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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 Eperon and preventive measures undertaken.
Concomitant use with furosemide: In the risperidone 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 was observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.
Cerebrovascular Adverse Events (CAE): In placebo-controlled trials in elderly patients with dementia there was a significantly higher incidence (approximately 3-fold increased) of CVAEs, such as stroke (including fatalities) and transient ischaemic attack in patients treated with risperidone compared with patients treated with placebo (mean age 85 years; range 73 to 97). The pooled data from six placebo-controlled studies in mainly elderly patients (>65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1009) 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. Eperon should be used with caution in patients with risk factors for stroke.
The risk of CVAEs was higher in patients on risperidone with mixed or vascular type of dementia when compared to Alzheimer's dementia.
Physicians are advised to assess the risks and benefits of the use of risperidone 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.
Patients should be re-assessed regularly to determine the need for continued treatment.
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 postmarketing with concomitant use of risperidone and antihypertensive treatment. Eperon should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see Dosage & Administration). A dose reduction should be considered if hypotension occurs.
Leukopenia, Neutropenia, and Agranulocytosis: Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including Eperon. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during past-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Eperon 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 X 109/L) should discontinue Eperon and have their WBC followed until recovery.
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 Eperon and preventive measures undertaken.
Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS): Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, characterized by rhythmical involuntary movements, predominantly of the tongue and/or face. The onset of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.
Neuroleptic Malignant Syndrome (NMS): Neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated 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 antipsychotic drugs including risperidone should be discontinued.
Parkinson's disease and dementia with Lewy bodies: Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including Eperon, 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.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported in patients treated with atypical antipsychotics, including Eperon. 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. Any patient treated with atypical antipsychotics, including Eperon should be monitored for symptoms of hyperglycemia and diabetes mellitus (see Adverse Reactions).
However, epidemiological studies suggest an increased risk of diabetes and hyperglycaemia with atypical antipsychotics.
Patients with an established diagnosis of diabetes mellitus, risk factors for diabetes (eg obesity, family history of diabetes), or those who develop symptoms of hyperglycaemia during treatment with a typical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness.
Weight Gain: Significant weight gain has been reported. Monitoring weight gain is advisable when Eperon is being used.
QT Interval: As with other antipsychotics, caution should be exercised when Eperon is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome and in concomitant use with drugs known to prolong the QT interval.
Priapism: Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with Eperon during postmarketing surveillance (see Adverse Reactions).
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 Eperon see Adverse Reactions).
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.
Seizures: As with other antipsychotic drugs, Eperon should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
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 Eperon, 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 antiemetc 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 drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor.
Excipients: The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sunset yellow which is contained in Eperon 2 mg film-coated tablets may cause allergic reactions.
Effects on ability to drive and use machines: Eperon can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see Adverse Reactions). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
Elderly patients with dementia: Overall mortality: Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4.0% for risperidone-treated patients compared to 3.1% for placebo-treated patients. The 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).
