PACKING INSERT: QUETIAPINE FUMARATE TABLETS

PACKING INSERT: QUETIAPINE FUMARATE TABLETS

Name and Strength of Active Substance(s)

1.Quetiapine fumarate ….mg equivalent to

quetiapine                                       25mg

2.Quetiapine fumarate ….mg equivalent to

equivalent to quetiapine               300mg

Pharmacodynamics

Mechanism of action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT₂) and dopamine D₁– and D₂– receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT₂ relative to 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 norepinephrine 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 muscarinic or benzodiazepine receptors.

Pharmacodynamic effects

Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D₂-receptor blockade.

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

Indication

Treatment of schizophrenia

The antipsychotic efficacy of quetiapine was established in short-term (6 weeks) in adults and adolescents (13-17 years) schizophrenic inpatients.

The effectiveness of quetiapine in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use quetiapine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Treatment of acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct to lithium or divalproex

The efficacy of quetiapine in acute bipolar mania was established in 12 weeks in adults and 3 weeks in pediatric patients (10-17 years).

Treatment of depressive episodes associated with bipolar disorder

The efficacy of quetiapine was established in 8 weeks in bipolar I or bipolar II.

Maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex

The efficacy of quetiapine as adjunct maintenance therapy to lithium or divalproex was established in patients with Bipolar I Disorder. The physician who elects to use quetiapine for extended periods in bipolar disorder should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Prevention of recurrence in patients with bipolar disorder, in patients whose manic or depressive episode has responded to quetiapine treatment. 

Recommended Dosage

Schizophrenia

Adults

Quetiapine should be administered twice daily, with or without food. Quetiapine should generally be administered with an initial dose of 25 mg bid, with increases in increments of 25-50 mg bid or tid on the second and third day, as tolerated, to a target dose range of 300 to 400 mg daily by the fourth day, given bid or tid. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady state for quetiapine would not be achieved for approximately 1-2 days in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 25-50 mg bid are recommended.

Antipsychotic efficacy was demonstrated in a dose range of 150 to 750 mg/day in the clinical trials supporting the effectiveness of quetiapine. In a dose response study, doses above 300 mg/day were not demonstrated to be more efficacious than the 300 mg/day dose. In other studies, however, doses in the range of 400-500 mg/day appeared to be needed. The safety and efficacy doses above 800 mg/day have not been evaluated in clinical trials.

Adolescents (13-17 years)

Quetiapine should be administered twice daily. However, based on response and tolerability Quetiapine may be administered three times daily where needed. The total daily dose for the initial five days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3), 300 mg (Day 4) and 400 mg (Day 5). After day 5, the dose should be adjusted within the recommended dose range of 400 mg/day to 800 mg/day based on response and tolerability. Dosage adjustments should be in increments of no greater than 100 mg/day. Efficacy was demonstrated with Quetiapine at both 400 mg and 800 mg; however, no additional benefit was seen in the 800 mg group.

Mode of Administration

Oral

Contraindications

Hypersensitivity to the active substance or to any of the excipients of this product.

Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azoleantifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated.

Warnings and Precautions

Suicide/suicidal thoughts or clinical worsening

Depression in bipolar disorder 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. In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated.

Somnolence

Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.

Cardiovascular

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 and therefore dose reduction or more gradual titration should be considered if this occurs.

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.

Extrapyramidal symptoms

Quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder.

Tardive dyskinesia

Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic drugs including quetiapine. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of Quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including Quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, Quetiapine should be discontinued and appropriate medical treatment given.

Severe neutropenia

Severe neutropenia (neutrophil count <0.5 X 10⁹/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine. There was no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine. 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. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 10⁹/L).

Lipids

Increases in triglycerides and cholesterol have been observed in clinical trials with quetiapine. Lipid increases should be managed as clinically appropriate.

Metabolic Risk

Given the observed changes in weight, blood glucose (see hyperglycemia) and lipids seen in clinical studies, there may be possible worsening of the metabolic risk profile in individual patients, which should be managed as clinically appropriate.

QT Prolongation

Quetiapine was not associated with a persistent increase in absolute QT intervals. However, with overdose QT prolongation was observed. 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 with medicines known to increase QTc interval, and concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesemia.

Withdrawal

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable.

Elderly patients with dementia-related psychosis

Quetiapine is not approved for the treatment of dementia-related psychosis. An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in controlled trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with risk factors for stroke.

Additional information

Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3.

Special Considerations in Treating Pediatric (Schizophrenia and Bipolar I Disorder )

Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

Effect on ability to drive and use machines

Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility to this is known.

Interactions with Other Medicaments

Given the primary central nervous system effects of quetiapine, Quetiapine should be used with caution in combination with other centrally acting drugs and alcohol.

Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. Concomitant administration of quetiapine with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.

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).

The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antipsychotics risperidone or haloperidol. Concomitant use of Quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%.

The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine. The pharmacokinetics of lithium were not altered when co-administered with Quetiapine.

The pharmacokinetics of sodium valproate and Quetiapine were not altered to a clinically relevant extent when co-administered.

Formal interaction studies with commonly used cardiovascular drugs have not been performed.

Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QTc interval.

Statement on Usage During Pregnancy and Lactation [Specific package insert requirement for antipsychotic] Pregnancy and lactation

Neonates exposed to antipsychotic drugs 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.

Quetiapine tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

The safety and efficacy of quetiapine during human pregnancy have not yet been established. The degree to which quetiapine is excreted into human milk is unknown. Women who are breastfeeding should therefore be advised to avoid breastfeeding while taking quetiapine.

Adverse Effects / Undesirable Effects

The most commonly reported adverse drug reactions 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 oedema, have been associated with quetiapine.

Overdose and Treatment

Fatal outcome has been reported in clinical trials following an acute overdose at 13.6 grams, and in post-marketing on doses as low as 6 grams of quetiapine alone. However, survival has also been reported following acute overdoses of up to 30 grams. In postmarketing experience, there have been very rare reports of overdose of quetiapine alone, resulting in death or coma or QT-prolongation.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose.

In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension.

There is no specific antidote to quetiapine. In cases of severe signs, 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. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

Close medical supervision and monitoring should be continued until the patient recovers.

Storage Conditions

Store below 30°C