Risperidone 3mg Film-coated Tablets

1. Name Of The Medicinal Product

Risperidone 3mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 3 mg of the active substance risperidone.

Excipient: 183.75mg lactose monohydrate per tablet.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film coated Tablet

White, 11 x 6.5 mm oval biconvex, scored, coated tablet, marking "T3".

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Risperidone tablets are indicated for the treatment of acute and chronic schizophrenic psychoses, and other psychotic conditions, in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), and/or negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech) are prominent. Risperidone tablets also alleviate affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia.

Risperidone tablets are also effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Risperidone tablets are indicated for the treatment of mania in bipolar disorder. These episodes are characterized by symptoms such as elevated, expansive or irritable mood, inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility, or poor judgment, including disruptive or aggressive behaviours.

Risperidone tablets are not licensed for the treatment of behavioural symptoms of dementia (see section 4.4).

4.2 Posology And Method Of Administration

4.2. a Schizophrenia:

Switching from other antipsychotics: where medically appropriate, gradual discontinuation of the previous treatment while Risperidone therapy is initiated is recommended. Where medically appropriate when switching patients from depot antipsychotics, consider initiating Risperidone therapy in place of the next scheduled injection. The need for continuing existing antiparkinson medication should be re-evaluated periodically.

Adults

Risperidone tablets may be given once or twice daily. All patients, whether acute or chronic, should start with 2 mg/day Risperidone tablets. The dosage may be increased to 4 mg/day on the second day. Some patients, such as first episode patients, may benefit from a slower rate of titration. From then on the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg/day although in some, an optimal response may be obtained at lower doses.

Doses above 10 mg/day generally have not been shown to provide additional efficacy to lower doses and may increase the risk of extrapyramidal symptoms. Doses above 10 mg/day should only be used in individual patients if the benefit is considered to outweigh the risk. Doses above 16 mg/day have not been extensively evaluated for safety and therefore should not be used.

Elderly

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Children

Use of Risperidone tablets for schizophrenia in children aged less than 15 years has not been formally evaluated.

Renal and liver disease

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Risperidone tablets should be used with caution in this group of patients until further experience is gained.

4.2. b Bipolar Mania:

Adults

Risperidone should be administered on a once daily schedule, starting with 2 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. A dosing range between 1 and 6 mg per day is recommended.

As with all symptomatic treatments, the continued use of Risperidone tablets must be evaluated and justified on an ongoing basis.

Elderly

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Renal and liver disease

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Risperidone tablets should be used with caution in this group of patients until further experience is gained.

Combined use with mood stabilisers

There is limited information on the combined use of Risperidone tablets with carbamazepine in bipolar mania. Carbamazepine has been shown to induce the metabolism of risperidone producing lower plasma levels of the antipsychotic fraction of Risperidone tablets (see Section 4.5). It is therefore not recommended to co-administer Risperidone tablets with carbamazepine in bipolar mania patients until further experience is gained. The combined use with lithium or valproate does not require any adjustment of the dose of Risperidone tablets.

Method of administration

Oral use.

4.3 Contraindications

Risperidone tablets are contraindicated in patients with a known hypersensitivity to risperidone or any other ingredients in the product.

4.4 Special Warnings And Precautions For Use

Elderly patients with dementia

Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4.0% for risperidone–treated patients compared to 3.1% for placebo-treated patients. The mean age (range) of patients who died was 86 years (67-100).

In these trials treatment with furosemide plus risperidone was associated with a higher incidence of mortality compared to treatment with risperidone or furosemide alone, however, the mechanism for an interaction is unclear. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No consistent pattern for cause of death observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular Adverse Events (CAE)

Risperidone tablets are not recommended for the treatment of behavioural symptoms of dementia because of an increased risk of cerebrovascular adverse events (including cerebrovascular accidents and transient ischaemic attacks). Treatment of acute psychoses in patients with a history of dementia should be limited to short term only and should be under specialist advice.

Data from randomised clinical trials conducted in elderly >65 years) patients with dementia indicate that there is an approximately 3-fold increased risk of cerebrovascular adverse events (including cerebrovascular accidents and transient ischaemic attacks) with risperidone, compared with placebo. Cerebrovascular adverse events occurred in 3.3% (33/989) of patients treated with risperidone and 1.2% (8/693) of patients treated with placebo. The Odds Ratio (95% exact confidence interval) was 2.96 (1.33, 7.45).

Physicians should consider carefully the risk of cerebrovascular adverse events with Risperidone tablets (given the observations in elderly patients with dementia detailed above) before treating any patient with a previous history of CVA/TIA. Consideration should also be given to other risk factors for cerebrovascular disease including hypertension, diabetes, current smoking, atrial fibrillation, etc.

Alpha-blocking activity

Due to the alpha-blocking activity of Risperidone tablets, orthostatic hypotension can occur, especially during the initial dose-titration period. A dose reduction should be considered if hypotension occurs.

Risperidone tablets should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval and the dose should be gradually titrated. In clinical trials, Risperidone was not associated with an increase in QTc intervals. As with other antipsychotics, caution is advised when prescribing with medications known to prolong the QT interval.

If further sedation is required, an additional drug (such as a benzodiazepine) should be administered rather than increasing the dose of Risperidone tablets.

Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS)

Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, characterised by rhythmical involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK levels, has been reported to occur with neuroleptics. In this event all antipsychotic drugs including risperidone should be discontinued.

It is recommended to halve both the starting dose and the subsequent dose increments in geriatric patients and in patients with renal or liver insufficiency.

Caution should also be exercised when prescribing Risperidone tablets to patients with Parkinson's disease since, theoretically, it may cause a deterioration of the disease.

Hyperglycaemia

Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with Risperdal. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8 Undesirable effects).

Venous thromboembolism (VTE)

Cases of venous thrombolembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with risperidone and preventative measures undertaken.

Other

Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy.

As with other antipsychotics, patients should be advised of the potential for weight gain.

Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Possible interactions of Risperidone tablets with other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, it should be used with caution in combination with other centrally acting drugs including alcohol.

Risperidone tablets may antagonise the effect of levodopa and other dopamine-agonists.

Carbamazepine has been shown to decrease the plasma levels of the antipsychotic fraction of Risperidone tablets. A similar effect might be anticipated with other drugs which stimulate metabolising enzymes in the liver. On initiation of carbamazepine or other hepatic enzyme-inducing drugs, the dosage of Risperidone tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of such drugs, the dosage of Risperidone tablets should be re-evaluated and decreased if necessary.

Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Fluoxetine and paroxetine, CYP2D6 inhibitors, may increase the plasma concentration of risperidone but less so of the active antipsychotic fraction. When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone. Based on in vitro studies, the same interaction may occur with haloperidol. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increase the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction. Erythromycin, a CYP 3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction. The cholinesterase inhibitor galantamine does not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction. A study of donepezil in non-elderly healthy volunteers also showed no clinically relevant effect on the pharmacokinetics of risperidone and the antipsychotic fraction.

When Risperidone tablets are taken together with other highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins.

See section 4.4 (Special warnings and special precautions for use) regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.

Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate. The potential for reduced toleration of the combination treatment should be taken into consideration when co-administering risperidone and topiramate.

In patients on long-term lithium and older/typical neuroleptic therapy, no significant change occurred in the pharmacokinetics of lithium after substitution of the concomitant neuroleptic with risperidone.

Food does not affect the absorption of risperidone.

4.6 Pregnancy And Lactation

Pregnancy

Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed, typically delayed oestrus and changes in mating and nursing behaviour in rats. No teratogenic effect of risperidone was noted in any study. The safety of Risperidone tablets for use during human pregnancy has not been established. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy. Therefore, Risperidone should only be used during pregnancy if the benefits outweigh the risks.

Lactation

In animal studies, risperidone and 9-hydroxyrisperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving Risperidone should not breast feed.

4.7 Effects On Ability To Drive And Use Machines

Risperidone may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

4.8 Undesirable Effects

Risperidone tablets are generally well tolerated and in many instances it has been difficult to differentiate adverse events from symptoms of the underlying disease. Adverse events observed in association with the use of Risperidone tablets include:

Common: insomnia, agitation, anxiety, headache.

Less common: somnolence, fatigue, dizziness, impaired concentration, constipation, dyspepsia, nausea/vomiting, abdominal pain, blurred vision, priapism, erectile dysfunction, ejaculatory dysfunction, orgasmic dysfunction, urinary incontinence, rhinitis, rash and other allergic reactions.

Cerebrovascular accidents have been observed during treatment with risperidone. (see Section 4.4 Special warnings and precautions for use).

Hyperglycaemia and exacerbation of pre-existing diabetes have been reported in very rare cases during risperidone treatment.

The incidence and severity of extrapyramidal symptoms are significantly less than with haloperidol. However, in some cases the following extrapyramidal symptoms may occur: tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. If acute in nature, these symptoms are usually mild and are reversible upon dose reduction and/or administration of antiparkinson medication, if necessary. In clinical trials in patients with acute mania risperidone treatment resulted in an incidence of EPS>10%. This is lower than the incidence observed in patients treated with classical neuroleptics.

Occasionally, orthostatic dizziness, hypotension including orthostatic, tachycardia including reflex tachycardia and hypertension have been observed following administration of Risperidone tablets.

Risperidone tablets can induce a dose-dependent increase in plasma prolactin concentration. Possible associated manifestations are: galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and amenorrhoea.

Weight gain, oedema and increased hepatic enzyme levels have been observed during treatment with Risperidone tablets.

A decrease in neutrophil and/or thrombocyte count has been reported.

As with classical neuroleptics, rare cases of the following have been reported in schizophrenic patients: water intoxication with hyponatraemia, either due to polydipsia or to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH); tardive dyskinesia, body temperature dysregulation and seizures.

Benign pituitary adenomas have been reported very rarely in risperidone users during postmarketing surveillance. No causal association has been established.

Very rare cases of angioedema have been reported in postmarketing experience.

Sedation has been reported more frequently in children and adolescents than in adults. In general, sedation is mild and transient.

Withdrawal reactions have been reported in association with antipsychotic drugs (see section 4.4 Special warnings and special precautions for use).

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs-Frequency unknown.

4.9 Overdose

In general, reported signs and symptoms have been those resulting from an exaggeration of the drug's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, rare cases of QT-prolongation have been reported. In case of acute overdosage, the possibility of multiple drug involvement should be considered.

Establish and maintain a clear airway, and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to Risperidone tablets. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antipsychotics

ATC code: N05AX

Risperidone is a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole-derivatives.

Risperidone is a selective monoaminergic antagonist with a high affinity for both serotonergic 5-HT₂ and dopaminergic D₂ receptors. Risperidone binds also to alpha₁-adrenergic receptors and, with lower affinity, to H₁-histaminergic and alpha₂-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D₂ antagonist, that is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical neuroleptics. Balanced central serotonin and dopamine antagonism may reduce the tendency to cause extrapyramidal side effects, and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.

5.2 Pharmacokinetic Properties

Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absorption of risperidone is not affected by food.

The most important route of metabolism of risperidone is hydroxylation by cytochrome CYP 2D6 to 9-hydroxy-risperidone which has a similar pharmacological activity to risperidone. This hydroxylation is subject to debrisoquine-type genetic polymorphism but this does not affect the active antipsychotic fraction since this consists of risperidone and its active metabolite 9-hydroxyrisperidone. After oral administration, the elimination half-life of the active antipsychotic fraction is 24 hours.

A single-dose study showed higher active plasma concentrations and a slower elimination of risperidone in the elderly and in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency.

Topiramate modestly reduces the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance. The bioavailability of topiramate is slightly decreased when administered in combination with risperidone. This interaction is not likely to be clinically significant.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber other than those already provided in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose anhydrous

Cellulose, microcrystalline

Starch pregelatinised

Magnesium stearate

Hypromellose 6

Macrogol 6000

Titanium dioxide (E171)

6.2 Incompatibilities

No incompatibilities known.

6.3 Shelf Life

2 years (bottle) or 3 years (blister)

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

Blister pack: PVC-PVDC / Al foil. Pack sizes 14, 20, 28, 30, 42, 56 or 60 film coated tablets

HDPE Container with LDPE Cap. Pack sizes 20, 40, 60 or 100 film coated tablets

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavíkurvegi 76-78

220 Hafnarfjordur

Iceland.

8. Marketing Authorisation Number(S)

PL 30306/0093

9. Date Of First Authorisation/Renewal Of The Authorisation

01/04/2008

10. Date Of Revision Of The Text

17^th February 2010

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)