Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Elderly patients with dementia

Increased mortality in elderly people with dementia
In a meta-analysis of 17 controlled trials of atypical antipsychotics, including RISPERDAL, elderly patients with dementia treated with atypical antipsychotics have an increased mortality compared to placebo. In placebo-controlled trials with oral RISPERDAL in this population, the incidence of mortality was 4.0% for RISPERDAL-treated patients compared to 3.1% for placebo-treated patients. The odds ratio (95% exact confidence interval) was 1.21 (0.7; 2.1). The mean age (range) of patients who died was 86 years (range 67-100). Data from two large observational studies showed that elderly people with dementia who are treated with conventional antipsychotics are also at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known. 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.

Concomitant use with furosemide
In the RISPERDAL placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70-96) or furosemide alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use.
There was no increased incidence of mortality among patients taking other diuretics as concomitant treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular adverse events (CVAE)

An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics. The pooled data from six placebo-controlled studies with RISPERDAL in mainly elderly patients (> 65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1,009) of patients treated with risperidone and 1.2% (8/712) of patients treated with placebo. The odds ratio (95% exact confidence interval) was 2.96 (1.34; 7.50). The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations.
RISPERDAL should be used with caution in patients with risk factors for stroke.

The risk of CVAEs was significantly higher in patients with mixed or vascular type of dementia when compared to Alzheimer’s dementia. Therefore, patients with other types of dementias than Alzheimer’s should not be treated with risperidone.

Physicians are advised to assess the risks and benefits of the use of RISPERDAL in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be cautioned to immediately report signs and symptoms of potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems. All treatment options should be considered without delay, including discontinuation of risperidone.

RISPERDAL should only be used short term for persistent aggression in patients with moderate to severe Alzheimer’s dementia to supplement non-pharmacological approaches which have had limited or no efficacy and when there is potential risk of harm to self or others.

Patients should be reassessed regularly, and the need for continuing treatment reassessed.

Orthostatic hypotension
Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during the initial dose-titration period. Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment. RISPERDAL should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolaemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see section 4.2). A dose reduction should be considered if hypotension occurs.

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including RISPERDAL. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance.

Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of RISPERDAL 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 < 1 × 109/L) should discontinue RISPERDAL and have their WBC followed until recovery.

Tardive dyskinesia/extrapyramidal symptoms (TD/EPS)

Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical involuntary movements, predominantly of the tongue and/or face. The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics should be considered.

Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications.
Gradual withdrawal of stimulant treatment is recommended (see section 4.5).

Neuroleptic malignant syndrome (NMS)

Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels has been reported to occur with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all antipsychotics, including RISPERDAL, should be discontinued.

Parkinson’s disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including RISPERDAL, to patients with Parkinson’s Disease or Dementia with Lewy Bodies (DLB). Parkinson’s Disease may worsen with risperidone. Both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medicinal products; these patients were excluded from clinical trials. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with RISPERDAL. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Association with ketoacidosis has been reported very rarely and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic, including RISPERDAL, should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Weight gain

Significant weight gain has been reported with RISPERDAL use. Weight should be monitored regularly.
Hyperprolactinaemia

Hyperprolactinaemia is a common side effect of treatment with RISPERDAL. Evaluation of the prolactin plasma level is recommended in patients with evidence of possible prolactin-related side effects (e.g., gynaecomastia, menstrual disorders, anovulation, fertility disorder, decreased libido, erectile dysfunction, and galactorrhoea).

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin.
Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history.

RISPERDAL should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.

QT prolongation

QT prolongation has very rarely been reported post-marketing. As with other antipsychotics, caution should be exercised when risperidone is prescribed in patients with known cardiovascular disease, family history of QT prolongation, bradycardia, or electrolyte disturbances (hypokalaemia, hypomagnesaemia), as it may increase the risk of arrhythmogenic effects, and in concomitant use with medicines known to prolong the QT interval.

Seizures

RISPERDAL should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Priapism

Priapism may occur with RISPERDAL treatment due to its alpha-adrenergic blocking effects.
Body temperature regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing RISPERDAL® to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant treatment with anticholinergic activity, or being subject to dehydration.

Antiemetic effect

An antiemetic effect was observed in preclinical studies with risperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumour.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone (see section 4.2).

Venous thromboembolism

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

Intraoperative floppy iris syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including RISPERDAL® (see section 4.8).

IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1-blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Paediatric population
Before risperidone is prescribed to a child or adolescent with conduct disorder they should be fully assessed for physical and social causes of the aggressive behaviour such as pain or inappropriate environmental demands.

The sedative effect of risperidone should be closely monitored in this population because of possible consequences on learning ability. A change in the time of administration of risperidone could improve the impact of the sedation on attention faculties of children and adolescents.

Weight Gain
Risperidone was associated with mean increases in body weight and body mass index (BMI). Baseline weight measurement prior to treatment and regular weight monitoring are recommended. Changes in height in the long-term open-label extension studies were within expected age-appropriate norms. The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied.

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 the table below.

Table: 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                 RISPERDAL® 0.5-6 mg/day
(n=375)                        (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, RISPERDAL 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 RISPERDAL฀ 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.

Because of the potential effects of prolonged hyperprolactinaemia on growth and sexual maturation in 
children and adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning, and other potential prolactin-related effects.

Results from a small post-marketing observational study showed that risperidone-exposed subjects between the ages of 8-16 years were on average approximately 3.0 to 4.8 cm taller than those who received other atypical antipsychotic medications. This study was not adequate to determine whether exposure to risperidone had any impact on final adult height, or whether the result was due to a direct effect of risperidone on bone growth, or the effect of the underlying disease itself on bone growth, or the result of better control of the underlying disease with resulting increase in linear growth.

During treatment with risperidone regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.

Hyperglycemia and Diabetes Mellitus
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 the table below.

Table:         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)
RISPERDAL®
Placebo                                  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
0%                                            0.8%
(<100 mg/dL to ≥126 mg/dL)
(0/64)                                         (1/120)

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

Dyslipidemia

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 the table below.

Table          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) RISPERDAL®
Placebo                            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                                    2.4%                                           3.8% (<170 mg/dL to ≥200 mg/dL)                    (1/42)                                          (3/80) LDL                                            0%                                              0% (<110 mg/dL to ≥130 mg/dL)                    (0/16)                                          (0/16) HDL                                            0%                                              10% (≥40 mg/dL to <40 mg/dL)                      (0/19)                                          (2/20) Triglycerides                                  1.5%                                           7.1% (<150 mg/dL to ≥200 mg/dL)                    (1/65)                                         (8/113) 
In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL® 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).

For specific posology recommendations in children and adolescents see section 4.2.

Excipients
The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. (Pertains only to the film-coated tablets.)

Contains orange yellow S aluminium lake (sunset yellow) (E110). May cause allergic reactions. (Pertains only to the 2 mg film coated tablets).

The 1 ml oral solution contains benzoic acid (E210). Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non- conjugated bilirubin deposits in the brain tissue).


The film-coated tablets contain less than 1 mmol sodium (23 mg) per dose, that is to say, essentially ‘sodium free’.

Effects on Driving

4.7    Effects on ability to drive and use machines
RISPERDAL can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.