1. Name Of The Medicinal Product
RISPERDAL CONSTA
RISPERDAL CONSTA
RISPERDAL CONSTA
2. Qualitative And Quantitative Composition
1 vial contains 25 mg, 37.5 or 50mg risperidone.
1 ml reconstituted suspension contains 12.5 mg, 18.75mg or 25mg of risperidone.
Excipients: 1 ml reconstituted suspension contains 3 mg sodium.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for prolonged-release suspension for injection.
Vial with powder.
White to off-white free flowing powder.
Pre-filled syringe of solvent for reconstitution.
Clear, colourless aqueous solution.
4. Clinical Particulars
4.1 Therapeutic Indications
RISPERDAL CONSTA is indicated for the maintenance treatment of schizophrenia in patients currently stabilised with oral antipsychotics.
4.2 Posology And Method Of Administration
Adults
Starting dose:
For most patients the recommended dose is 25 mg intramuscular every two weeks. For those patients on a fixed dose of oral risperidone for two weeks or more, the following conversion scheme should be considered. Patients treated with a dosage of 4 mg or less oral risperidone should receive 25 mg RISPERDAL CONSTA, while patients treated with higher oral doses should be considered for the higher RISPERDAL CONSTA dose of 37.5 mg.
Where patients are not currently taking oral risperidone, the oral pre-treatment dosage should be considered when choosing the i.m. starting dose. The recommended starting dose is 25 mg RISPERDAL CONSTA every two weeks. Patients on higher dosages of the used oral antipsychotic should be considered for the higher RISPERDAL CONSTA dose of 37.5 mg.
Sufficient antipsychotic coverage with oral risperidone or the previous antipsychotic should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see section 5.2).
RISPERDAL CONSTA should not be used in acute exacerbations of schizophrenia without ensuring sufficient antipsychotic coverage with oral risperidone or the previous antipsychotic during the three-week lag period following the first RISPERDAL CONSTA injection.
Maintenance dose:
For most patients the recommended dose is 25 mg intramuscular every two weeks. Some patients may benefit from the higher doses of 37.5 mg or 50 mg. Upward dosage adjustment should not be made more frequently than every 4 weeks. The effect of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose. No additional benefit was observed with 75 mg in clinical trials. Doses higher than 50 mg every 2 weeks are not recommended.
Elderly
No dose adjustment is required. The recommended dose is 25 mg intramuscularly every two weeks. Where patients are not currently taking oral risperidone, the recommended dose is 25 mg RISPERDAL CONSTA every two weeks. For those patients on a fixed dose of oral risperidone for two weeks or more, the following conversion scheme should be considered. Patients treated with a dosage of 4 mg or less oral risperidone should receive 25 mg RISPERDAL CONSTA, while patients treated with higher oral doses should be considered for the higher RISPERDAL CONSTA dose of 37.5 mg.
Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see section 5.2). RISPERDAL CONSTA clinical data in elderly are limited. RISPERDAL CONSTA should be used with caution in elderly.
Hepatic and renal impairment
RISPERDAL CONSTA has not been studied in hepatically and renally impaired patients.
If hepatically or renally impaired patients require treatment with RISPERDAL CONSTA, a starting dose of 0.5 mg twice daily oral risperidone is recommended during the first week. The second week 1 mg twice daily or 2 mg once daily can be given. If an oral total daily dose of at least 2 mg is well tolerated, an injection of 25 mg RISPERDAL CONSTA can be administered every 2 weeks.
Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see section 5.2).
Paediatric population
RISPERDAL CONSTA is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
Method of administration
RISPERDAL CONSTA should be administered every two weeks by deep intramuscular deltoid or gluteal injection using the appropriate safety needle. For deltoid administration, use the 1-inch needle alternating injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between the two buttocks. Do not administer intravenously (see section 4.4 and section 6.6).
For instructions on preparation and handling RISPERDAL CONSTA, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
For risperidone-naive patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with RISPERDAL CONSTA (see section 4.2).
Elderly patients with dementia
RISPERDAL CONSTA has not been studied in elderly patients with dementia, hence it is not indicated for use in this group of patients. RISPERDAL CONSTA is not licensed for the treatment of dementia-related behavioural disturbances.
Increased mortality in elderly people with dementia
In a meta-analysis of 17 controlled trials of atypical antipsychotics, including oral 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
Concomitant use with furosemide
In the oral 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% (33/1009) 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. RISPERDAL CONSTA should be used with caution in patients with risk factors for stroke.
Orthostatic hypotension
Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during initiation of treatment. Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. Risperidone should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease). The risk/benefit of further treatment with RISPERDAL CONSTA should be assessed if clinically relevant orthostatic hypotension persists.
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.
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 CONSTA, should be discontinued.
Parkinson's disease and dementia with Lewy bodies
Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including RISPERDAL CONSTA, 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 CONSTA. 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 CONSTA, 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 CONSTA use. Weight should be monitored regularly.
Hyperprolactinaemia
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 CONSTA 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 postmarketing. 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 CONSTA 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 CONSTA 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 CONSTA 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.
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 CONSTA and preventative measures undertaken.
Renal or hepatic impairment
Although oral risperidone has been studied, RISPERDAL CONSTA has not been studied in patients with renal or liver insufficiency. RISPERDAL CONSTA should be administered with caution in this group of patients (see section 4.2).
Administration
Care must be taken to avoid inadvertent injection of RISPERDAL CONSTA into a blood vessel.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially 'sodium-free'.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction studies were performed with oral RISPERDAL.
As with other antipsychotics, caution is advised when prescribing risperidone with medicinal products known to prolong the QT interval, e.g., class Ia antiarrhythmics (e.g., quinidine, dysopiramide, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), tricyclic antidepressants (i.e., amitriptyline), tetracyclic antidepressant (i.e., maprotiline), some antihistaminics, other antipsychotics, some antimalarials (i.e., chinice and mefloquine), and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesiaemia), bradycardia, or those which inhibit the hepatic metabolism of risperidone. This list is indicative and not exhaustive.
Potential for RISPERDAL CONSTA to affect other medicinal products
Risperidone should be used with caution in combination with other centrally-acting substances notably including alcohol, opiates, antihistamines and benzodiazepines due to the increased risk of sedation.
RISPERDAL CONSTA may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.
Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment.
RISPERDAL does not show a clinically relevant effect on the pharmacokinetics of lithium, valproate, digoxin or topiramate.
Potential for other medicinal products to affect RISPERDAL CONSTA
Carbamazepine has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be observed with e.g. rifampicin, phenytoin and phenobarbital which also induce CYP 3A4 hepatic enzyme as well as P-glycoprotein. When carbamazepine or other CYP 3A4 hepatic enzyme/P
Fluoxetine and paroxetine, CYP 2D6 inhibitors, increase the plasma concentration of risperidone, but less so of the active antipsychotic fraction. It is expected that other CYP 2D6 inhibitors, such as quinidine, may affect the plasma concentrations of risperidone in a similar way. When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL CONSTA.
Verapamil, an inhibitor of CYP 3A4 and P-gp, increases the plasma concentration of risperidone.
Galantamine and donepezil do not show a clinically relevant effect on the pharmacokinetics of risperidone and on the active antipsychotic fraction.
Phenothiazines, tricyclic antidepressants, and some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increase the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction. Erythromycin, a CYP 3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction.
See section 4.4 regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of risperidone in pregnant women. According to postmarketing data reversible extrapyramidal symptoms in the neonate were observed following the use of risperidone during the last trimester of pregnancy. Consequently, newborns should be monitored carefully. Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen (see section 5.3). The potential risk for humans is unknown. Therefore, RISPERDAL CONSTA should not be used during pregnancy unless clearly necessary.
Lactation
In animal studies, risperidone and 9-hydroxy-risperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxy-risperidone are also excreted in human breast milk in small quantities. There are no data available on adverse effects in breast-feeding infants. Therefore, the advantage of breast-feeding should be weighed against the potential risks for the child.
4.7 Effects On Ability To Drive And Use Machines
RISPERDAL CONSTA has 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.
4.8 Undesirable Effects
The most frequently reported adverse drug reactions (ADRs) (incidence
Serious injection site reactions including injection site necrosis, abscess, cellulitis, ulcer, haematoma, cyst, and nodule were reported postmarketing. The frequency is considered not known (cannot be estimated from the available data). Isolated cases required surgical intervention.
The following are all the ADRs that were reported in clinical trials and postmarketing. The following terms and frequencies are applied: very common (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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a Hyperprolactinemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, galactorrhea.
b Extrapyramidal disorder may occur: Parkinsonism (salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal), akathisia (akathisia, restlessness, hyperkinesia, and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia. Dystonia includes dystonia, muscle spasms, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus. Tremor includes tremor and parkinsonian rest tremor. It should be noted that a broader spectrum of symptoms are included, that do not necessarily have an extrapyramidal origin.
c In placebo-controlled trials diabetes mellitus was reported in 0.18% in risperidone-treated subjects compared to a rate of 0.11% in placebo group. Overall incidence from all clinical trials was 0.43% in all risperidone-treated subjects.
The following is a list of additional ADRs associated with risperidone that have been identified as ADRs during clinical trials investigating the oral risperidone formulation (RISPERDAL) but were not determined to be ADRs in the clinical trials investigating RISPERDAL CONSTA.
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Class effects
As with other antipsychotics, very rare cases of QT prolongation have been reported postmarketing with risperidone. Other class-related cardiac effects reported with antipsychotics which prolong 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 and cases of deep vein thrombosis, have been reported with antipsychotic drugs (frequency unknown).
Weight gain
In the 12-week double-blind, placebo-controlled trial, 9% of patients treated with RISPERDAL CONSTA, compared with 6% of patients treated with placebo, experienced a weight gain of
4.9 Overdose
While overdose is less likely to occur with parenteral than with oral medicinal products, information pertaining to oral is presented.
Symptoms
In general, reported signs and symptoms have been those resulting from an exaggeration of the known pharmacological effects of risperidone. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, QT
In case of acute overdose, the possibility of multiple drug involvement should be considered.
Treatment
Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to RISPERDAL. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medicinal product should be administered. Close medical supervision and monitoring should continue until the patient recovers.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other antipsychotics, ATC code: N05AX08
Mechanism of action
Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and alpha2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Altho
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