Produktinformationen för Risperidon Mylan 0,5 mg, 1 mg, 2 mg munsönderfallande tablett, MTnr 21767, 21768, 21769, gäller vid det tillfälle då

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1 Produktinformationen för Risperidon Mylan 0,5 mg, 1 mg, 2 mg munsönderfallande tablett, MTnr 21767, 21768, 21769, gäller vid det tillfälle då läkemedlet godkändes. Informationen kommer inte att uppdateras eftersom läkemedlet inte marknadsförs i Sverige. Av samma anledning finns inte någon svensk produktinformation. Den engelska produktinformationen kommer dock att uppdateras när Sverige är referensland i proceduren. Om läkemedelsnamnet i följande produktinformation inte stämmer med namnet på dokumentet, beror det på att läkemedlet i Sverige är godkänt under ett annat namn. 1

2 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT RISPERIDON MYLAN 0.5 mg orodispersible tablets RISPERIDON MYLAN 1 mg orodispersible tablets RISPERIDON MYLAN 2 mg orodispersible tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each orodispersible tablet 0.5 mg contains 0.5 mg risperidone. Each orodispersible tablet 1 mg contains 1 mg risperidone. Each orodispersible tablet 2 mg contains 2 mg risperidone. Excipients: aspartame (E951), sorbitol (E420). For a full list of excipients, see section PHARMACEUTICAL FORM Orodispersible tablet. Round, slightly convex, pink marbled orodispersible tablets 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Risperidone is indicated for the treatment of schizophrenia. Risperidone is indicated for the maintenance treatment in order to prevent relapse in chronic schizophrenia in patients having shown a response to initial treatment. 4.2 Posology and method of administration Risperidon Mylan orodispersible tablets should not be divided. When administration of 0.25 mg or dose increments of 0.25 mg is necessary another preparation containing risperidone should be used. Acute and chronic treatment of schizophrenia Adults and adolescents 15 years The daily dose of risperidone may be taken once daily or twice daily. For some patients, taking into account the risk of orthostatic hypotension of risperidone, a twice daily administration is preferable, particularly when initiating the treatment in out patients. Patients should be started on risperidone 2 mg/day. On the second day, this dose may be increased to 4 mg/day. This dose can either be maintained, or adjusted according to individual response. For most patients, the optimal daily dose of risperidone ranges between 4mg/day and 6mg/day. In some patients, a slower titration phase and a lower maintenance dose may be appropriate. 2

3 Doses above 10 mg daily have not been shown to provide additional antipsychotic effect in clinical studies and may increase the risk of extrapyramidal symptoms. The safety of doses exceeding 16 mg/day has not been established and, therefore, doses above this level should not be used. If further sedation is desired, another medication (e.g. benzodiazepine) should be administered instead of increasing the dose. Elderly: Patients should be started on 0.5 mg twice daily. This dose can be increased as required by 0.5 mg twice daily to 1-2 mg twice daily. Caution should be exercised as clinical experience in the elderly is limited. Children and adolescents under 15 years of age: Risperidone is not recommended for use in children under 15 years of age with schizophrenia due to a lack of clinical data. Switching from other antipsychotics to risperidone When changing from another neuroleptic to risperidone, the previous treatment should be gradually withdrawn. When changing from depot neuroleptics, treatment with risperidone should start when the next injection is planned. The need to continue existing treatment for extrapyramidal symptoms (with anti-parkinsonian agents) must be regularly reassessed. Hepatic and renal disease: Patients with impaired renal function are less able to eliminate the active antipsychotic fractions than patients with normal renal function. Therefore the starting dose and subsequent doses should be halved and dose titration should be slower in patients with the above indication. No dose adjustment is required in mild hepatic impairment. Caution should be exercised when treating patients with moderate-severe hepatic impairment. There is limited data on this patient group. (See section 5.2). Method of administration Oral use. As the orodispersible tablets are fragile, they should not be pushed through the foil as this will cause damage to the tablet. The blister is opened by pulling up the edge of the foil and peeling it off. Then the tablet should be tipped out. The tablet should be taken immediately after removal from the blister. The tablet begins disintegrating within a few seconds when placed on the tongue and the use of water is unnecessary. No attempt should be made to divide the tablet. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings and precautions for use Elderly patients with dementia: Overall mortality risk Elderly patients with dementia treated with atypical antipsychotic active substances had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic active substances, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4% for risperidone-treated patients compared to 3.1% for placebo-treated patients. The mean age of patients who died was 86 years (range ). 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. 3

4 No consistent pattern for cause of death was 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, dehydratation was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia. Cerebrovascular events In placebo-controlled studies on elderly patients with dementia, patients treated with risperidone were compared with patients receiving placebo. The mean age of the patients in these groups was 85, ranging between 73 and 97 years old. A significantly higher incidence of cerebrovascular adverse events was seen in patients treated with risperidone than in those of the placebo group. Typical cerebrovascular adverse events were cerebrovascular events (including death) and transient ischaemic attack. Data collected from six placebo-controlled studies, principally on patients with dementia (>65 years), showed that cerebrovascular events (serious and non-serious together) occurred in 3.3 % (33/989) of patients treated with risperidone. Similar events occurred in 1.2 % (8/693) of patients receiving placebo. The relative risk (95 % confidence interval) was 2.96 ( ). Prescribers are recommended to weigh the risks against the benefits before administering risperidone to elderly patients with dementia. The individual risk of cerebrovascular events should be considered. Patients/carers should be advised to report signs and symptoms of possible cerebrovascular events immediately. These signs may include sudden weakness or numbness of the face, arms or legs and speech or visual disturbances. All treatment options should be considered as soon as possible, including withdrawal of risperidone. The patient s condition should be regularly evaluated, as well as the need for continued medication. Alpha-blocking activity Due to its alpha-blocking activity, risperidone may cause orthostatic hypotension, particularly during the initial dose-titration period. Risperidone should be used with caution in patients with cardiovascular and the dosage should be carefully titrated (see section 4.2). A dose reduction should be considered if hypotension occurs. Tardive dyskinesia/ Extrapyramidal symptoms When medicinal products that inhibit the dopamine receptors are administered, tardive dyskinesia may develop. Typical symptoms of tardive dyskinesia are autonomic, rhythmical muscle movements of the tongue and face, and around the mouth. Extrapyramidal symptoms have been shown to give rise to an increased tendency to tardive dyskinesia. If symptoms of tardive dyskinesia develop in patients, withdrawal of antipsychotic treatment should be carefully considered. Neuroleptic malignant syndrome During the treatment with neuroleptics, neuroleptic malignant syndrome may occur, which is mainly characterised by hyperthermia, tachypnoea, sweating, muscle rigidity, autonomic instability, altered consciousness, leukocytosis and elevated serum creatine phosphokinase concentrations. Rhabdomyolysis and associated renal failure is, in most cases, life-threatening. If neuroleptic malignant syndrome develops, antipsychotic treatment should be discontinued. Paradoxically, antipsychotics may exacerbate symptoms such as excitation, agitation and aggression. At the onset of such symptoms, as with other antipsychotics, the risperidone dose may need to be reduced or the treatment discontinued. Special dosage requirements for the elderly and patients with hepatic and renal impairment are given in section

5 Caution should be exercised when risperidone is prescribed to patients with Lewy body dementia or Parkinson s disease. In theory, risperidone treatment can make these diseases worse. The risk of neuroleptic malignant syndrome may also be increased. It is well-known that classic antipsychotics can reduce the seizure threshold. Caution should be exercised when treating patients with epilepsy. QT-interval As risperidone can prolong the QT-interval, caution is advised when treating patients with family history of QT prolongation, known cardiovascular disease (e.g. congenital long QTc syndrome, coronary heart disease, disturbances in conduction, arrhythmia) or concomitant treatment with medicinal products, which also induce QT interval prolongation or hypokalemia. Simultaneous treatment with other neuroleptics should be avoided. Caution should be exercised when prescribing risperidone to patients with non drug-related hyperprolactinaemia. Special caution should be exercised in patients with prolactin-dependent tumours (e.g. breast cancer). Hyperglycaemia Hyperglycaemia or deterioration in existing diabetes has been reported in very rare cases during risperidone treatment. Diabetics and patients with risk factors for diabetes mellitus must receive appropriate clinical follow-up. Patients should be advised of the potential for weight gain. Acute withdrawal symptoms, such as nausea, vomiting, sweating and insomnia have been reported in rare cases when treatment with high-dose antipsychotic medication was discontinued abruptly. Psychotic symptoms may also return, and there have been reports of involuntary movements developing (e.g. akathisia, dystonia and dyskinesia). Therefore gradual withdrawal is recommended. There is a lack of experience of preventative long-term treatment of bipolar disorder. Risperidone may favour weight gain. Patients should be given advice to reduce their food intake in order to prevent this effect. Risperidon Mylan orodispersible tablets contain a source of phenylalanine (aspartame). It may be harmful for people with phenylketonuria. Risperidon Mylan orodispersible tablets contain sorbitol also. Patients with rare hereditary problems of fructose intolerance should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction The risks of using risperidone in combination with other products have not been systematically studied. Caution should be exercised when combining risperidone with other substances that act on the central nervous system. Antipsychotics may potentiate the sedative effect of alcohol. Patients should therefore be advised not to consume alcohol. The risk of onset of tardive dyskinesia is increased by concomitant use of other antipsychotics, lithium, antidepressants, antiparkinson agents and active substances that have a central anticholinergic effect. The anti alpha- 1 adrenergic effect (especially with other antipsychotics or antihistamines of the phenothiazines group, or tricyclic antidepressants as well) can induce orthostatic hypotension and thus increase the blood pressure lowering effect of phenoxybenzamine, labetalol and other alpha- 5

6 blocking sympatholytics, methyldopa, reserpine and other centrally acting antihypertensive agents. Conversely, the hypotensive effect of guanethidine is blocked. Risperidone may reduce the effect of levodopa and other dopaminergic agonists. If this combination is deemed necessary, particularly in end-stage Parkinson s disease, the lowest effective dose of each treatment should be prescribed. Carbamazepine causes a reduction in risperidone and its active metabolite plasma levels. Similar effects can be observed with other products that induce liver enzymes. When discontinuing treatment with carbamazepine or other liver enzyme-inducing products, the risperidone dose must be re-evaluated and (if necessary) reduced. Quinidine, fluoxetine, paroxetine, terbinafine and other potent CYP2D6 inhibitors can increase plasma concentrations of the antipsychotic fraction. Therefore dosage of risperidone should be reevaluated on initiation or discontinuation of such medicinal products. Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentration of risperidone, but only slightly that of the active antipsychotic fraction. Ranitidine and cimetidine may increase the plasma concentration of risperidone but the antipsychotic effect does not necessarily increase as the plasma concentration of active metabolites is decreased. Caution is advised with the concomitant treatment of other medicinal products that can prolong the QT-interval, e.g. other neuroleptics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium or cisapride. Caution is advised when risperidone is co-administered with other medicinal products that may cause electrolyte disturbances, e.g. thiazide diuretics (hypokalaemia), as they increase the risk of malignant arrhythmia (see also section 4.4). Similarly, caution is also advised when risperidone is coadministered with other medicinal products that can increase the concentration of risperidone in the blood. The cholinesterase-inhibitors galantmin and donezepil do not have a clinical relevant effect on the pharmacokinetic of risperidone and the active antipsychotic fraction. Risperidone has no clinically relevant effect on the pharmacokinetics of lithium, valproate, digoxin or topiramate. For interactions with furosemide in elderly patients with dementia see section 4.4. During co-administration with other highly protein-bound medicinal products, no clinically relevant displacement of either medicinal product from the plasma proteins has been seen 4.6 Pregnancy and lactation Pregnancy There are no adequate data from the use of risperidone in pregnant women. Risperidone was not teratogenic in animal studies. Pharmacological effects have been found on parturition and postnatal development (see section 5.3), the potential risk of these effects for humans is unknown.. The use of neuroleptic medicinal products during the last trimester of pregnancy has resulted in long term but reversible neurological disturbances of extrapyramidal nature in the infant. Risperidone should only be administered during pregnancy if the benefits to the mother outweigh the possible risks to the foetus or new-born infant. Caution should be exercised when prescribing to pregnant women and newborns should be monitored carefully. 6

7 Lactation Risperidone and its active metabolite 9-hydroxy risperidone are excreted in human breast milk in such quantities that there is a risk to the infant even at therapeutic doses. Risperidone should not be administered while breast-feeding. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Antipsychotics, such as risperidone, may adversely affect the ability to drive and use machines. Patients should be advised not to drive or operate machinery until their individual susceptibility to risperidone has been evaluated. 4.8 Undesirable effects In many instances it has been difficult to differentiate undesirable effects from symptoms of the underlying disease. The following adverse events have been reported for risperidone: Common: 1/100, < 1/10 Uncommon: 1/1,000, < 1/100 Rare: 1/10,000, <1/1,000 Very rare: < 1/10,000, not known (cannot be estimated from the available data) Frequency Common Uncommon Rare Very rare Organ class Blood and lymphatic system Metabolism and nutrition Psychiatric Agitation, anxiety A slight reduction in the number of neutrophils and platelets has been reported. Hyperglycaemia and exacerbation of pre-existing diabetes mellitus Nervous system Insomnia, headache, sedation 1) Drowsiness, fatigue, dizziness, concentration difficulties, extrapyramidal symptoms 2) : tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia Cerebrovascular events (stroke and transient ischaemic attack) 7

8 Frequency Common Uncommon Rare Very rare Organ class Eye Cardiac Respiratory, thoracic and mediastinal Gastrointestinal Hepatobiliary Skin and subcutaneous tissue Musculoskeletal and connective tissue Renal and urinary Reproductive system and breast Weight gain Blurred vision Hypotension (also orthostatic hypotension), tachycardia (also reflex tachycardia), orthostatic dizziness or hypertension Rhinitis Constipation, dyspepsia, nausea/vomiting, stomach pains rash and other allergic reactions incontinence priapism, erectile dysfunction, ejaculatory dysfunction, orgasmic dysfunction Prolonged QT interval, Torsade de Pointes, cardiac arrest, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia galactorrhea, gynaecomastia, menstrual and amenorrhea Elevated liver enzyme values Swelling, Pruritus, exanthema, photosensitivity Muscle weakness 1) Sedation has been more frequently reported in children and adolescents than in adults. In general, sedation is mild and transient. 2) These symptoms are usually mild and reversible upon dose reduction and/or, if necessary, administration of anti-parkinson medicinal products. Endocrine system Risperidone can induce a dose-dependent increase in prolactin concentrations. Because of this, galactorrhea, gynaecomastia, menstrual and even complete absence of menstruation (amenorrhea) can occur. Furthermore, tissue culture studies have suggested that growth of human breast tumour cells may be stimulated by prolactin. Although clinical and epidemiological studies have yet to establish a clear link between neuroleptic use and breast cancer, caution should be exercised in patients with a relevant previous history of this disease. Benign pituitary adenomas have been reported very rarely in risperidone users during postmarketing surveillance. No causal 8

9 association has been established. Hyperglycaemia and exacerbation of existing diabetes have been reported in very rare cases during risperidone treatment. Disturbances in water balance due to excessive intake of fluid or disturbances in the secretion of antidiuretic hormone, tardive dyskinesia (see section 4.4), neuroleptic malignant syndrome, disturbances in the temperature regulation of the body and seizures have been reported during risperidone treatment. Sedation has been reported more frequently in children and adolescents than in adults, and often diminishes with continued treatment. Cerebrovascular events Cerebrovascular adverse events, including stroke and transient ischaemic attack, have been reported during risperidone treatment (see section 4.4). Cardiac events Treatment with risperidone may cause a prolonged QT-interval. Cases of sudden death which may be cardiac in origin have been reported during risperidone treatment (see section 4.4). 4.9 Overdose Symptoms Reported symptoms of overdose are similar to the known pharmacological effects of risperidone. The most common symptoms are drowsiness, tachycardia, hypotension and extrapyramidal symptoms. Overdose of up to 360 mg has been reported. Available data seem to suggest a wide safety margin. In cases of overdose, isolated cases of QT prolongation have been reported. In the case of an acute overdose, the possibility of multiple active substances involvement should be considered. Treatment A clear airway should be established and maintained in order to ensure adequate oxygenation. 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 ECG monitoring to detect possible arrhythmias. There is no known antidote for risperidone. Therefore, the treatment of risperidone overdose is symptomatic. 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 medicinal products 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: N05AX08 Risperidone is a selective monoaminergic antagonist with a high affinity for serotonergic 5-HT 2 receptors and dopaminergic D 2 receptors. Risperidone also binds to alpha 1 -adrenergic receptor and, with lower affinity, histamine H 1 and alpha 2 adrenergic receptors. Risperidone has no affinity for the cholinergic receptors. Although risperidone, as a potent D 2 antagonist, improves the positive symptoms of schizophrenia, it causes less depression of motor 9

10 activity and induction of catalepsy, when compared with conventional neuroleptics. Dominating central serotonin antagonism may reduce extrapyramidal side effect liability and extend therapeutic activity to the negative and affective symptoms of schizophrenia. 5.2 Pharmacokinetic properties Risperidone is completely absorbed following oral administration. Peak plasma concentrations are reached within 1-2 hours. Absorption is not significantly influenced by food intake. Risperidone is metabolised by cytochrome P-450 2D6 (CYP 2D6)-enzyme to 9-hydroxyrisperidone, which has similar pharmacological properties to risperidone. Risperidone and 9-hydroxy-risperidone form the active antipsychotic fraction. After oral administration to psychotic patients, the elimination half-life in ultra-rapid metabolisers is 3 hours. In slow metabolisers the half-life of risperidone is lengthened to 16 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction is 24 hours. Steady-state of risperidone is reached within one day in most patients. Steady-state of 9- hydroxyrisperidone is reached within 4-5 days of dosing. Within the therapeutic range, blood levels of the active pharmacological fraction are proportional to the dose administered. Risperidone is rapidly distributed throughout the body. Its volume of distribution is 1-2 l/kg. In plasma, risperidone is bound to albumin and alpha 1 -acid glycoprotein. The plasma protein binding of risperidone is 88%, whilst that of 9-hydroxyrisperidone is 77%. One week after administration, 70% of ingested risperidone is excreted in the urine and 14% in the faeces. In urine, risperidone and 9-hydroxyrisperidone represent 35-45% of the administered dose. In single-dose studies the plasma concentrations of risperidone were higher than normally and the elimination was slower with elderly patients and patients with renal impairment. In patients with hepatic impairment the plasma concentrations were normal. 5.3 Preclinical safety data Conventional animal studies on pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity reveal no other risks for the patient than those which could be expected based on the pharmacological mechanism of action. In animal reproduction studies pharmacologically active doses revealed maternal toxicity, prolongation of the partus and increased postnatal deaths related to the pharmacodynamic action. The effects on postnatal development were shown to be predominantly due to the pharmacodynamic action on the dams (e.g. sedation and reduced care for the pups). These effects are not relevant for the assessment of a potential risk in humans. Risperidone was not genotoxic in conventional studies. In oral carcinogenicity studies in rats and mice, increases were observed in hypophyseal adenoma (mouse), pancreatic endocrine adenoma (rat) and mammary gland adenocarcinoma (both species). These tumours may be associated with higher prolactin levels. The significance of prolactindependent tumours in humans is unclear. In vitro and in vivo models show that high doses of risperidone cause a prolonged QT-interval, which has been associated with an increased risk of torsades de pointes in patients. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol Basic butylated methacrylate copolymer Povidone K25 10

11 Microcrystalline cellulose Low-substituted hydroxypropylcellulose Aspartame (E951) Crospovidone Red iron oxide (E172) Spearmint flavour (containing in particular sorbitol (E420)) Peppermint flavour (containing in particular sorbitol (E420), levomenthol) Calcium silicate Magnesium stearate. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage condition. 6.5 Nature and contents of container Perforated unit dose blister (OPA/Aluminium/PVC/Aluminium). Pack sizes of 10, 14, 28, 30, 56 and 60 orodispersible tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Mylan SAS, 117 Allée des Parcs, Saint-Priest, France 8. MARKETING AUTHORISATION NUMBER(S) 0.5 mg orodispersible tablets: mg orodispersible tablets: mg orodispersible tablets: DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13/10/ DATE OF REVISION OF THE TEXT