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PRODUCT INFORMATION

SERDOLECTâ TABLETS

ECG monitoring is required before and during treatment with sertindole; see PRECAUTIONS.

Clinical studies have shown that sertindole prolongs the QT interval to a greater extent than some other antipsychotics. Sertindole should therefore only be used for people who are not responsive to, or intolerant of at least one other antipsychotic agent.

Prescribing physicians should comply fully with the required safety measures; see CONTRAINDICATIONS and PRECAUTIONS.

NAME OF THE MEDICINE Sertindole Chemical name: 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone CAS number: 106516-24-9 Molecular formula: C24H26ClFN4O Molecular weight: 440.9 Structural formula:

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DESCRIPTION Sertindole is a white to off-white fine powder, practically insoluble in water. It is soluble in 0.1 N acetic acid, sparingly soluble in ethanol, and freely soluble in dichloromethane. Serdolect 4 mg tablets are oval, yellow, biconvex film-coated tablets marked with “S4” on one side. Serdolect 12 mg tablets are oval, beige, biconvex film-coated tablets marked with “S12” on one side. Serdolect 16 mg tablets are oval, rose, biconvex film-coated tablets marked with “S16” on one side. Serdolect 20 mg tablets are oval, pink, biconvex film-coated tablets marked with “S20” on one side. They contain the following excipients: starch - maize, lactose, hydroxypropylcellulose, cellulose - microcrystalline, croscarmellose sodium and magnesium stearate as well as a coating of hypromellose, titanium dioxide, macrogol 400 and 4 mg tablets: iron oxide yellow CI77492. 12 mg tablets: iron oxide yellow CI77492, iron oxide red CI77491. 16 mg tablets: iron oxide red CI77491. 20 mg tablets: iron oxide yellow CI77492, iron oxide red CI77491, iron oxide black CI77499. PHARMACOLOGY Pharmacological actions Pharmacotherapeutic group: limbic selective antipsychotics, ATC-code: N05A E 03 It has been proposed that the neuropharmacological profile of sertindole, as an antipsychotic drug, is derived from its selective inhibitory effect on mesolimbic dopaminergic neurons and is due to balanced inhibitory effects on central dopamine D2 and serotonin 5HT2 receptors as well as on α1-adrenergic receptors. In animal pharmacology studies, sertindole inhibited spontaneously active dopamine neurons in the mesolimbic ventral tegmental area (VTA) with a selectivity ratio of more than 100 compared to dopamine neurons in substantia nigra pars compacta (SNC). Inhibition of SNC activity is thought to be involved in movement side effects (EPS) associated with many antipsychotic drugs. Antipsychotic drugs are known to increase serum prolactin levels through dopamine blockade. The prolactin levels in patients receiving sertindole remained within normal limits, both in short-term studies and during long-term treatment (1 year). However, hyperprolactinaemia and prolactin-related events have occasionally been reported with post-marketing sertindole use.

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Sertindole has no effect on muscarinic and histaminic H1 receptors. This is confirmed by the absence of anticholinergic and sedative effects related to those receptors. Pharmacokinetics Elimination of sertindole occurs via hepatic metabolism, with a mean terminal half-life of approximately 3 days. The clearance of sertindole decreases with multiple dosing to a mean around 14 L/h (females have approximately 20% lower apparent clearance than males, although lean-mass corrected clearances are comparable). Therefore, upon multiple dosing, accumulation is greater than predicted from a single dose, due to an increase in the systemic bioavailability. However, at steady state, clearance is dose independent and plasma concentrations are proportional to dose. There is moderate inter-subject variability in sertindole pharmacokinetics, due to the polymorphism in the cytochrome P450 2D6 (CYP2D6). Patients who are deficient in this hepatic enzyme have sertindole clearances that are ½ - ⅓ of those who are CYP2D6 extensive metabolisers. These poor metabolisers (up to 10% of the population) will therefore have plasma levels 2 - 3 times the normal. Sertindole concentration is not predictive of therapeutic effect for an individual patient; thus, dosing individualisation is best achieved by assessment of therapeutic effect and tolerability. Absorption Sertindole is well absorbed with a tmax of sertindole after oral administration of approximately 10 hours. Different dose strengths are bioequivalent. Food and aluminium-magnesium antacids have no clinically significant effect on the rate or the extent of sertindole absorption. Distribution The apparent volume of distribution (Vβ/F) of sertindole after multiple dosing is approximately 20 L/kg. Sertindole is about 99.5% bound to plasma proteins, primarily to albumin and α1-acid glycoprotein. In patients treated with recommended doses, 90% of the measured concentrations are below 140 ng/mL (~ 320 nmol/L). Sertindole penetrates into red blood cells with a 1.0 blood/plasma ratio. Sertindole readily penetrates the blood-brain and placental barriers. Metabolism Two metabolites have been identified in human plasma: dehydrosertindole (oxidation of the imidazolidinone ring) and norsertindole (N-dealkylation). Concentrations of dehydrosertindole and norsertindole are approximately 80% and 40%, respectively, of the parent compound at steady state. Sertindole activity is primarily due to the parent drug and the metabolites do not appear to have significant pharmacological effects in humans. Elimination Sertindole and its metabolites are eliminated very slowly, with a total recovery of 50 - 60% of a radiolabelled oral dose 14 days after administration. Approximately 4% of the dose is excreted into the urine as parent drug plus metabolites of which less than 1% is present as parent drug. Faecal excretion is the major route of excretion and accounts for the rest of the parent drug and metabolites.

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CLINICAL TRIALS The efficacy of sertindole for the treatment of schizophrenia was demonstrated by four short-term active-controlled studies (three were haloperidol-controlled studies, two of which were also placebo-controlled, and one was a risperidone-controlled study), as well as one long-term trial of 52 weeks duration comparing sertindole to haloperidol. Several rating scales were used for assessing psychiatric signs and symptoms. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology, used to evaluate the effects of drug treatment in schizophrenia. The Clinical Global Impression (CGI) scale reflects the impression of a skilled observer (familiar with the manifestations of schizophrenia) of the overall clinical state of the patient. Short-term studies Short-term efficacy of sertindole was demonstrated by three phase III, randomised, placebo- and/or haloperidol-controlled studies of 8 weeks duration in hospitalised patients with schizophrenia (DSM-III-R). The primary efficacy variable was the mean change from baseline to final evaluation in total Positive and Negative Syndrome Scale (PANSS) score. Secondary efficacy variables included PANSS positive and negative subscales, Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI). 1) 477 (ITT) patients were randomised to treatment with placebo (n = 71), sertindole 12 mg (n = 72), sertindole 20 mg (n = 65), sertindole 24 mg (n = 70), haloperidol 4 mg (n = 68), haloperidol 8 mg (n = 63), and haloperidol 16 mg (n = 68). All doses of sertindole and haloperidol resulted in a statistically significant reduction in the total PANSS score when compared with placebo (ITT, LOCF). Mean Change from Baseline to Day 56 in total PANSS Score (LOCF) Sertindole 12 mg

Sertindole 20 mg

Sertindole 24 mg

Haloperidol 4 mg

Haloperidol 8 mg

Haloperidol 16 mg

Placebo

-9.9* -17.6* -10.7* -11.8* -16.5* -11.9* 0.7 * statistically significant (P< 0.05) 2) 438 (ITT) patients were randomised to treatment with placebo (n = 106), sertindole 20 mg (n = 111), sertindole 24 mg (n = 108), and haloperidol 16 mg (n = 113). Sertindole 20 mg and 24 mg and haloperidol 16 mg resulted in a statistically significant reduction in the total PANSS score when compared with placebo (ITT, LOCF). Mean Change from Baseline to Day 56 in total PANSS Score (LOCF) Sertindole 20 mg Sertindole 24 mg Placebo Haloperidol 16 mg -7.5* -10.3* -1.2 -13.3*

* statistically significant (P< 0.05) 3) 595 (ITT) patients were randomised to treatment with sertindole 8 mg (n = 116), sertindole 16 mg (n = 120), sertindole 20 mg (n = 121), sertindole 24 mg (n = 115), and haloperidol 10 mg (n = 123).

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Mean Change from Baseline to Day 56 in total PANSS Score (LOCF) Sertindole 8 mg Sertindole 16 mg Sertindole 20 mg Sertindole 24 mg Haloperidol 10 mg -16.2 -23.8* -20.1 -23.1* -22.8* * statistically significant (P< 0.05) Long-term efficacy In Phase III open, uncontrolled studies with flexible dosing of sertindole from 4mg to 24 mg daily, efficacy was maintained for over 12 months. Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness. INDICATIONS Sertindole is indicated for the treatment of schizophrenia. Due to cardiovascular safety concerns, sertindole should be used only for people who are not responsive to, or intolerant of at least one other antipsychotic medicine. Due to its slow onset of action sertindole should not be used in emergency situations for urgent relief of symptoms in acutely disturbed patients. CONTRAINDICATIONS Hypersensitivity to sertindole or any of the excipients. Sertindole is contraindicated in patients with known uncorrected hypokalaemia, and those with known uncorrected hypomagnesaemia. Sertindole is contraindicated in patients with a history of clinically significant cardiovascular disease, congestive heart failure, cardiac hypertrophy, arrhythmia, or bradycardia (< 50 beats per minute). Furthermore, sertindole should not be initiated in patients with congenital long QT syndrome or a family history of this disease, or in patients with known acquired QT interval prolongation (QTc above 450 msec in males and 470 msec in females). Sertindole is contraindicated in patients with severe hepatic impairment.

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Contraindications with certain other medicines: Sertindole is contraindicated in patients receiving drugs having a risk of causing torsade de pointes as increases in the QT interval related to sertindole treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval. Relevant classes include:

Anti-arrhythmics

amiodarone, disopyramide, procainamide, sotalol. dofetilide*, ibutilide*, quinidine*.

Anti-psychotics

chlorpromazine, droperidol, haloperidol ziprasidone, lithium mesoridazine*, thioridazine*, pimozide*.

Macrolides

clarithromycin, erythromycin

Quinolone antibiotics

sparfloxacin*

Anti-malarials

Chloroquine, halofantrine*

Anti-cancer agents

arsenic trioxide

Anti-infectives

pentamidine

Anti-anginals

bepridil*

GI stimulants

cisapride*

Anti-lipidemics

probucol*

Opiate agonists

Methadone, levomethadyl*

* Not registered in Australia Contraindications for co-administration. Co-administration of sertindole is contraindicated with drugs known to potently inhibit hepatic cytochrome P450 3A enzymes (see Interactions with other medicines). Relevant classes include

Anti-fungals

ketoconazole, itraconazole, fluconazole

Macrolides erythromycin, clarithromycin, telithromycin*

HIV protease inhibitors indinavir, ritonavir, nelfinavir, saquinavir

Calcium blockers

verapamil, diltiazem

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Anti-emetics aprepitant

Anti-depressants nefazodone*

* Not registered in Australia The above list is not exhaustive and other individual drugs known to potently inhibit CYP3A enzymes (e.g. cimetidine) are also contraindicated. PRECAUTIONS Cardiovascular - Clinical studies have shown that sertindole prolongs the QT interval to a greater extent than some other antipsychotics. QTc prolongation increased with increasing dose. Prolongation of the QTc interval in some drugs is associated with the ability to cause Torsade de Pointes-type (TdP) arrhythmia (a potentially fatal polymorphic ventricular tachycardia) and sudden death. Pooled data from short-term, placebo-controlled clinical trials showed sertindole was associated with an increase in QTcB from baseline of 19 msec and in QTcF of about 18 to 21 msec compared with a decrease in the intervals for patients given placebo and minimal changes with haloperidol. (refer Adverse Effects). Non-clinical studies have shown that sertindole and its metabolite dehydrosertindole increase the QTc interval in several mammalian species at clinically relevant concentrations via inhibition of the inward rectifying potassium channel (Ikr). However, other torsadogenic biomarkers were elicited only at high concentrations/ doses in in vitro or animal models. Sertindole should therefore only be used for patients who have failed to adequately respond to appropriate treatment with at least one other antipsychotic medicine either because of insufficient efficacy or intolerable adverse effects. Prescribing physicians should comply fully with the required safety measures. ECG monitoring: § ECG monitoring is mandatory prior to and during treatment with sertindole. § Sertindole is contraindicated if a QTc interval of more than 450 msec in males or

470 msec in females is observed at baseline, i.e., before starting sertindole treatment.

§ ECG monitoring should be conducted at baseline (before starting sertindole), upon reaching steady state after approximately 3 weeks or when reaching 16 mg and again after 3 months of treatment.

§ During maintenance treatment ECGs should be repeated at a minimum of 12 monthly intervals.

§ During maintenance treatment, ECG measurements should take place prior to and after 3 weeks after any increase in dose.

§ An ECG is recommended after the addition or increase of dosage of concomitant medication that may increase the sertindole concentration (see Interactions with other medicines).

§ If a QTc interval of more than 500 msec is observed during treatment with sertindole, treatment should be discontinued.

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§ Should the QTc be prolonged by more than 60 msec from baseline at any time during the treatment, the ECG should be repeated. If QTc prolongation remains high (greater than or equal to 60 msec) the dosage should be lowered and a search made for any explanatory factor that may contribute to the increase in QTc. If no explanatory factor is found (e.g. low baseline value, autonomic imbalance dramatically affecting heart rate) and QTc prolongation remains greater or equal to 60 msec, the drug should be withdrawn.

§ For patients with symptoms such as palpitations, convulsions, or syncope that could indicate the occurrence of arrhythmias, the prescriber should initiate urgent evaluation, including an ECG.

§ ECG monitoring is ideally conducted in the morning and the Fridericia formulae for calculating the QTc interval are preferred.

The risk of QT prolongation is increased in patients receiving concomitant treatment with drugs that prolong the QTc interval or drugs that inhibit sertindole metabolism (see CONTRAINDICATIONS). Electrolyte disturbances - Baseline serum potassium and magnesium levels should be measured before commencing treatment with sertindole in patients at risk of significant electrolyte disturbances. Low serum potassium and magnesium should be corrected before proceeding with treatment. Monitoring of serum potassium is recommended for patients experiencing vomiting, diarrhoea, treatment with potassium-depleting diuretics (e.g. frusemide), or other electrolyte disturbances. Postural hypotension - Due to the α1-blocking activity of sertindole, symptoms of postural hypotension may occur during the initial dose-titration period. Parkinsonism - Antipsychotic drugs may inhibit the effects of dopamine agonists. Sertindole should be used cautiously in patients with Parkinson’s disease. SSRIs - Some SSRIs, like fluoxetine and paroxetine (potent CYP2D6 inhibitors), may increase the plasma levels of sertindole by a factor of 2 - 3. Sertindole should therefore only be used concomitantly with these drugs with extreme caution, and only if the potential benefit outweighs the risk. A lower maintenance dose of sertindole may be needed and careful ECG monitoring should be undertaken before and after any dose adjustment of these drugs (see Interactions with other medicines). Poor CYP2D6 metabolisers - Precaution is advised when co-administrating drugs known to potently inhibit hepatic cytochrome 2D6 enzymes. Relevant classes include:

Anti-depressants

bupropion, paroxetine, fluoxetine

Anti-arrhythmics quinidine*

* Not registered in Australia Delayed onset of action - The effect of sertindole is evident approximately 2 to 4 weeks after commencing treatment. It is therefore not suitable for management of acutely disturbed patients.

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Reduced hepatic function - Patients with mild/moderate hepatic dysfunction should be closely observed. Slower titration and a lower maintenance dose are recommended. The maintenance dose in patients with moderate hepatic impairment (serum albumin below 3.4 g/dL) should not exceed 12 mg/day. Hyperglycaemia and Diabetes Mellitus – Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients with atypical antipsychotics including Serdolect. 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 atypical antipsychotics. Precise risk estimates for hyperglycaemic-related adverse events in patients treated with atypical antipsychotics are not available. Patients with 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 anti-diabetic treatment despite discontinuation of the suspect drug. In patients with significant treatment-emergent hyperglycaemia, discontinuation of sertindole should be considered. Tardive dyskinesia - Tardive dyskinesia is thought to be caused by dopamine receptor hypersensitivity in the basal ganglia as a result of chronic receptor blockade by antipsychotics. A low incidence (comparable to that of placebo) of extrapyramidal symptoms during treatment with sertindole has been seen in clinical studies. However, long-term treatment with antipsychotic compounds (especially at high dosages) is associated with the risk of tardive dyskinesia. If signs of tardive dyskinesia appear, dosage reduction or drug discontinuation should be considered. Akathisia – The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particularly attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse. Seizures - Sertindole should be used with caution in patients with a history of seizures.

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Neuroleptic Malignant Syndrome - A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. In such an event or with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines including sertindole should be withdrawn. Suicide – The possibility of a suicide attempt is inherent in schizophrenia and close supervision of high-risk patients should accompany therapy. Prescriptions of sertindole should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Weight gain – As with all antipsychotics patients receiving sertindole should receive regular monitoring of weight. The mean increase in weight in short-term placebo-controlled clinical trials (2-3 month) in patients on maintenance doses of 12-24 mg/day sertindole was 2.9 kg with 24% reporting a gain ≥ 7% versus 0.2 kg and 10% reporting a gain ≥ 7% in the placebo group. In long term clinical trials patients taking 24 mg/day sertindole for 12 months experienced a mean increase in weight from baseline of 5 kg (5-6%) change with 48% reporting a gain of ≥ 7% and 21% reporting a gain of ≥ 15% from baseline. Withdrawal - Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable. Venous thromboembolism (VTE) – cases 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 sertindole and preventive measures undertaken. Effects on ability to drive and use machines - Sertindole is not sedative, however, patients should be advised not to drive or operate machinery until their individual susceptibility is known. Excipients - The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not receive this medicine. Effects on fertility Oral administration of sertindole was shown to impair male fertility in mice and rats at systemic exposures similar to or less than that anticipated in humans at the maximum recommended clinical dose. The adult fertility impairment, which was reversible, was likely to be due to α1-adrenoceptor antagonism. Male offspring of sertindole-treated rats have also shown reduced mating and fertility (see Use in pregnancy).

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In humans, adverse events such as hyperprolactinaemia, galactorrhoea, erectile dysfunction, ejaculation disorder and ejaculation failure have been reported. These events may have a negative impact on female and/or male sexual function and fertility. If clinically significant hyperprolactinaemia, galactorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation. Use in pregnancy Category C There are no adequate and well controlled studies in pregnant women. Non teratogenic class effect: Neonates exposed to antipsychotic drugs (including sertindole) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market 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 additional medical treatment or monitoring. Sertindole should be used during pregnancy only if the anticipated benefit outweighs the risk and administered dose and duration of treatments should be as low and short as possible. Animal reproduction studies have not shown evidence of teratogenic effects. Sertindole, and its metabolites, cross the placenta in rats but were not teratogenic in rats or rabbits at oral doses up to 5 and 3 mg/kg/day, respectively. These doses correspond to 5 times the human exposure at the maximum recommended clinical dose (based on AUC) in rats and 2 times the maximum recommended clinical dose (expressed as body surface area) in rabbits. Oral administration of sertindole to rats from late gestation to weaning was associated with impaired neonatal survival, pup development, sexual maturation, and reduced fertility at exposures less than anticipated clinically. Use in lactation There are no human data on the excretion of sertindole into breast milk or on the safety of sertindole exposure in infants. Sertindole and/or its metabolites are excreted into rat milk and may contribute to impaired neonatal survival, pup development, sexual maturation and fertility (see Use in pregnancy). Paediatric use The safety and efficacy of sertindole in children and adolescents under the age of 18 have not been established. Use in the elderly Sertindole is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in elderly patients with dementia. An approximate 3-fold increase in risk of cerebrovascular adverse events has been seen in randomised placebo-controlled clinical trials in the dementia

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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. Therefore, sertindole should be used with caution in patients with risk factors for stroke. In view of the increased risk of significant cardiovascular disease in the elderly, sertindole should be used with care in patients above 65 years of age. Treatment should only be initiated after a thorough cardiovascular examination (see DOSAGE AND ADMINISTRATION). Carcinogenicity Carcinogenicity studies with oral sertindole were conducted at doses up to 10 mg/kg/day in mice and up to 3 mg/kg in rats, equivalent to twice the maximum recommended clinical dose and the maximum recommended clinical dose, respectively, based on body surface area. Increased incidences of mammary gland, pituitary and pancreatic islet cell tumours were observed in female rodents. These are likely to be due to chronically elevated prolactin levels, which are a class effect of antipsychotic drugs that antagonise dopamine D2 receptors. While serum prolactin levels were not measured during the sertindole carcinogenicity studies, other studies showed that sertindole elevated serum prolactin levels by up to 10-fold in rats at doses twice those used in the carcinogenicity studies. The relevance for human risk of the findings of prolactin-mediated endocrine tumours in rodents is unknown but likely to be low as human clinical studies of sertindole of up to one-year duration have not shown an increase in circulating prolactin concentrations. However, since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, sertindole should be used cautiously in patients with previously detected breast cancer or in patients with pituitary tumours. Possible manifestations associated with elevated prolactin levels are amenorrhoea, galactorrhoea and menorrhagia. Genotoxicity An increase in the incidence of polyploidy was observed at cytotoxic concentrations of sertindole in human lymphocytes in vitro, but the weight of evidence from negative mutagenicity and clastogenicity studies, including in vivo studies, suggests that sertindole is unlikely to be genotoxic. Interactions with other medicines Sertindole is extensively metabolised by the CYP2D6 and CYP3A isozymes of the cytochrome P450 system. CYP2D6 is polymorphic in the population and both isozymes can be inhibited by a variety of psychotropic and other drugs (see PRECAUTIONS). CYP2D6 - The plasma concentration of sertindole is increased by a factor of 2 - 3 in patients concurrently taking fluoxetine or paroxetine (potent CYP2D6 inhibitors), sertindole should therefore only be used concomitantly with these or other CYP2D6 inhibitors with extreme caution. A lower maintenance dose of sertindole may be needed and careful ECG monitoring should be undertaken before and after any dose adjustment of these drugs (see PRECAUTIONS).

CYP3A - Minor increases (< 25%) in sertindole plasma concentrations have been noted for macrolide antibiotics (e.g. erythromycin, a CYP3A inhibitor) and calcium channel antagonists (diltiazem, verapamil). However, the consequences could be

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greater in CYP2D6 poor metabolisers (since elimination of sertindole by both CYP2D6 and CYP3A would be affected). Since it is not possible to routinely identify patients who are poor metabolisers of CYP2D6 the concomitant administration of CYP3A inhibitors and sertindole is contraindicated, as this may lead to significant increases in sertindole levels (see CONTRAINDICATIONS). Grapefruit juice should also be avoided as it may reduce metabolism of sertindole. Agents known to induce CYP isozymes - The metabolism of sertindole may be significantly enhanced by agents known to induce CYP isozymes, notably rifampicin, carbamazepine, phenytoin and phenobarbital, which can decrease the plasma concentrations of sertindole by a factor of 2 - 3. Reduced antipsychotic efficacy in patients receiving these drugs or other inducing agents may require the dose of sertindole to be adjusted to the upper dosage range. ADVERSE EFFECTS Safety Study The Sertindole Cohort Prospective (SCoP) Study was an open, randomised controlled study comparing the safety of sertindole with risperidone with limited intervention to ensure compliance with restrictions to use. Approximately 10,000 patients were enrolled with total patient exposure of approximately 15,000 patient-years. The primary endpoints were all-cause mortality and cardiac events (including arrhythmias requiring hospitalisation). Secondary endpoints included cause-specific mortality (cardiac, suicide and other) and suicide attempts (fatal and non-fatal). During antipsychotic monotherapy with sertindole or risperidone, the all-cause mortality rate for sertindole was 0.63 deaths per 100 patient years and was not different from that for risperidone (hazard ratio of 0.980 with an upper confidence limit of 1.405). The estimated all-cause mortality ratio of sertindole to risperidone for the entire treatment period (with or without add-on antipsychotic treatment) including a 30-day safety follow-up period was 1.117 with an upper confidence limit of 1.500. Cardiac events, including arrhythmia, requiring hospitalisation (second primary endpoint) were very infrequent. There was no difference between treatment groups (3 cases in the sertindole group and 1 in the risperidone group). Cardiac mortality was statistically significantly higher in the sertindole group (17 deaths in the sertindole patients and 8 deaths in the risperidone patients during the entire treatment period, HR 2.131 (95%CI 0.911 – 4.985). This analysis included patients with and without add-on antipsychotic treatment and also included a 30-day safety follow-up period) During the entire treatment period (with and without add-on antipsychotic treatment including a 30 day safety follow-up period) 47 patients in the sertindole group and 63 in the risperidone group attempted suicide. These results were not statistically significant, HR 0.804 (95%CI 0.551 – 1.174). Patients in either group who received add-on sertindole, risperidone or clozapine were excluded from this analysis.

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Treatment Emergent Adverse Events with an incidence of ≥ 1% in any group in the placebo-controlled trials are included in the table below. Figures marked with * indicate adverse reactions where the incidence in the sertindole group is statistically significantly different from the incidence in the placebo group (p < 0.05).

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System Organ Class and Preferred Term Placebo

n (%) Sertindole

n (%)

Patients Treated 290 704

Patients with Treatment Emergent Adverse Event 251 (86.6%) 630 (89.5%)

BODY AS A WHOLE

Abdominal pain 20 (6.9%) 43 (6.1%)

Accidental injury 22 (7.6%) 45 (6.4%)

Asthenia 26 (9.0%) 61 (8.7%)

Back pain 12 (4.1%) 42 (6.0%)

Chest pain 8 (2.8%) 30 (4.3%)

Fever 5 (1.7%) 16 (2.3%)

Headache 116 (40.0%) 265 (37.6%)

Infection 20 (6.9%) 60 (8.5%)

Malaise 4 (1.4%) 2 (0.3%)

Neck pain 6 (2.1%) 11 (1.6%)

Pain 14 (4.8%) 31 (4.4%)

Pelvic pain 2 (0.7%) 7 (1.0%)

CARDIOVASCULAR SYSTEM

Electrocardiogram abnormal 4 (1.4%) 13 (1.8%)

Hypertension 4 (1.4%) 3 (0.4%)

Hypotension 4 (1.4%) 4 (0.6%)

Palpitation 4 (1.4%) 6 (0.9%)

Postural hypotension (See PRECAUTIONS) 4 (1.4%) 34 (4.8%)*

QT interval prolonged (See PRECAUTIONS) 0 (0.0%) 11 (1.6%)*

Tachycardia 2 (0.7%) 14 (2.0%)

CENTRAL AND PERIPHERAL NERVOUS SYSTEM

Abnormal dreams 3 (1.0%) 10 (1.4%)

Abnormal gait 3 (1.0%) 11 (1.6%)

Agitation 3 (1.0%) 7 (1.0%)

Akathisia 17 (5.9%) 28 (4.0%)

Cogwheel rigidity 8 (2.8%) 14 (2.0%)

Depression 4 (1.0%) 3 (0.4%)

Dizziness 22 (7.6%) 85 (12.1%)*

Dyskinesia 4 (1.4%) 3 (0.4%)

Dystonia 8 (2.8%) 8 (1.1%)

Extrapyramidal syndrome 1 (0.3%) 9 (1.3%)

Hypertonia 15 (5.2%) 57 (8.1%)

Insomnia 96 (33.1%) 221 (31.4%)

Movement disorder 9 (3.1%) 15 (2.1%)

Nervousness 5 (1.7%) 11 (1.6%)

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System Organ Class and Preferred Term Placebo n (%)

Sertindole n (%)

Oculogyric crisis 3 (1.0%) 2 (0.3%)

Paraesthesia 1 (0.3%) 19 (2.7%)*

Somnolence 32 (11.0%) 103 (14.6%)

Speech disorder 1 (0.3%) 7 (1.0%)

Tardive dyskinesia 3 (1.0%) 4 (0.6%)

Tremor 22 (7.6%) 32 (4.5%)

GASTROINTESTINAL SYSTEM

Anorexia 6 (2.1%) 4 (0.6%)

Constipation 31 (10.7%) 101 (14.3%)

Diarrhoea 9 (3.1%) 15 (2.1%)

Dry mouth 13 (4.5%) 67 (9.5%)*

Dyspepsia 47 (16.2%) 111 (15.8%)

Dysphagia 3 (1.0%) 8 (1.1%)

Faecal incontinence 3 (1.0%) 3 (0.4%)

Flatulence 7 (2.4%) 17 (2.4%)

Increased salivation 5 (1.7%) 11 (1.6%)

Liver function tests abnormal 0 (0.0%) 7 (1.0%)

Nausea 24 (8.3%) 49 (7.0%)

Nausea and vomiting 6 (2.1%) 10 (1.4%)

Tooth disorder 29 (10.0%) 55 (7.8%)

Vomiting 31 (10.7%) 50 (7.1%)

METABOLIC AND NUTRITIONAL

Peripheral oedema 1 (0.3%) 21 (3.0%)*

Weight gain 3 (1.0%) 25 (3.6%)*

MUSCULOSKELETAL SYSTEM

Arthralgia 5 (1.7%) 30 (4.3%)

Joint disorder 2 (0.7%) 9 (1.3%)

Myalgia 29 (10.0%) 81 (11.5%)

RESPIRATORY SYSTEM

Cough increased 15 (5.2%) 41 (5.8%)

Dyspnoea 2 (0.7%) 20 (2.8%)*

Epistaxis 3 (1.0%) 16 (2.3%)

Lung disorder 1 (0.3%) 9 (1.3%)

Pharyngitis 15 (5.2%) 43 (6.1%)

Rhinitis 32 (11.0%) 188 (26.7%)*

Wheezing 5 (1.7%) 17 (2.4%)

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System Organ Class and Preferred Term Placebo n (%)

Sertindole n (%)

SKIN AND APPENDAGES

Acne 5 (1.7%) 8 (1.1%)

Dry skin 3 (1.0%) 15 (2.1%)

Pruritus 3 (1.0%) 17 (2.4%)

Rash 19 (6.6%) 39 (5.5%)

Skin disorder 13 (4.5%) 23 (3.3%)

Sweating 5 (1.7%) 5 (0.7%)

SPECIAL SENSES

Amblyopia 8 (2.8%) 25 (3.6%)

Conjunctivitis 2 (0.7%) 13 (1.8%)

Ear disorder 3 (1.0%) 13 (1.8%)

Ear pain 5 (1.7%) 8 (1.1%)

Eye disorder 4 (1.4%) 2 (0.3%)

Eye pain 4 (1.4%) 8 (1.1%)

Otitis media 3 (1.0%) 2 (0.3%)

UROGENITAL SYSTEM

Abnormal ejaculation (gs) 6 (2.5%) 75 (12.9%)*

Dysuria 3 (1.0%) 6 (0.9%)

Dysmenorrhoea (gs) 3 (6.4%) 10 (8.2%)

Impotence 1 (0.4%) 14 (2.4%)

Urinary frequency 5 (1.7%) 9 (1.3%)

Urinary incontinence 12 (4.1%) 31 (4.4%)

Urinary tract infection 5 (1.7%) 5 (0.7%)

Vaginitis (gs) 1 (2.1%) 9 (7.4%) * = Statistically significant difference sertindole vs placebo (p < 0.05) gs = gender-specific Extrapyramidal Symptoms (EPS) The incidences of patients treated with sertindole reporting EPS-related adverse events were similar to those of patients treated with placebo. In addition, in placebo-controlled clinical trials, the percentage of sertindole-treated patients requiring anti-EPS medication was indistinguishable from that of placebo-treated patients. Some of the adverse drug reactions will appear at the beginning of treatment and disappear with continuous treatment, e.g. postural hypotension. Other events observed during the pre-marketing evaluation of sertindole Following is a list of WHO terms that reflect adverse events occurring at an incidence of < 1% and serious adverse events from ongoing trials. All reported events are included except those already listed in the above Table or elsewhere in the Adverse Effects section, and those occurring in only one patient. It is important to emphasise

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that, although the events reported occurred during treatment with sertindole, they were not necessarily caused by it. Events are further categorised by body system and are listed below. Uncommon adverse events are those occurring in less than 1/100 patients but at least 1/1,000 patients and rare adverse events are those that occurred in less than 1/1,000 patients but more than 1/10,000 patients. Body as a whole Uncommon: Chest pain substernal, face oedema, flu syndrome, neck rigidity, overdose, suicide attempt. Cardiovascular system Uncommon: Pallor, peripheral vascular disorder, syncope, Torsades de Pointes (see PRECAUTIONS), vasodilation. Central and peripheral nervous system Uncommon: Amnesia, anxiety, ataxia, confusion, incoordination, libido decreased, libido increased, miosis, nystagmus, personality disorder, psychosis, reflexes decreased, reflexes increased, stupor, suicidal tendency, urinary retention, vertigo. Rare: Cases reported as Neuroleptic Malignant Syndrome (NMS) have been reported in association with sertindole (see PRECAUTIONS). Endocrine system Uncommon: Diabetes mellitus. Gastrointestinal system Uncommon: Abnormal stools, gastritis, gingivitis, glossitis, increased appetite, mouth ulceration, rectal disorder, rectal haemorrhage, stomatitis, tongue disorder, ulcerative stomatitis. Haemic and lymphatic system Uncommon: Anaemia, ecchymosis, hypochromic anaemia, leukopenia. Metabolic and nutritional disorders Uncommon: Hyperglycaemia, hyperlipemia, oedema. Musculoskeletal system Uncommon: Bone pain, myasthenia, twitching. Respiratory system Uncommon: Bronchitis, hyperventilation, pneumonia, sinusitis. Skin and appendages Uncommon: Furunculosis, herpes simplex, nail disorder, psoriasis, pustular rash, skin discolouration, skin hypertrophy, skin ulcer. Special senses Uncommon: Abnormal vision, keratoconjunctivitis, lacrimation disorder, otitis externa, pupillary disorder, taste perversion.

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Urogenital system Uncommon: Anorgasmia, penis disorder (gs), urinary urgency. DOSAGE AND ADMINISTRATION Note: ECG monitoring is required before and during treatment with sertindole; see PRECAUTIONS. Clinical studies have shown that sertindole prolongs the QT interval to a greater extent than some other antipsychotics. Sertindole should be used only for people who are not responsive to, or intolerant of at least one other antipsychotic medicine. Prescribing physicians should comply fully with the required safety measures; see CONTRAINDICATIONS and PRECAUTIONS. Adults Sertindole is administered orally once daily with or without meals. In patients where sedation is required, a benzodiazepine may be co-administered. Titration All patients should be started on sertindole 4 mg/day. The dose should be increased by increments of 4 mg after 4 - 5 days on each dose until the optimal daily maintenance dose, within the range of 12 - 20 mg, is reached. Due to the a1-blocking activity of sertindole, symptoms of postural hypotension may occur during the initial dose-titration period. A starting dose of 8 mg or a rapid increase in dose carries a significantly increased risk of postural hypotension. Maintenance Dependent on individual patient response, the dose may be increased to 20 mg/day. The blood pressure of the patients should be monitored during titration and early maintenance treatment. Elderly patients A pharmacokinetic study showed no difference between young and elderly subjects. However, only limited clinical trial data exist for patients greater than 65 years of age. Treatment should only be initiated after a thorough cardiovascular examination. Slower titration and lower maintenance doses may be appropriate in elderly patients (see PRECAUTIONS). Reduced hepatic function Patients with mild/moderate hepatic impairment require slower titration and a lower maintenance dose (see PRECAUTIONS). The maintenance dose in patients with moderate hepatic impairment (serum albumin below 3.4 g/dL) should not exceed 12 mg/day. Reduced renal function Sertindole can be given at the usual dosage to patients with renal impairment. The pharmacokinetics of sertindole is not affected by haemodialysis. Re-titration of sertindole in patients for whom treatment has previously been discontinued When restarting sertindole treatment in patients who have had an interval of less than 1 week without sertindole, re-titration of sertindole is not required and their

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maintenance dose can be re-introduced. Otherwise, the recommended titration schedule should be followed. An ECG should be taken prior to re-titration of sertindole. Switching from other antipsychotics Treatment with sertindole can be initiated according to the recommended titration schedule concomitantly with cessation of other oral antipsychotics. For patients treated with depot antipsychotics, sertindole is initiated in place of the next depot injection. OVERDOSAGE Experience with sertindole in acute overdose is limited. Fatal cases have occurred. However, patients taking estimated dosages up to 840 mg have recovered without sequelae. Symptoms Reported signs and symptoms of overdose were somnolence, slurred speech, tachycardia, hypotension, and transient prolongation of the QTc interval. Cases of Torsade de Pointes have been observed, often in combination with other drugs known to induce TdP. Treatment In case of acute overdose, establishment of an airway and maintenance of adequate oxygenation should be ensured. Continuous monitoring of ECG and vital signs should commence immediately. If the QTc interval is prolonged, it is recommended that the patient be monitored until the QTc interval has normalised. A half-life of sertindole of 2 - 4 days should be taken into account. Intravenous access should be established, and the administration of activated charcoal with laxative should be considered. Activated charcoal may reduce absorption of the drug if given within 1 or 2 hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. The possibility of multiple drug involvement should be considered. There is no specific antidote to sertindole and it is not dialysable, therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, adrenaline and dopamine should be used with caution, since b stimulation combined with a1 antagonism associated with sertindole may worsen hypotension. If antiarrhythmic therapy is administered, agents such as quinidine, disopyramide, and procainamide carry a theoretical hazard of QT interval-prolonging effects that might be additive to those of sertindole.

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In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. PRESENTATION AND STORAGE CONDITIONS Serdolect tablets ○ Film-coated tablets containing 4 mg sertindole. ○ Blister packs of 7, 10, 20, 28, 30, 50, 98 and 100 tablets*. ○ Film-coated tablets containing 12 mg sertindole. ○ Blister packs of 7, 20, 28, 50, 98 and 100 tablets*. ○ Film-coated tablets containing 16 mg sertindole. ○ Blister packs of 7, 20, 28, 50, 98 and 100 tablets*. ○ Film-coated tablets containing 20 mg sertindole. ○ Blister packs of 7, 20, 28, 50, 98 and 100 tablets*. * Not all pack sizes may be marketed Storage conditions Store below 25°C. Store in the original package. Protect from light. Shelf-life 5 years NAME AND ADDRESS OF THE SPONSOR Australian Sponsor: Lundbeck Australia Pty Ltd 1 Innovation Road North Ryde NSW 2113 Ph: (02) 8669 1000 POISON SCHEDULE OF THE MEDICINE Prescription only medicine (S4) DATE OF APPROVAL Date of TGA approval: 6 July 2010 Date of the most recent safety related notification: 29 June 2012 “Serdolect” is the registered trademark of H. Lundbeck A/S.