RISPERDAL

RISPERIDONE ZENTIVA is indicated in the treatment of schizophrenia.

RISPERIDONE ZENTIVA is indicated in the treatment of moderate to severe manic episodes associated with bipolar disorders.

RISPERIDONE ZENTIVA is indicated in the short-term treatment (up to 6 weeks) of persistent aggression in patients with moderate to severe Alzheimer's dementia not responding to non-pharmacological approaches and when there is a risk of harm to the patient themselves or others.

RISPERIDONE ZENTIVA is indicated in the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from 5 years of age and adolescents presenting with below-average intellectual functioning or mental retardation diagnosed according to DSM-IV criteria, in whom the severity of aggressive behaviors or other disruptive behaviors requires pharmacological treatment. Pharmacological treatment should be an integral part of a broader treatment program, including psychosocial and educational measures. It is recommended that risperidone be prescribed by a specialist in child neurology and child and adolescent psychiatry or a physician very familiar with the treatment of conduct disorder in children and adolescents.

Pregnancy

There are no adequate data on the use of risperidone during pregnancy.

Risperidone has not shown teratogenic effects in studies conducted in animals but other types of reproductive toxicity have been observed (see section 5.3). The potential risk in humans is unknown.

Newborns exposed to antipsychotics (including RISPERIDONE ZENTIVA) during the third trimester of pregnancy present a risk of adverse reactions including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in terms of severity and duration after delivery. The following reactions have been reported: agitation, hypertonia, hypotonia, tremors, somnolence, respiratory distress, feeding disorder.

Consequently, newborns must be closely monitored. RISPERIDONE ZENTIVA should not be used during pregnancy unless manifestly necessary. When discontinuation is necessary during pregnancy, it must not be carried out suddenly.

Breastfeeding

In animal studies, risperidone and 9-hydroxy-risperidone are excreted in milk. It has been shown that risperidone and 9-hydroxy-risperidone are also excreted in breast milk in small quantities. There are no data available on adverse effects in the breastfed infant. Consequently, the benefits of breastfeeding should be weighed against the potential risks to the child.

Fertility

As with other D2 dopamine receptor antagonists, risperidone increases prolactin levels. Hyperprolactinemia may inhibit hypothalamic GnRH, leading to a decrease in the secretion of pituitary gonadotropins. Subsequently, this may inhibit reproductive function by altering gonadal steroidogenesis in male and female patients.

No relevant effect has been observed in non-clinical studies.

RISPERIDONE ZENTIVA may have a minor or moderate influence on the ability to drive and use machines due to potential effects on the nervous system and vision (see section 4.8). Consequently, patients must be informed not to drive or use machines until their individual sensitivity is known.

The most frequently reported adverse effects (AE) (frequency ³ 10 %) are: Parkinsonism, sedation/somnolence, headache, and insomnia.

Adverse effects that appeared dose-dependently included parkinsonism and akathisia.

The following AEs are all the AEs reported with risperidone during clinical trials and post-marketing by frequency category estimated from clinical trials of risperidone. The following terms and frequencies are used: very frequent ( ³ 1/10), frequent ( ³ 1/100 to < 1/10), uncommon ( ³ 1/1 000 to < 1/100), rare ( ³ 1/10 000 to < 1/1000), and very rare (< 1/10 000).

Within each frequency group, adverse effects are presented in descending order of severity.

a Hyperprolactinaemia may in some cases lead to gynaecomastia, menstrual disorders, amenorrhoea, anovulation, galactorrhoea, fertility disorders, decreased libido, erectile dysfunction.

b In controlled versus placebo trials, diabetes was reported in 0.18 % of subjects treated with risperidone compared to a rate of 0.11 % in the placebo group. The overall incidence in all clinical trials was 0.43 % in all subjects treated with risperidone.

c Not observed during clinical studies with risperidone but observed in the post-marketing environment with risperidone.

d Extrapyramidal disorder may include: Parkinsonism, (hypersalivation, musculoskeletal rigidity, parkinsonism, salivation, cogwheel phenomenon, bradykinesia, hypokinesia, fixed facies, muscle twitch, akinesia, neck rigidity, muscle rigidity, parkinsonian gait and abnormal eyelid reflex, parkinsonian resting tremor), akathisia (akathisia, restlessness, hyperkinesia, and restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitch, choreoathetosis, athetosis, and myoclonus), dystonia.

Dystonia includes dystonia, hypertonia, torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, ocular revolution, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus. It is noted that a wider spectrum of symptoms is included, which do not necessarily have an extrapyramidal origin.

Insomnia includes: initial insomnia, middle of the night insomnia. Convulsion includes: Grand mal seizure; menstrual disorder includes: irregular menstruation, oligomenorrhea; oedema includes: generalized oedema, peripheral oedema, pitting oedema.

Adverse effects observed with paliperidone-based formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse effect profiles of these compounds (including both oral and injectable formulations) apply to each other. In addition to the adverse effects above, the following adverse effects have been observed during the use of paliperidone-based products and may be expected with risperidone.

· Cardiac disorders: orthostatic tachycardia syndrome.

Class effects

As with other antipsychotics, very rare cases of QT prolongation have been reported post-marketing with risperidone. Other class cardiac effects reported with antipsychotics that prolong the QT interval include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest and torsades de pointes.

Venous thromboembolism

Cases of venous thromboembolism, including cases of pulmonary embolism as well as deep vein thrombosis, have been reported with antipsychotics (frequency undetermined).

Weight gain

The percentages of adult schizophrenic patients treated with risperidone and placebo and reaching the weight gain criterion of ≥ 7 % were compared in a pooled analysis of placebo-controlled trials lasting 6 to 8 weeks, showing a significantly higher incidence of weight gain in the risperidone group (18 %) compared to placebo (9 %). In a pool of placebo-controlled clinical studies lasting 3 weeks in adults presenting with an acute manic episode, the incidence of weight gain ≥ 7 % at the end of the study was comparable in the risperidone (2,5 %) and placebo (2,4 %) groups, and was slightly higher in the active control group (3,5 %).

In a population of children and adolescents presenting with conduct disorders and other disruptive behavior disorders, in long-term studies, weight gain was on average 7,3 kg after 12 months of treatment. The expected weight gain for normal children aged 5-12 years is 3 to 5 kg per year. Between 12-16 years, a weight gain of the order of 3 to 5 kg per year is maintained in girls, while boys gain approximately 5 kg per year.

Additional information on particular populations

The adverse effects which have been reported with a higher incidence in elderly demented patients or in pediatric patients than in the adult population are described below:

Elderly demented patients

Transient ischemic attacks and strokes are adverse effects reported in clinical trials with a frequency of 1,4 % and 1,5 % respectively, in elderly demented patients. The following adverse effects have also been reported with a frequency ≥ 5 % in elderly demented patients and with a frequency at least double the frequency observed in other adult populations: urinary tract infection, peripheral edema, lethargy, and cough.

Pediatric population

In general, it can be assumed that the adverse effects in children are of a similar nature to those observed in adults.

The following adverse effects have been reported with a frequency ≥ 5 % in pediatric patients (5 to 17 years) and with a frequency at least double the frequency observed in clinical trials conducted in adults: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, sensation of dizziness, cough, pyrexia, tremor, diarrhea, and enuresis.

The effect of long-term treatment with risperidone on sexual maturation and height has not been adequately studied (see section 4.4, subsection "Pediatric population").

Reporting of suspected adverse effects

Reporting of suspected adverse effects after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: www.signalement-sante.gouv.fr .