Risperidon: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Für Fachkreise

Anwendungsgebiete

1.1 Schizophrenie

Risperidon ist angezeigt zur Behandlung der Schizophrenie. Die Wirksamkeit wurde in 4 Kurzzeitstudien bei Erwachsenen, 2 Kurzzeitstudien bei Jugendlichen (13 bis 17 Jahre) und einer Langzeit-Erhaltungsstudie bei Erwachsenen belegt [siehe Klinische Studien (14.1)].

1.2 Bipolare Manie

Monotherapie

Risperidon ist angezeigt zur Behandlung akuter manischer oder gemischter Episoden im Rahmen einer Bipolar-I-Störung. Die Wirksamkeit wurde in 2 Kurzzeitstudien bei Erwachsenen und einer Kurzzeitstudie bei Kindern und Jugendlichen (10 bis 17 Jahre) belegt [siehe Klinische Studien (14.2)].

Begleittherapie

Risperidon als Begleittherapie zu Lithium oder Valproat ist angezeigt zur Behandlung akuter manischer oder gemischter Episoden im Rahmen einer Bipolar-I-Störung. Die Wirksamkeit wurde in einer Kurzzeitstudie bei Erwachsenen belegt [siehe Klinische Studien (14.3)].

1.3 Reizbarkeit im Zusammenhang mit autistischer Störung

Risperidon ist angezeigt zur Behandlung der Reizbarkeit im Zusammenhang mit autistischer Störung, einschließlich Symptomen wie Aggression gegenüber anderen, absichtlicher Selbstverletzung, Wutanfällen und rasch wechselnden Stimmungen. Die Wirksamkeit wurde in 3 Kurzzeitstudien bei Kindern und Jugendlichen (5 bis 17 Jahre) belegt [siehe Klinische Studien (14.4)].

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1.1 Schizophrenia

Risperidone is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see Clinical Studies (14.1)].

1.2 Bipolar Mania

Monotherapy

Risperidone is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies (14.2)].

Adjunctive Therapy

Risperidone adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see Clinical Studies (14.3)].

1.3 Irritability Associated with Autistic Disorder

Risperidone is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [see Clinical Studies (14.4)].

Dosierung und Art der Anwendung

Schwere Nieren- und Leberfunktionsstörung bei Erwachsenen: eine niedrigere Anfangsdosis von 0,5 mg zweimal täglich anwenden. Eine Erhöhung auf Dosen über 1,5 mg zweimal täglich ist in Abständen von einer Woche oder länger möglich.

2.1 Schizophrenie

Erwachsene

Übliche Anfangsdosis

Risperidon kann einmal oder zweimal täglich angewendet werden. Die Anfangsdosis beträgt 2 mg pro Tag. Die Dosis kann je nach Verträglichkeit in Abständen von 24 Stunden oder mehr in Schritten von 1 bis 2 mg pro Tag auf eine empfohlene Dosis von 4 bis 8 mg pro Tag erhöht werden. Bei einigen Patienten kann eine langsamere Titration angemessen sein. Die Wirksamkeit wurde in einem Bereich von 4 mg bis 16 mg pro Tag belegt. Für Dosen über 6 mg pro Tag bei zweimal täglicher Gabe wurde jedoch keine höhere Wirksamkeit als für niedrigere Dosen nachgewiesen; sie waren mit mehr extrapyramidalen Symptomen und anderen unerwünschten Wirkungen verbunden und werden im Allgemeinen nicht empfohlen. In einer einzelnen Studie zur Stützung der einmal täglichen Gabe waren die Wirksamkeitsergebnisse für 8 mg im Allgemeinen stärker als für 4 mg. Die Sicherheit von Dosen über 16 mg pro Tag wurde in klinischen Studien nicht untersucht [siehe Klinische Studien (14.1)].

Jugendliche

Die Anfangsdosis beträgt 0,5 mg einmal täglich, verabreicht als tägliche Einzeldosis morgens oder abends. Die Dosis kann je nach Verträglichkeit in Abständen von 24 Stunden oder mehr in Schritten von 0,5 mg oder 1 mg pro Tag auf eine empfohlene Dosis von 3 mg pro Tag angepasst werden. Obwohl die Wirksamkeit in Studien bei jugendlichen Patienten mit Schizophrenie in Dosen zwischen 1 mg und 6 mg pro Tag belegt wurde, wurde über 3 mg pro Tag kein zusätzlicher Nutzen beobachtet, und höhere Dosen waren mit mehr unerwünschten Ereignissen verbunden. Dosen über 6 mg pro Tag wurden nicht untersucht.

Patienten mit anhaltender Somnolenz können davon profitieren, die halbe Tagesdosis zweimal täglich einzunehmen.

Erhaltungstherapie

Obwohl nicht bekannt ist, wie lange ein Patient mit Schizophrenie mit Risperidon behandelt werden sollte, wurde die Wirksamkeit von Risperidon 2 mg pro Tag bis 8 mg pro Tag bei der Verzögerung von Rückfällen in einer kontrollierten Studie bei erwachsenen Patienten belegt, die seit mindestens 4 Wochen klinisch stabil waren und anschließend über einen Zeitraum von 1 bis 2 Jahren nachbeobachtet wurden [siehe Klinische Studien (14.1)]. Sowohl erwachsene als auch jugendliche Patienten, die akut ansprechen, sollten im Allgemeinen über die akute Episode hinaus mit ihrer wirksamen Dosis weiterbehandelt werden. Die Patienten sollten regelmäßig erneut beurteilt werden, um die Notwendigkeit einer Erhaltungstherapie festzustellen.

Wiederaufnahme der Behandlung bei Patienten nach vorherigem Absetzen

Obwohl keine Daten speziell zur Wiederaufnahme der Behandlung vorliegen, wird empfohlen, nach einer Unterbrechung der Behandlung mit Risperidon das initiale Titrationsschema zu befolgen.

Umstellung von anderen Antipsychotika

Es liegen keine systematisch erhobenen Daten speziell zur Umstellung schizophrener Patienten von anderen Antipsychotika auf Risperidon oder zur Behandlung von Patienten mit gleichzeitig angewendeten Antipsychotika vor.

2.2 Bipolare Manie

Übliche Dosis

Erwachsene

Der Anfangsdosisbereich liegt bei 2 mg bis 3 mg pro Tag. Die Dosis kann in Abständen von 24 Stunden oder mehr in Schritten von 1 mg pro Tag angepasst werden. Der wirksame Dosisbereich liegt bei 1 mg bis 6 mg pro Tag, wie in den placebokontrollierten Kurzzeitstudien untersucht. In diesen Studien wurde eine kurzfristige (3 Wochen) antimanische Wirksamkeit in einem flexiblen Dosisbereich von 1 mg bis 6 mg pro Tag belegt [siehe Klinische Studien (14.2 , 14.3)]. Risperidon-Dosen über 6 mg pro Tag wurden nicht untersucht.

Kinder und Jugendliche

Die Anfangsdosis beträgt 0,5 mg einmal täglich, verabreicht als tägliche Einzeldosis morgens oder abends. Die Dosis kann je nach Verträglichkeit in Abständen von 24 Stunden oder mehr in Schritten von 0,5 mg oder 1 mg pro Tag auf die empfohlene Zieldosis von 1 mg bis 2,5 mg pro Tag angepasst werden. Obwohl die Wirksamkeit in Studien bei Kindern und Jugendlichen mit bipolarer Manie in Dosen zwischen 0,5 mg und 6 mg pro Tag belegt wurde, wurde über 2,5 mg pro Tag kein zusätzlicher Nutzen beobachtet, und höhere Dosen waren mit mehr unerwünschten Ereignissen verbunden. Dosen über 6 mg pro Tag wurden nicht untersucht.

Patienten mit anhaltender Somnolenz können davon profitieren, die halbe Tagesdosis zweimal täglich einzunehmen.

Erhaltungstherapie

Aus kontrollierten Studien liegen keine Daten vor, die dem Arzt als Leitfaden für die längerfristige Behandlung eines Patienten dienen können, dessen Zustand sich während der Behandlung einer akuten manischen Episode mit Risperidon bessert. Obwohl allgemein Einigkeit besteht, dass eine pharmakologische Behandlung über ein akutes Ansprechen bei Manie hinaus wünschenswert ist, sowohl zur Aufrechterhaltung des initialen Ansprechens als auch zur Prävention neuer manischer Episoden, liegen keine systematisch erhobenen Daten vor, die die Anwendung von Risperidon in einer solchen längerfristigen Behandlung (d. h. über 3 Wochen hinaus) stützen. Der Arzt, der Risperidon über längere Zeiträume anwendet, sollte die langfristigen Risiken und den Nutzen des Arzneimittels für den einzelnen Patienten regelmäßig neu beurteilen.

2.3 Reizbarkeit im Zusammenhang mit autistischer Störung – Pädiatrie (Kinder und Jugendliche)

Die Dosierung von Risperidon sollte entsprechend dem Ansprechen und der Verträglichkeit des Patienten individuell angepasst werden. Die Tagesgesamtdosis von Risperidon kann einmal täglich verabreicht werden, oder die Hälfte der Tagesgesamtdosis kann zweimal täglich verabreicht werden.

Bei Patienten mit einem Körpergewicht unter 20 kg ist die Behandlung mit 0,25 mg pro Tag zu beginnen. Bei Patienten mit einem Körpergewicht größer oder gleich 20 kg ist die Behandlung mit 0,5 mg pro Tag zu beginnen. Nach mindestens vier Tagen kann die Dosis auf die empfohlene Dosis von 0,5 mg pro Tag bei Patienten unter 20 kg und 1,0 mg pro Tag bei Patienten mit einem Körpergewicht größer oder gleich 20 kg erhöht werden. Diese Dosis ist mindestens 14 Tage lang beizubehalten. Bei Patienten, die kein ausreichendes klinisches Ansprechen erreichen, kann die Dosis in Abständen von 2 Wochen oder mehr in Schritten von 0,25 mg pro Tag bei Patienten unter 20 kg bzw. in Schritten von 0,5 mg pro Tag bei Patienten mit einem Körpergewicht größer oder gleich 20 kg erhöht werden. Der wirksame Dosisbereich liegt bei 0,5 mg bis 3 mg pro Tag. Für Kinder mit einem Körpergewicht unter 15 kg liegen keine Dosierungsdaten vor.

Sobald ein ausreichendes klinisches Ansprechen erreicht und aufrechterhalten wurde, ist eine schrittweise Senkung der Dosis zu erwägen, um das optimale Verhältnis von Wirksamkeit und Sicherheit zu erreichen. Der Arzt, der Risperidon über längere Zeiträume anwendet, sollte die langfristigen Risiken und den Nutzen des Arzneimittels für den einzelnen Patienten regelmäßig neu beurteilen.

Patienten mit anhaltender Somnolenz können von einer einmal täglichen Dosis vor dem Schlafengehen, von der Einnahme der halben Tagesdosis zweimal täglich oder von einer Dosisreduktion profitieren.

2.4 Dosierung bei Patienten mit schwerer Nieren- oder Leberfunktionsstörung

Bei Patienten mit schwerer Niereninsuffizienz (Clcr< 30 ml/min) oder Leberfunktionsstörung (10–15 Punkte nach Child-Pugh-System) beträgt die Anfangsdosis 0,5 mg zweimal täglich. Die Dosis kann in Schritten von 0,5 mg oder weniger, zweimal täglich verabreicht, erhöht werden. Bei Dosen über 1,5 mg zweimal täglich ist in Abständen von einer Woche oder mehr zu erhöhen [siehe Anwendung bei besonderen Patientengruppen (8.6 und 8.7)].

2.5 Dosisanpassungen bei bestimmten Wechselwirkungen

Wird Risperidon gleichzeitig mit Enzyminduktoren (z. B. Carbamazepin) angewendet, sollte die Risperidon-Dosis bis auf das Doppelte der üblichen Dosis des Patienten erhöht werden. Beim Absetzen von Enzyminduktoren wie Carbamazepin kann es erforderlich sein, die Risperidon-Dosis zu verringern [siehe Wechselwirkungen (7.1)]. Eine ähnliche Wirkung ist bei gleichzeitiger Anwendung von Risperidon mit anderen Enzyminduktoren (z. B. Phenytoin, Rifampicin und Phenobarbital) zu erwarten.

Wird Fluoxetin oder Paroxetin gleichzeitig mit Risperidon angewendet, sollte die Risperidon-Dosis reduziert werden. Bei gleichzeitiger Anwendung mit diesen Arzneimitteln sollte die Risperidon-Dosis bei Erwachsenen 8 mg pro Tag nicht überschreiten. Bei Beginn der Therapie sollte Risperidon langsam titriert werden. Beim Absetzen von Enzyminhibitoren wie Fluoxetin oder Paroxetin kann es erforderlich sein, die Risperidon-Dosis zu erhöhen [siehe Wechselwirkungen (7.1)].

2.6 Anwendung von Risperidon Lösung zum Einnehmen

Risperidon Lösung zum Einnehmen kann direkt aus der kalibrierten Applikationsspritze für Zubereitungen zum Einnehmen verabreicht oder vor der Anwendung mit einem Getränk gemischt werden. Risperidon Lösung zum Einnehmen ist mit folgenden Getränken kompatibel: Wasser, Kaffee, Orangensaft und fettarme Milch; sie ist NICHT kompatibel mit Cola oder Tee.

2.7 Hinweise zur Anwendung von Risperidon Schmelztabletten

Entnahme der Tablette

Risperidon Schmelztabletten 0,5 mg, 1 mg und 2 mg

Risperidon Schmelztabletten 0,5 mg, 1 mg und 2 mg werden in Blisterpackungen mit je 4 Tabletten geliefert.

Die Blisterpackung erst unmittelbar vor der Anwendung öffnen. Zur Entnahme einer einzelnen Tablette eine der vier Blistereinheiten entlang der Perforation abtrennen. Die Ecke an der gekennzeichneten Stelle umknicken. Die Folie abziehen, um die Tablette freizulegen. Die Tablette NICHT durch die Folie drücken, da die Tablette dadurch beschädigt werden könnte.

Risperidon Schmelztabletten 3 mg und 4 mg

Risperidon Schmelztabletten 3 mg und 4 mg werden in einem kindergesicherten Beutel geliefert, der einen Blister mit je 1 Tablette enthält.

Der kindergesicherte Beutel ist an der Kerbe aufzureißen, um an den Blister zu gelangen. Die Blisterpackung erst unmittelbar vor der Anwendung öffnen. Die Folie von der Seite abziehen, um die Tablette freizulegen. Die Tablette NICHT durch die Folie drücken, da die Tablette dadurch beschädigt werden könnte.

Einnahme der Tablette

Die Tablette mit trockenen Händen aus der Blistereinheit nehmen und sofort die gesamte Risperidon Schmelztablette auf die Zunge legen. Die Risperidon Schmelztablette sollte sofort eingenommen werden, da die Tablette nach der Entnahme aus der Blistereinheit nicht aufbewahrt werden kann. Risperidon Schmelztabletten zerfallen im Mund innerhalb von Sekunden und können anschließend mit oder ohne Flüssigkeit geschluckt werden. Die Patienten sollten nicht versuchen, die Tablette zu teilen oder zu kauen.

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Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.

2.1 Schizophrenia

Adults

Usual Initial Dose

Risperidone can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [see Clinical Studies (14.1)].

Adolescents

The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment.

Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics.

2.2 Bipolar Mania

Usual Dose

Adults

The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [see Clinical Studies (14.2 , 14.3)]. Risperidone doses higher than 6 mg per day were not studied.

Pediatrics

The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)

The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily.

For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.

Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.

2.4 Dosing in Patients with Severe Renal or Hepatic Impairment

For patients with severe renal impairment (Clcr< 30 mL/min) or hepatic impairment (10–15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [see Use in Specific Populations (8.6 and 8.7)].

2.5 Dose Adjustments for Specific Drug Interactions

When risperidone is co-administered with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased up to double the patient's usual dose. It may be necessary to decrease the risperidone dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)]. Similar effect may be expected with co-administration of risperidone with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).

When fluoxetine or paroxetine is co-administered with risperidone, the dose of risperidone should be reduced. The risperidone dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, risperidone should be titrated slowly. It may be necessary to increase the risperidone dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7.1)].

2.6 Administration of Risperidone Oral Solution

Risperidone Oral Solution can be administered directly from the calibrated oral dosing syringe, or can be mixed with a beverage prior to administration. Risperidone Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.

2.7 Directions for Use of Risperidone Orally Disintegrating Tablets

Tablet Accessing

Risperidone Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg

Risperidone Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each.

Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet.

Risperidone Orally Disintegrating Tablets 3 mg and 4 mg

Risperidone Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each.

The child-resistant pouch should be torn open at the notch to access the blister. Do not open the blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push the tablet through the foil, because this could damage the tablet.

Tablet Administration

Using dry hands, remove the tablet from the blister unit and immediately place the entire Risperidone Orally Disintegrating Tablet on the tongue. The Risperidone Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. Risperidone Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.

Darreichungsformen und Stärken

Risperidone Tablets are available in the following strengths and colors: 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All are capsule shaped, and imprinted with "PATR" on one side and either "Ris 0.5", "R1", "R2", "R3", or "R4" on the other side according to their respective strengths.

Risperidone Oral Solution is available in a 1 mg/mL strength.

Risperidone Orally Disintegrating Tablets are available in the following strengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with "P0.5", "P1", "P2", "P3", or "P4" according to their respective strengths.

Gegenanzeigen

Risperidon Tabletten, Lösung zum Einnehmen oder Schmelztabletten sind kontraindiziert bei Patienten mit bekannter Überempfindlichkeit gegen Risperidon oder Paliperidon oder gegen einen der sonstigen Bestandteile der Darreichungsformen Risperidon Tabletten, Lösung zum Einnehmen oder Schmelztabletten. Bei Patienten, die mit Risperidon behandelt wurden, und bei Patienten, die mit Paliperidon behandelt wurden, wurden Überempfindlichkeitsreaktionen, einschließlich anaphylaktischer Reaktionen und Angioödem, berichtet. Paliperidon ist ein Metabolit von Risperidon.

Englisches Original anzeigen

Risperidone Tablets, Oral Solution, or Orally Disintegrating Tablets are contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the Risperidone Tablets, Oral Solution, or Orally Disintegrating Tablets formulations. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

Nebenwirkungen

The following are discussed in more detail in other sections of the labeling:

Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
Tardive dyskinesia [see Warnings and Precautions (5.4)]
Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.5)]
Hyperprolactinemia [see Warnings and Precautions (5.6)]
Orthostatic hypotension [see Warnings and Precautions (5.7)]
Falls [see Warnings and Precautions (5.8)]
Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9)]
Potential for cognitive and motor impairment [see Warnings and Precautions (5.10)]
Seizures [see Warnings and Precautions (5.11)]
Dysphagia [see Warnings and Precautions (5.12)]
Priapism [see Warnings and Precautions (5.13)]
Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
Patients with Phenylketonuria [see Warnings and Precautions (5.15)].

The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions (6.1)].

The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia

Adult Patients with Schizophrenia

Table 8 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

Table 8. Adverse Reactions in ≥2% of Risperidone-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials
| Percentage of Patients Reporting Reaction
| Risperidone |
System/Organ Class Adverse Reaction | 2–8 mg per day (N=366) | >8–16 mg per day (N=198) | Placebo (N=225)
Cardiac Disorders | | |
Tachycardia | 1 | 3 | 0
Eye Disorders | | |
Vision blurred | 3 | 1 | 1
Gastrointestinal Disorders | | |
Nausea | 9 | 4 | 4
Constipation | 8 | 9 | 6
Dyspepsia | 8 | 6 | 5
Dry mouth | 4 | 0 | 1
Abdominal discomfort | 3 | 1 | 1
Salivary hypersecretion | 2 | 1 | <1
Diarrhea | 2 | 1 | 1
General Disorders | | |
Fatigue | 3 | 1 | 0
Chest pain | 2 | 2 | 1
Asthenia | 2 | 1 | <1
Infections and Infestations | | |
Nasopharyngitis | 3 | 4 | 3
Upper respiratory tract infection | 2 | 3 | 1
Sinusitis | 1 | 2 | 1
Urinary tract infection | 1 | 3 | 0
Investigations | | |
Blood creatine phosphokinase increased | 1 | 2 | <1
Heart rate increased | <1 | 2 | 0
Musculoskeletal and Connective Tissue Disorders | | |
Back pain | 4 | 1 | 1
Arthralgia | 2 | 3 | <1
Pain in extremity | 2 | 1 | 1
Nervous System Disorders | | |
ParkinsonismParkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson's disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. | 14 | 17 | 8
Akathisia | 10 | 10 | 3
Sedation | 10 | 5 | 2
Dizziness | 7 | 4 | 2
Dystonia | 3 | 4 | 2
Tremor | 2 | 3 | 1
Dizziness postural | 2 | 0 | 0
Psychiatric Disorders | | |
Insomnia | 32 | 25 | 27
Anxiety | 16 | 11 | 11
Respiratory, Thoracic and Mediastinal Disorders | | |
Nasal congestion | 4 | 6 | 2
Dyspnea | 1 | 2 | 0
Epistaxis | <1 | 2 | 0
Skin and Subcutaneous Tissue Disorders | | |
Rash | 1 | 4 | 1
Dry skin | 1 | 3 | 0
Vascular Disorders | | |
Orthostatic hypotension | 2 | 1 | 0

Pediatric Patients with Schizophrenia

Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.

Table 9. Adverse Reactions in ≥5% of Risperidone-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial
| Percentage of Patients Reporting Reaction
| Risperidone |
System/Organ Class Adverse Reaction | 1–3 mg per day (N=55) | 4–6 mg per day (N=51) | Placebo (N=54)
Gastrointestinal Disorders | | |
Salivary hypersecretion | 0 | 10 | 2
Nervous System Disorders | | |
Sedation | 24 | 12 | 4
ParkinsonismParkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. | 16 | 28 | 11
Tremor | 11 | 10 | 6
Akathisia | 9 | 10 | 4
Dizziness | 7 | 14 | 2
Dystonia | 2 | 6 | 0
Psychiatric Disorders | | |
Anxiety | 7 | 6 | 0

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania

Adult Patients with Bipolar Mania

Table 10 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

Table 10. Adverse Reactions in ≥2% of Risperidone-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials
| Percentage of Patients Reporting Reaction
System/Organ Class Adverse Reaction | Risperidone 1–6 mg per day (N=448) | Placebo (N=424)
Eye Disorders | |
Vision blurred | 2 | 1
Gastrointestinal Disorders | |
Nausea | 5 | 2
Diarrhea | 3 | 2
Salivary hypersecretion | 3 | 1
Stomach discomfort | 2 | <1
General Disorders | |
Fatigue | 2 | 1
Nervous System Disorders | |
ParkinsonismParkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. | 25 | 9
Sedation | 11 | 4
Akathisia | 9 | 3
Tremor | 6 | 3
Dizziness | 6 | 5
Dystonia | 5 | 1
Lethargy | 2 | 1

Table 11 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.

Pediatric Patients with Bipolar Mania

Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.

Table 12. Adverse Reactions in ≥5% of Risperidone-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials
| Percentage of Patients Reporting Reaction
| Risperidone |
System/Organ Class Adverse Reaction | 0.5–2.5 mg per day (N=50) | 3–6 mg per day (N=61) | Placebo (N=58)
Eye Disorders | | |
Vision blurred | 4 | 7 | 0
Gastrointestinal Disorders | | |
Abdominal pain upper | 16 | 13 | 5
Nausea | 16 | 13 | 7
Vomiting | 10 | 10 | 5
Diarrhea | 8 | 7 | 2
Dyspepsia | 10 | 3 | 2
Stomach discomfort | 6 | 0 | 2
General Disorders | | |
Fatigue | 18 | 30 | 3
Metabolism and Nutrition Disorders | | |
Increased appetite | 4 | 7 | 2
Nervous System Disorders | | |
Sedation | 42 | 56 | 19
Dizziness | 16 | 13 | 5
ParkinsonismParkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. | 6 | 12 | 3
Dystonia | 6 | 5 | 0
Akathisia | 0 | 8 | 2
Psychiatric Disorders | | |
Anxiety | 0 | 8 | 3
Respiratory, Thoracic and Mediastinal Disorders | | |
Pharyngolaryngeal pain | 10 | 3 | 5
Skin and Subcutaneous Tissue Disorders | | |
Rash | 0 | 7 | 2

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder

Table 13 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.

Table 13. Adverse Reactions in ≥5% of Risperidone-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials
| Percentage of Patients Reporting Reaction
System/Organ Class Adverse Reaction | Risperidone 0.5–4.0 mg/day | Placebo
| (N=107) | (N=115)
Gastrointestinal Disorders | |
Vomiting | 20 | 17
Constipation | 17 | 6
Dry mouth | 10 | 4
Nausea | 8 | 5
Salivary hypersecretion | 7 | 1
General Disorders and Administration Site Conditions | |
Fatigue | 31 | 9
Pyrexia | 16 | 13
Thirst | 7 | 4
Infections and Infestations | |
Nasopharyngitis | 19 | 9
Rhinitis | 9 | 7
Upper respiratory tract infection | 8 | 3
Investigations | |
Weight increased | 8 | 2
Metabolism and Nutrition Disorders | |
Increased appetite | 44 | 15
Nervous System Disorders | |
Sedation | 63 | 15
Drooling | 12 | 4
Headache | 12 | 10
Tremor | 8 | 1
Dizziness | 8 | 2
ParkinsonismParkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. | 8 | 1
Renal and Urinary Disorders | |
Enuresis | 16 | 10
Respiratory, Thoracic and Mediastinal Disorders | |
Cough | 17 | 12
Rhinorrhea | 12 | 10
Nasal congestion | 10 | 4
Skin and Subcutaneous Tissue Disorders | |
Rash | 8 | 5

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients.

Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia

Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and Labyrinth Disorders: ear pain, tinnitus

Endocrine Disorders: hyperprolactinemia

Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune System Disorders: drug hypersensitivity

Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia

Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis

Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia

Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence

Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis

Vascular Disorders: hypotension, flushing

Additional Adverse Reactions Reported with Risperidone Long-Acting Injection

The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of Risperidone Long-Acting Injection, regardless of frequency of occurrence:

Cardiac Disorders: bradycardia

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blepharospasm

Gastrointestinal Disorders: toothache, tongue spasm

General Disorders and Administration Site Conditions: pain

Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess

Injury and Poisoning: fall

Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased

Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain

Nervous System Disorders: convulsion, paresthesia

Psychiatric Disorders: depression

Skin and Subcutaneous Tissue Disorders: eczema

Vascular Disorders: hypertension

Discontinuations Due to Adverse Reactions

Schizophrenia - Adults

Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were:

Table 14. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Schizophrenia Trials
| Risperidone |
Adverse Reaction | 2–8 mg/day (N=366) | >8–16 mg/day (N=198) | Placebo (N=225)
Dizziness | 1.4% | 1.0% | 0%
Nausea | 1.4% | 0% | 0%
Vomiting | 0.8% | 0% | 0%
Parkinsonism | 0.8% | 0% | 0%
Somnolence | 0.8% | 0% | 0%
Dystonia | 0.5% | 0% | 0%
Agitation | 0.5% | 0% | 0%
Abdominal pain | 0.5% | 0% | 0%
Orthostatic hypotension | 0.3% | 0.5% | 0%
Akathisia | 0.3% | 2.0% | 0%

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Schizophrenia - Pediatrics

Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).

Bipolar Mania - Adults

In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone-treated patients were:

Table 15. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials
Adverse Reaction | Risperidone 1–6 mg/day (N=448) | Placebo (N=424)
Parkinsonism | 0.4% | 0%
Lethargy | 0.2% | 0%
Dizziness | 0.2% | 0%
Alanine aminotransferase increased | 0.2% | 0.2%
Aspartate aminotransferase increased | 0.2% | 0.2%

Bipolar Mania - Pediatrics

In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).

Autistic Disorder - Pediatrics

In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n=156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.

Dose Dependency of Adverse Reactions in Clinical Trials

Extrapyramidal Symptoms

Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Table 16.
Dose Groups | Placebo | Risperidone 2 mg | Risperidone 6 mg | Risperidone 10 mg | Risperidone 16 mg
Parkinsonism | 1.2 | 0.9 | 1.8 | 2.4 | 2.6
EPS Incidence | 13% | 17% | 21% | 21% | 35%

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):

Table 17.
Dose Groups | Risperidone 1 mg | Risperidone 4 mg | Risperidone 8 mg | Risperidone 12 mg | Risperidone 16 mg
Parkinsonism | 0.6 | 1.7 | 2.4 | 2.9 | 4.1
EPS Incidence | 7% | 12% | 17% | 18% | 20%

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Other Adverse Reactions

Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in Body Weight

Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5.5), Adverse Reactions (6), and Use in Specific Populations (8.4)].

Changes in ECG Parameters

Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8–16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4–6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.

In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes.

In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

Warnhinweise und Vorsichtsmaßnahmen

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

Risperidone is not approved for the treatment of dementia-related psychosis [see Boxed Warning].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue Risperidone and provide symptomatic treatment and monitoring.

5.4 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. 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 hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone, 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, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
| | Risperidone
| Placebo | 1–8 mg/day | >8–16 mg/day
| Mean change from baseline (mg/dL)
| n=555 | n=748 | n=164
Serum Glucose | -1.4 | 0.8 | 0.6
| Proportion of patients with shifts
Serum Glucose (<140 mg/dL to ≥200 mg/dL) | | |
| 0.6% (3/525) | 0.4% (3/702) | 0% (0/158)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 years of age), Bipolar Mania (10–17 years of age), or Autistic Disorder (5 to 17 years of age)
| Placebo | Risperidone 0.5–6 mg/day
| Mean change from baseline (mg/dL)
| n=76 | n=135
Serum Glucose | -1.3 | 2.6
| Proportion of patients with shifts
Serum Glucose (<100 mg/dL to ≥126 mg/dL) | 0% | 0.8%
| (0/64) | (1/120)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
| | Risperidone
| Placebo | 1–8 mg/day | >8–16 mg/day
| Mean change from baseline (mg/dL)
Cholesterol | n=559 | n=742 | n=156
Change from baseline | 0.6 | 6.9 | 1.8
Triglycerides | n=183 | n=307 | n=123
Change from baseline | -17.4 | -4.9 | -8.3
| Proportion of patients With Shifts
Cholesterol (<200 mg/dL to ≥240 mg/dL) | 2.7% | 4.3% | 6.3%
| (10/368) | (22/516) | (6/96)
Triglycerides (<500 mg/dL to ≥500 mg/dL) | 1.1% (2/180) | 2.7% (8/301) | 2.5% (3/121)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5.

Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)
| Placebo | Risperidone 0.5–6 mg/day
| Mean change from baseline (mg/dL)
Cholesterol | n=74 | n=133
Change from baseline | 0.3 | -0.3
LDL | n=22 | n=22
Change from baseline | 3.7 | 0.5
HDL | n=22 | n=22
Change from baseline | 1.6 | -1.9
Triglycerides | n=77 | n=138
Change from baseline | -9.0 | -2.6
| Proportion of patients with shifts
Cholesterol (<170 mg/dL to ≥200 mg/dL) | 2.4% (1/42) | 3.8% (3/80)
LDL (<110 mg/dL to ≥130 mg/dL) | 0% (0/16) | 0% (0/16)
HDL (≥40 mg/dL to <40 mg/dL) | 0% (0/19) | 10% (2/20)
Triglycerides (<150 mg/dL to ≥200 mg/dL) | 1.5% (1/65) | 7.1% (8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7.

Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age)
| Placebo (n=375) | Risperidone 0.5–6 mg/day (n=448)
Weight (kg) | |
Change from baseline | 0.6 | 2.0
Weight Gain | |
≥7% increase from baseline | 6.9% | 32.6%

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5–2.5 mg group, 1.44 kg in the risperidone 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with risperidone for any indication, weight gain should be assessed against that expected with normal growth.

5.6 Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

5.7 Orthostatic Hypotension

Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration (2.1 , 2.4)].

Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication.

5.8 Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm³) should discontinue risperidone and have their WBC followed until recovery.

5.10 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely.

5.11 Seizures

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures.

5.12 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see Boxed Warning and Warnings and Precautions (5.1)].

5.13 Priapism

Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.

5.14 Body Temperature Regulation

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

5.15 Patients with Phenylketonuria

Inform patients that Risperidone Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each 4 mg Risperidone Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg Risperidone Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg Risperidone Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg Risperidone Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg Risperidone Orally Disintegrating Tablet contains 0.14 mg phenylalanine.

Wechselwirkungen

7.1 Pharmacokinetic-related Interactions

The dose of risperidone should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and Dosage and Administration (2.5)]. Dose adjustment is not recommended for Risperidone when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18].

Effect of Risperidone on Other Drugs

Lithium

Repeated oral doses of risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Dose adjustment for lithium is not recommended.

Valproate

Repeated oral doses of risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of risperidone. Dose adjustment for valproate is not recommended.

Digoxin

Risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

7.2 Pharmacodynamic-related Interactions

Centrally Acting Drugs and Alcohol

Given the primary CNS effects of risperidone, caution should be used when Risperidone is taken in combination with other centrally acting drugs and alcohol.

Drugs with Hypotensive Effects

Because of its potential for inducing hypotension, risperidone may enhance the hypotensive effects of other therapeutic agents with this potential.

Levodopa and Dopamine Agonists

Risperidone may antagonize the effects of levodopa and dopamine agonists.

Methylphenidate

Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of risperidone and methylphenidate [see Adverse Reactions (6.2)].

Clozapine

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Schwangerschaft, Stillzeit, Kinder, ältere Menschen

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy (see Clinical Considerations).

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m² body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m² body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m² body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m² body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m² body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m² body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m² body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m² body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m² body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m² and the only dose tested in the study.

8.2 Lactation

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations). There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for risperidone and any potential adverse effects on the breastfed child from risperidone or from the mother's underlying condition.

Clinical Considerations

Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of risperidone (D₂ receptor antagonism), treatment with risperidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.6)].

8.4 Pediatric Use

Approved Pediatric Indications

Schizophrenia

The efficacy and safety of risperidone in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1.1) , Adverse Reactions (6.1) , and Clinical Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.

Safety and effectiveness of risperidone in children less than 13 years of age with schizophrenia have not been established.

Bipolar I Disorder

The efficacy and safety of risperidone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2) , Adverse Reactions (6.1) , and Clinical Studies (14.2)].

Safety and effectiveness of risperidone in children less than 10 years of age with bipolar disorder have not been established.

Autistic Disorder

The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3) , Adverse Reactions (6.1) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone as patients treated for irritability associated with autistic disorder.

A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone.

Adverse Reactions in Pediatric Patients

Tardive Dyskinesia

In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment [see also Warnings and Precautions (5.4)].

Weight Gain

Weight gain has been observed in children and adolescents during treatment with risperidone. Clinical monitoring of weight is recommended during treatment.

Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the risperidone group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Somnolence

Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [see Adverse Reactions (6.1 and 6.2)]. Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1 , 2.2 , and 2.3)].

Hyperprolactinemia

Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received risperidone had elevated levels of prolactin compared to 3–7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.

In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients.

Growth and Sexual Maturation

The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

Juvenile Animal Studies

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m² body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m² body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

8.5 Geriatric Use

Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4, 2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4)].

8.6 Renal Impairment

In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [see Dosage and Administration (2.4)].

8.7 Hepatic Impairment

While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α₁-acid glycoprotein. Risperidone doses should be reduced in patients with liver disease [see Dosage and Administration (2.4)].

8.8 Patients with Parkinson's Disease or Lewy Body Dementia

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to risperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Überdosierung

10.1 Human Experience

Premarketing experience included eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience includes reports of acute risperidone overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of risperidone and paroxetine.

10.2 Management of Overdosage

For the most up to date information on the management of risperidone overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to risperidone.

Klinische Pharmakologie

12.1 Mechanism of Action

The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D₂) and serotonin Type 2 (5HT₂) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D₂ and 5HT₂ may explain some of the other effects of risperidone [see Clinical Pharmacology (12.1)].

12.2 Pharmacodynamics

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT₂), dopamine Type 2 (D₂), α₁ and α₂ adrenergic, and H₁ histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D₁ and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10⁻⁵ M) for cholinergic muscarinic or β₁ and β₂ adrenergic receptors.

12.3 Pharmacokinetics

Absorption

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Pharmacokinetic studies showed that Risperidone Orally Disintegrating Tablets and Risperidone Oral Solution are bioequivalent to Risperidone Tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5–6 days (measured in extensive metabolizers).

Food Effect

Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.

Distribution

Auszug – vollständiger Text im Originaldokument. Original auf DailyMed (FDA/NLM)

Quelle: U.S. Food and Drug Administration (FDA), Prescribing Information, über DailyMed (NLM); gemeinfrei. Keine Werbung, keine Therapieempfehlung. Bei Fragen zur eigenen Behandlung: Ärztin, Arzt oder Apotheke.