Consumer medicine information

Seronia_CMI_Apr12

Quetiapine

BRAND INFORMATION

Brand name

Seronia Tablets

Active ingredient

Quetiapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Seronia_CMI_Apr12.

What is in this leaflet

This leaflet answers some common questions about SERONIA.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking SERONIA against the benefits they expect it will have for you.

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet with your medicine.

You may need to read it again.

What SERONIA is used for

SERONIA is used to treat:

  • schizophrenia
  • acute mania associated with Bipolar 1 Disorder.

Schizophrenia and Bipolar 1 Disorder are mental illnesses with disturbances in thinking, feelings and behaviour.

SERONIA belongs to a group of medicines called antipsychotics. These medicines work by improving the symptoms of certain types of mental illnesses.

Your doctor may have prescribed SERONIA for another reason. Ask your doctor if you have any questions about why SERONIA has been prescribed for you.

SERONIA is not recommended for use in children as there have been no studies of its effects in children.

SERONIA is available only with a doctor's prescription.

There is no evidence that SERONIA is addictive.

Before you take it

When you must not take it

Do not take SERONIA if you are allergic to medicines containing quetiapine or any of the ingredients listed at the end of this leaflet.

Do not take SERONIA if the expiry date (Exp.) printed on the pack has passed.

Do not take SERONIA if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether SERONIA is safe during pregnancy. Your doctor will discuss the risks and benefits of taking SERONIA.

Tell your doctor if you are breastfeeding or wish to breastfeed.

It is recommended that you do not breastfeed while taking SERONIA.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • heart problems
  • problems with your circulation
  • liver problems
  • diabetes (or a family history of diabetes)
  • seizures or fits
  • any condition that affects blood flow to the brain
  • dementia or related behavioural disorders (especially in the elderly).

Your doctor may want to take special care if you have any of these conditions.

If you have not told your doctor about any of the above, tell them before you start taking SERONIA.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by SERONIA, or may affect how well it works. These include:

  • medicines for anxiety or depression
  • lorazepam - a medicine to help you sleep
  • medicines for epilepsy
  • medicines for high blood pressure
  • antibiotics such as rifampicin and erythromycin
  • ketoconazole, an antifungal agent
  • glucocorticoids - medicine used to treat inflammation
  • medicines for HIV
  • thioridazine, used to treat schizophrenia.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking SERONIA.

How to take it

How much to take

Your doctor will decide what dose of SERONIA you should take and how long you need to take it.

The total daily dose is slowly increased depending on your condition. The usual dose may be between 150 mg and 800 mg a day. Some people may need a different dose. Your dose will depend on your response.

If you are elderly, or have liver problems, your doctor will adjust your dose to suit you.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take SERONIA

Swallow the tablets with a glass of water. Do not split, chew, or crush the tablets.

SERONIA is taken twice a day.

If you forget to take it

If it is almost time for your next dose (within 6 hours), skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

Ask your doctor or pharmacist if you are not sure what to do.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much SERONIA. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much SERONIA, you may feel drowsy, dizzy and have fast heart beats.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking SERONIA.

Before starting any new medicine, tell your doctor or pharmacist that you are taking SERONIA.

Tell your doctor if you become pregnant while taking SERONIA.

Visit your doctor regularly so they can check on your progress.

Tell your doctor immediately, or go to the nearest hospital if you have any of the following suicidal thoughts or other mental/ mood changes:

  • thoughts of talks of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts of self-harm
  • increase in aggressive behaviour, irritability or agitation
  • worsening of depression

Things you must not do

Do not stop taking SERONIA, or lower the dose, without checking with your doctor.

Stopping SERONIA suddenly may cause nausea, vomiting or insomnia. Discuss any changes of dose with your doctor.

Do not use SERONIA to treat any other conditions unless your doctor tells you to.

Do not give SERONIA to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how SERONIA affects you.

SERONIA may cause drowsiness or dizziness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when getting up from a sitting or lying position if it makes you feel light-headed.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure.

Be careful when drinking alcohol while taking SERONIA.

Combining SERONIA and alcohol can make you more sleepy or dizzy.

Avoid drinking large quantities of grapefruit juice.

This medicine may be affected by grapefruit juice.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking SERONIA.

Like all other medicines, SERONIA may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • feeling sleepy
  • feeling dizzy or faint
  • increase in weight
  • swelling of the hands, ankles or feet
  • abnormal dreams/ nightmares
  • feeling weak
  • fainting
  • dry mouth
  • constipation
  • indigestion
  • runny or stuffy nose.

These are all mild side effect of SERONIA.

If any of the following happen, stop taking SERONIA and tell your doctor immediately, or go to Accident and Emergency at the nearest hospital:

  • abnormal muscle movements, including difficulty starting muscle movements, shaking, restlessness or muscle stiffness without pain
  • uncontrolled movements of the tongue, mouth, cheeks or jaw
  • a sudden increase in body temperature, with sweating, or a fast heart beat
  • very fast breathing
  • muscle stiffness
  • fits (seizures)
  • severe allergic reaction (may include severe difficulty breathing, shock, swelling of the face, lips tongue or other parts of the body, skin rash, hayfever, or you may feel faint).

These are very serious side effects. If you have them, you may have had a serious reaction to SERONIA. You may need urgent medical attention or hospitalisation.

All of these side effects are rare or very rare.

Occasionally, SERONIA may be associated with changes in your liver or blood, which may require your doctor to do certain blood tests.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After using SERONIA

Storage

Keep your medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store SERONIA or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking SERONIA, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

SERONIA comes in 5 strengths of tablets:

  • SERONIA 25 - round orange tablet marked ‘QT’ on one side and ‘>’ on the other
  • SERONIA 100 - round yellow tablet marked ‘QT’ over ‘100’ on one side and ‘>’ on the other
  • SERONIA 200 - round white tablet marked ‘QT’ over ‘200’ on one side and ‘>’ on the other
  • SERONIA 300 - capsule shaped white tablet marked ‘QT’ over ‘300’ on one side and ‘>’ on the other.

SERONIA 100 are available as packs of 90. SERONIA 25, 150, 200 and 300 are in packs of 60 tablets.

Ingredients

The active ingredient in SERONIA is quetiapine fumarate.

  • each SERONIA 25 tablet contains 25 mg of quetiapine
  • each SERONIA 100 tablet contains 100 mg of quetiapine
  • each SERONIA 200 tablet contains 200 mg of quetiapine
  • each SERONIA 300 tablet contains 300 mg of quetiapine

The tablets also contain:

  • microcrystalline cellulose
  • calcium hydrogen phosphate
  • povidone
  • lactose
  • magnesium stearate
  • Opadry II 85F63196 Orange (SERONIA 25 only)
  • Opadry II 85F62513 Yellow (SERONIA 100 only)
  • Opadry II 85F18378 White (SERONIA 200 and SERONIA 300 only).

The tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonard NSW 2065
Australia

Australian Registration Numbers:
SERONIA 25 - AUST R 143704
SERONIA 100 - AUST R 143710
SERONIA 200 - AUST R 143716
SERONIA 300 - AUST R 143717

This leaflet was last revised in April 2012.

BRAND INFORMATION

Brand name

Seronia Tablets

Active ingredient

Quetiapine

Schedule

S4

 

Name of the medicine

Quetiapine fumarate.

Excipients.

Microcrystalline cellulose, calcium hydrogen phosphate, povidone, lactose, magnesium stearate, Opadry II 85F63196 Orange (ARTG 12679; 25 mg tablets), Opadry II 85F62513 Yellow (ARTG 12678; 100 mg tablets), Opadry II 85F62517 Yellow (ARTG 12680; 150 mg tablets) and Opadry II 85F18378 White (ARTG 12135; 200 mg and 300 mg tablets). The tablets are gluten free.

Description

Chemical name: bis [2-(2- [4-(dibenzo[b,f][1,4] -thiazepin-11-yl) piperazin-1-yl] ethoxy) ethanol] fumarate. Molecular formula: C42H50N6O4S2.C4H4O4. MW: 883.11. CAS: 111974-72-2. Quetiapine fumarate is a white to off white crystalline powder. It displays good solid state stability and has an aqueous solubility of 3.29 mg/mL at 25°C and exhibits suitable tableting properties when combined with appropriate excipients. Quetiapine fumarate is a weak acid (pKa 3.3, 6.8) which exhibits moderate pH dependent solubility (94.3 to 2.37 mg/mL at pH values from 1 to 9) and lipophilicity characteristics (log P) which vary with pH (0.45 in water, 1.37 at pH 5, 2.65 at pH 7 and 2.59 at pH 9). Quetiapine fumarate has no chiral centres and only one morphological entity has been detected.

Pharmacology

Pharmacodynamics.

Quetiapine is an atypical antipsychotic agent. Quetiapine and the human plasma metabolite, N-desalkyl quetiapine, interact with a broad range of neurotransmitter receptors. Quetiapine and N-desalkyl quetiapine 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 effects (EPS) liability of quetiapine. Additionally, N-desalkyl quetiapine has high affinity at serotonin 5HT1-receptors. Quetiapine and N-desalkyl quetiapine also have high affinity at histaminergic and adrenergic α1-receptors, with a lower affinity at adrenergic α2-receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors. Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade. The extent to which the N-desalkyl quetiapine metabolite contributes to the pharmacological activity of quetiapine in humans is not known.
In preclinical tests predictive of EPS, quetiapine is unlike standard antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2-receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine containing neurons following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol sensitised or drug naive Cebus monkeys after acute and chronic administration. The results of these tests predict that quetiapine should have minimal EPS liability, and it has been hypothesised that agents with a lower EPS liability may also have a lower liability to produce tardive dyskinesia.

Preclinical data.

Acute toxicity studies.

Quetiapine has low acute toxicity. Findings in mice (median lethal dose > 500 mg/kg PO; 100 mg/kg IP), rats (median lethal dose > 500 mg/kg PO; 100 mg/kg IP) and dogs (dose limit study 10 to 75 mg/kg PO) were typical of neuroleptic agents and included decreased motor activity, ptosis, loss of righting reflex, prostration, 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 (e.g. 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 was seen in mice, rats and monkeys. This hypertrophy was secondary to compensatory elevations of circulating TSH brought about by increased hepatic metabolism of thyroid hormones.
Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.
Transient increases in heart rate were not accompanied by consistent effects on blood pressure in dogs.
Posterior triangular cataracts seen after six 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, although an increase in lens relucency was seen at the highest dose. No effects on the lens were seen in rodents. Monitoring in clinical studies did not reveal drug related corneal opacities in humans.
No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies, however there was evidence for reduced lymphocytes in the bone marrow of dogs and in the circulation of monkeys.

Pharmacokinetics.

Absorption.

Quetiapine is well absorbed and the bioavailability of quetiapine is not significantly affected by administration with food.

Distribution.

The elimination half-lives of quetiapine and N-desalkyl quetiapine are approximately 7 and 12 hours respectively. Quetiapine is approximately 83% bound to plasma proteins. Steady-state peak molar concentrations of the active metabolite N-desalkyl quetiapine are 35% of that observed for quetiapine.
The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear across the approved dosage range. The kinetics of quetiapine do not differ between men and women.

Metabolism.

Quetiapine is extensively metabolised by the liver following oral administration, with parent compound accounting for less than 5% of unchanged drug related material in the urine or faeces, following the administration of radiolabelled quetiapine. The average molar dose fraction of free quetiapine and the active human plasma metabolite N-desalkyl quetiapine is < 5% excreted in the urine.
In vitro investigations established that CYP3A4 is likely to be the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. N-desalkyl quetiapine is primarily formed and eliminated via CYP3A4. CYP2D6 and CYP2C9 are also involved in quetiapine metabolism.
Quetiapine and several of its metabolites (including N-desalkyl quetiapine) were found to be weak to modest inhibitors of human cytochrome P450 3A4, 2C19, 2D6, 1A2 and 2C9 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 coadministration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.

Excretion.

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.

Use in renal impairment.

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/minute/1.73 m2), but the individual clearance values are within the range for normal subjects.

Use in hepatic impairment.

The mean plasma clearance of quetiapine was reduced in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects. Since quetiapine is extensively metabolised by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed in these patients (see Dosage and Administration).

Clinical Trials

Schizophrenia.

The efficacy of quetiapine was established in short-term controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) and Scale for Assessing Negative Symptoms (SANS).
The main trials were as follows.
1. A six week placebo controlled trial (n = 361) involving five fixed doses of quetiapine (75, 150, 300, 600 and 750 mg/day on a tid (three times daily) schedule).
2. A six week placebo controlled trial (n = 109) involving titration of quetiapine in doses up to 750 mg/day on a tid schedule.
3. A six week placebo controlled trial (n = 286) involving titration of quetiapine in high (up to 750 mg/day on a tid schedule) and low (up to 250 mg/day on a tid schedule) doses.
4. A six week dose and dose regimen comparison trial (n = 618) involving two fixed doses of quetiapine (450 mg/day on both bid (twice daily) and tid schedules and 50 mg/day on a bid schedule).
Quetiapine has been shown to be effective in the treatment of both positive and negative symptoms of schizophrenia. In a comparative clinical trial of ten weeks duration, quetiapine has been shown to be as effective as risperidone, using a 40% or more decline in the baseline Positive and Negative Symptom Scale (PANSS) score as a definition of response; although statistically comparative efficacy was not demonstrated when using a 30% decline in PANSS score, the differences between treatments were modest in absolute terms and in all probability not clinically meaningful.
In three placebo controlled clinical trials using variable doses of quetiapine, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics. A placebo controlled trial evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anticholinergics.
Unlike many other antipsychotics, quetiapine does not produce sustained elevations in prolactin, which is considered a feature of atypical agents. In a multiple fixed dose clinical trial, there were no differences in prolactin levels at study completion for quetiapine across the recommended dose range and placebo.
It has been demonstrated that quetiapine is effective when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately seven hours. This is further supported by the data from a positron emission tomography (PET) study which identified that for quetiapine, 5HT2 and D2-receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

Mania.

The efficacy of quetiapine in the treatment of manic episodes was established in two short-term placebo controlled trials in patients who met DSM-IV criteria for bipolar I disorder. These trials included patients with or without psychotic features and excluded patients with rapid cycling or mixed episodes.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an eleven item clinician rated scale used to assess the degree of manic symptomatology (irritability, disruptive/ aggressive behaviour, 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 primary outcome in these trials was change from baseline in the YMRS total score at day 21.
Secondary outcomes were also assessed. The Clinical Global Impression-Bipolar Version reflects the clinician's impression of the severity (CGI-BP severity) of the patient's overall bipolar illness and improvement from baseline (CGI-BP improvement). In addition, the Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess the effects of quetiapine on depressive symptoms, and the Positive and Negative Symptoms Scale (PANSS) was used to assess the efficacy in psychosis, agitation and aggression. The Global Assessment Scale (GAS) was used to assess improvement in functional status.
The results of the trials follow:
In two 12 week trials (n = 300, n = 299) comparing quetiapine to placebo, quetiapine was superior to placebo in reducing manic symptoms. Of those patients with a clinical response, 87% received doses of quetiapine between 400 and 800 mg per day. The mean last week median dose of quetiapine in responders was approximately 600 mg/day.
The majority of patients who responded at day 21 maintained responses to day 84. On secondary endpoints, quetiapine was also clinically and statistically superior to placebo. Improvements were observed in CGI-BP severity and improvement, MADRS total score, PANSS total score, PANSS activation subscale and in the GAS score. The effectiveness of quetiapine was unaffected by age, gender, ethnicity or the presence of psychotic symptoms at baseline.
The efficacy of quetiapine when used in combination with other antimanic treatments such as lithium and sodium valproate has not been demonstrated.
In controlled trials evaluating doses of quetiapine up to 800 mg/day for the treatment of bipolar mania, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics. The safety of doses above 800 mg/day for this indication has not been established.

Indications

Treatment of schizophrenia.
As monotherapy for the short-term treatment of acute mania associated with bipolar I disorder.

Contraindications

Hypersensitivity to any component of this product.

Precautions

Concomitant illness.

Seronia should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or other conditions predisposing to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications).
Quetiapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnosis were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with quetiapine, caution should be observed in cardiac patients.

Orthostatic hypotension.

Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope especially during the initial dose titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope has been commonly reported (see Adverse Effects). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

QT interval.

In clinical trials, quetiapine was not associated with a persistent increase in QTc intervals. However, 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 drugs known to prolong the QTc interval, and concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.

Seizures.

In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo (see Adverse Effects). As with other antipsychotics, caution is recommended when treating patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia; close supervision of high risk patients should accompany drug therapy. Prescriptions for Seronia should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

Extrapyramidal symptoms (EPS).

In placebo controlled clinical trials for schizophrenia and bipolar mania, the incidence of EPS was no different from that of placebo across the recommended therapeutic dose range. In short-term, placebo controlled clinical trials for bipolar depression, the incidence of EPS was higher in quetiapine treated patients than in placebo treated patients (see Adverse Effects). Seronia is not approved for the treatment of bipolar depression.

Tardive dyskinesia.

If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of Seronia should be considered (see Adverse Effects).

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, Seronia should be discontinued and appropriate medical treatment given.

Body temperature regulation.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Seronia for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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 Effects.

Hepatic enzyme inducers.

Concomitant use of Seronia with hepatic enzyme inducers such as carbamazepine may substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher doses of Seronia may need to be considered if Seronia is used concomitantly with a hepatic enzyme inducer.

CYP3A4 inhibitors.

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. As a consequence of this, lower doses of Seronia 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 (see Interactions with Other Medicines).

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including quetiapine (see Adverse Effects). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment emergent hyperglycaemia related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Increased risk of mortality in elderly patients with dementia related psychosis.

Elderly patients with dementia related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo. A meta-analysis of 17 placebo controlled trials with dementia related behavioural disorders showed a risk of death in the drug treated patients of approximately 1.6 to 1.7 times that seen in placebo treated patients. The clinical trials included in the meta-analysis were undertaken with Zyprexa (olanzapine), Abilify (aripiprazole), Risperdal (risperidone) and quetiapine. Over the course of these trials averaging about ten weeks in duration, 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. Seronia is not approved for the treatment of elderly patients with dementia related psychosis or behavioural disorders.

Withdrawal.

Acute withdrawal symptoms such as nausea, vomiting and insomnia have been described after abrupt cessation of antipsychotic drugs including Seronia (see Adverse Effects). Gradual withdrawal is advisable.

Dysphagia.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Quetiapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (e.g. elderly patients).

Lipids.

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

Lactose.

Seronia tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use in pregnancy.

(Category B3)
The safety and efficacy of quetiapine during human pregnancy have not been established. Therefore, Seronia should only be used during pregnancy if the benefits justify the potential risks.
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.
Teratogenic effects were not observed following administration of quetiapine at oral doses up to 200 mg/kg in rats (less than the exposure to quetiapine at the maximum recommended clinical dose based on AUC (area under the curve)) and 100 mg/kg in rabbits (approximately twice the maximum clinical exposure based on BSA (body surface area)).

Nonteratogenic class effect.

Neonates exposed to antipsychotic drugs (including quetiapine) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket 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 required additional medical treatment or monitoring.
Quetiapine should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.

Use in lactation.

The degree to which quetiapine is excreted into human milk is unknown, however in a study in lactating rats the concentration of quetiapine and/or its metabolites was higher in milk than in plasma. Women who are breastfeeding should therefore be advised to avoid breastfeeding while taking Seronia.

Carcinogenicity.

In the rat study (20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia. The incidence of carcinoma of the adrenal cortex was increased in male rats at the highest dose.
In the 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.

Genotoxicity.

Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen. Quetiapine showed no evidence of genotoxicity in a series of assays for gene mutation (bacteria and Chinese hamster ovary cells) and chromosomal damage (human lymphocytes and the in vivo micronucleus test).

Interactions

CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. CYP2D6 and CYP2C9 are also involved. Quetiapine (administration of multiple daily doses up to 750 mg/day, on a tid (three times daily) schedule) did not induce the hepatic enzyme systems involved in the metabolism of antipyrine.

Other drugs that affect quetiapine.

Demonstrated interactions.

Carbamazepine.

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), coadministration 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, a higher dose of Seronia, depending on clinical response, should be considered. It should be noted that the recommended daily dose of Seronia is 750 mg/day for the treatment of schizophrenia, and 800 mg/day for the treatment of manic episodes associated with bipolar disorder, and continued treatment at higher doses should only be considered as a result of careful consideration of the benefit/ risk assessment for an individual patient.

Phenytoin.

Coadministration of quetiapine (250 mg tid) and phenytoin (100 mg tid; microsomal enzyme inducer) caused increases in clearance of quetiapine by fivefold. Increased doses of Seronia may be required to maintain control of psychotic symptoms in patients coadministered Seronia and phenytoin or other hepatic enzyme inducers (e.g. carbamazepine, barbiturates, rifampicin, glucocorticoids). The dose of Seronia may need to be reduced if phenytoin is withdrawn and replaced with a noninducer (e.g. sodium valproate).

CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics and protease inhibitors).

During concomitant administration of drugs which are potent CYP3A4 inhibitors (such as systemic ketoconazole or erythromycin) plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials.
In a multiple dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, coadministration of ketoconazole (200 mg once daily for four days) 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 Seronia should be reduced during concomitant use of quetiapine and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors). 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 (see Interactions with Other Medicines).
It is also not recommended to take Seronia together with grapefruit juice.

Thioridazine.

Thioridazine (200 mg bid (twice daily)) increased the oral clearance of quetiapine (300 mg bid) by 65%.

Potential interactions that have been excluded.

Cimetidine.

The pharmacokinetics of quetiapine (150 mg tid) were not significantly altered (20% decrease in clearance) following coadministration with cimetidine (400 mg tid for four days; a known P450 enzyme inhibitor). Dosage adjustment for quetiapine is not required when it is given with cimetidine.

Risperidone and haloperidol.

The pharmacokinetics of quetiapine were not significantly altered following coadministration with the antipsychotics risperidone (3 mg bid) or haloperidol (7.5 mg bid).

Imipramine and fluoxetine.

The pharmacokinetics of quetiapine were not significantly altered following coadministration with the antidepressants imipramine (75 mg bid; a known CYP2D6 inhibitor) or fluoxetine (60 mg once daily; a known CYP3A4 and CYP2D6 inhibitor).

Effects of quetiapine on other drugs.

(See Pharmacology, Pharmacokinetics.)

Demonstrated interactions.

Lorazepam.

The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg tid dosing. Dosage adjustment is not required.

Theoretical interactions.

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

Levodopa and dopamine agonists.

As it exhibits in vitro dopamine antagonism, Seronia may antagonise the effects levodopa and dopamine agonists.

Potential interactions that have been excluded.

Lithium.

The pharmacokinetics of lithium were not altered when coadministered with quetiapine (250 mg bid).

Sodium valproate.

The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when coadministered.

Cardiovascular medicines.

Caution should be used when Seronia is used concomitantly with medicines known to cause electrolyte imbalance or to increase QTc interval.
Because of its potential for inducing hypotension, Seronia may enhance the effects of certain antihypertensive medicines.

Effect on ability to drive or operate machinery.

Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Patients likely to drive or operate other machines should therefore be cautioned appropriately.

Effects on laboratory tests.

As with other antipsychotics, transient leucopenia and/or neutropenia have been observed in patients administered quetiapine. There were no cases of persistent severe neutropenia reported in controlled clinical trials with quetiapine. During postmarketing experience, resolution of leucopoenia and/or neutropenia has followed cessation of therapy with quetiapine. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leucopenia and/or neutropenia. Occasionally, eosinophilia has been observed (see Adverse Effects).
Asymptomatic elevations in serum transaminase (ALT, AST) or gamma-glutamyl transferase levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment (see Adverse Effects).
Small elevations in nonfasting serum triglyceride levels and total cholesterol (predominantly low density lipoprotein (LDL) cholesterol) have been observed during treatment with quetiapine.
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. There was no evidence of clinically significant changes in thyrotropin (thyroid stimulating hormone, TSH) concentration over time. 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.

Adverse 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.
The incidences of adverse drug reactions associated with quetiapine therapy, according to CIOMS format, can be seen in Table 1.
In placebo controlled clinical trials in schizophrenia and bipolar mania the incidence of EPS was no different to placebo (schizophrenia: quetiapine 10.9%, placebo 11.3%; bipolar mania: quetiapine 15.7%, placebo 15.2%). (See Precautions, Extrapyramidal symptoms). In two short-term studies in bipolar depression the incidence of EPS from the combined data was 11.8% for quetiapine compared to 5.5% for placebo (see Precautions, Extrapyramidal symptoms). In these studies, the incidence of the individual adverse events (e.g. akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. Seronia is not approved for the treatment of bipolar depression.
Very rare postmarketing cases of tardive dyskinesia and very rare postmarketing cases of other EPS related events (e.g. dyskinesia, tremor, muscle spasm, dystonia, muscle twitching) have been received (see Precautions).
Very rare postmarketing cases of anaphylactic reaction have been received.
Very rare cases of cataract and urinary retention have been reported in the postmarketing data, but no causal link between these reports and quetiapine has been established.

Dosage and Administration

Seronia should be administered twice daily, with or without food.

Schizophrenia.

Adults.

The total daily dose for the first four 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 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.

Monotherapy. Acute mania in bipolar I disorder.

Adults.

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/day by day 6 should be in increments of no greater than 200 mg/day.
The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg/day. The usual effective dose is in the range of 400 to 800 mg/day.

Elderly.

As with other antipsychotics, Seronia should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of quetiapine was reduced by 30 to 50% in elderly subjects when compared with younger patients.

Children and adolescents.

The safety and efficacy of Seronia have not been evaluated in children and adolescents.

Renal impairment.

Dosage adjustment is not necessary.

Hepatic impairment.

Quetiapine is extensively metabolised by the liver. Therefore, Seronia should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased in increments of 25 to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.

Overdosage

Contact the Poisons Information Centre on 131 126 for advice on the management of an overdose.
In clinical trials, experience with quetiapine in overdosage is limited. Estimated doses of quetiapine up to 30 g have been taken, without fatal consequences and with patients recovering without sequelae, however, death has been reported in a clinical trial following an overdose of quetiapine 13.6 g 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.

Symptoms.

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

Treatment.

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. While the prevention of absorption in overdose has not been investigated, administration of activated charcoal together with a laxative should be considered.
Close medical supervision and monitoring should be continued until the patient recovers.

Presentation

Tablets (coated, marked > on reverse), 25 mg (orange, round, marked QT on one side): 60's (blister pack); 100 mg (yellow, round, marked QT over 100): 90's (blister pack); 150 mg* (yellow, round, marked QT over 150), 200 mg (white to off white, round, marked QT over 200), 300 mg (white to off white, capsule shaped, marked QT over 300): 60's (blister pack).
*Not currently not marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.