Lactation
Pregnancy and Lactation: The safety and efficacy of quetiapine during human pregnancy have not been established (see Pharmacology: Toxicology: Pre-clinical Safety Data: Reproduction studies under Actions, for animal reproductive toxicology data). Therefore, quetiapine should only be used during pregnancy if the benefits justify the potential risks.
The degree to which quetiapine is excreted into human milk is unknown. Women who are breast feeding should therefore be advised to avoid breast feeding while taking quetiapine.
Adverse Reactions
The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia. As with other antipsychotics, weight gain, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral edema, have been associated with quetiapine.
The incidences of ADRs associated with quetiapine therapy, are tabulated as follows according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995). (See table.)

Click on icon to see table/diagram/image

Extrapyramidal Symptoms: The following clinical trials (monotherapy and combination therapy) included treatment with quetiapine.
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo, bipolar mania: 11.2% for quetiapine and 11.4% for placebo). In long-term studies of schizophrenia and bipolar disorder the aggregated exposure adjusted incidence of treatment-emergent extrapyramidal symptoms was similar between quetiapine and placebo.
Thyroid Level: Quetiapine treatment was associated with small dose-related decreases in thyroid hormone levels, particularly total T4 and free T4. The reduction in total and free T4 was maximal within the first two to four weeks of quetiapine treatment, with no further reduction during long-term treatment. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.
About 0.7% (26/3489) of quetiapine patients experienced Thyroid Stimulating Hormone (TSH) increases in monotherapy studies. Six of the patients with TSH increases needed replacement thyroid treatment. In the mania adjunct studies, 12% (24/196) of the quetiapine treated patients compared to 7% (15/203) placebo treated patients had elevated TSH levels.
As with other antipsychotics, quetiapine may be associated with weight gain, predominantly during the early weeks of treatment.
As with other antipsychotics, quetiapine may cause prolongation of the QTc interval, but in clinical trials, this was not associated with a persistent increase (see Precautions).
Acute withdrawal reactions have been reported (see Precautions).
Post-Market Adverse Reactions: Hepatic failure, including fatalities, has also been reported very rarely during the post-marketing period.
Drug Interactions
Concomitant use of quetiapine with hepatic enzyme inducers such as carbamazepine may substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher doses of quetiapine may need to be considered if quetiapine is used concomitantly with a hepatic enzyme inducer.
During concomitant administration of drugs, which are potent CYP3A4 inhibitors (such as azole antifungals and macrolide antibiotics, and protease inhibitors), plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials. (See Pharmacology: Pharmacokinetics under Actions). As a consequence of this, lower doses of quetiapine should be used. Special consideration should be given in elderly and debilitated patients. The risk benefit ratio needs to be considered on an individual basis in all patients.
Interactions with other Medicaments and other Forms of Interaction: Given the primary central nervous system effects of quetiapine, quetiapine should be used with caution in combination with other centrally acting drugs and alcohol.
Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QT interval (see Precautions).
The pharmacokinetics of lithium was not altered when co-administered with quetiapine.
The pharmacokinetics of valproic acid and quetiapine were not altered to a clinically relevant extent when co-administered as valproate semisodium (also known as divalproex sodium (USAN) and quetiapine (quetiapine fumarate). Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship.
The pharmacokinetics of quetiapine were not significantly altered following coadministration with the antipsychotics risperidone or haloperidol. However, coadministration of quetiapine and thioridazine caused increases in clearance of quetiapine.
Quetiapine did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, in a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, and hence, in each patient, consideration for a higher dose of quetiapine, depending on clinical response, should be considered. It should be noted that the recommended maximum daily dose of quetiapine is 600 to 800 mg/day depending on indication (see Dosage & Administration).
Continued treatment at higher doses should only be considered as a result of careful consideration of the benefit risk assessment for an individual patient. Co-administration of quetiapine with another microsomal enzyme inducer, phenytoin, also caused increases in clearance of quetiapine. Increased doses of quetiapine may be required to maintain control of psychotic symptoms in patients co-administered quetiapine and phenytoin and other hepatic enzyme inducers (eg, barbiturates, rifampicin etc). The dose of quetiapine may need to be reduced if phenytoin or carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (eg, sodium valproate).
CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. The pharmacokinetics of quetiapine was not altered following coadministration with cimetidine, a known P450 enzyme inhibitor. The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).
In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, co-administration of ketoconazole resulted in an increase in mean Cmax and AUC of quetiapine of 235% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half life of quetiapine increased from 2.6 to 6.8 hours, but the mean tmax was unchanged.
Due to the potential for an interaction of a similar magnitude in a clinical setting, the dosage of quetiapine should be reduced during concomitant use of quetiapine and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors).
Storage
Store at or below 30°C.
MIMS Class
ATC Classification
N05AH04 - quetiapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.
Presentation/Packing
FC tab 25 mg (peach, round, biconvex, engraved "APO" on one side, "QUE" over "25" on the other side) x 100's. 100 mg (yellow, round, biconvex, film-coated tablet, engraved "APO" on one side, "QUE" over "100" on the other side) x 100's. 200 mg (white, round, biconvex, engraved "APO" on one side, "QUE" over "200" on the other side) x 100's.
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