- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Vial with powder.White to off-white free flowing powder.
Pre-filled syringe of solvent for reconstitution.Clear, colourless aqueous solution.
AdultsStarting 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.
ElderlyNo 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 impairmentRISPERDAL 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 populationThe safety and efficacy of RISPERDAL CONSTA in children below 18 years of age have not been established. No data are available.
Method of administrationRISPERDAL 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 reconstitution of the medicinal product before administration, see section 6.6.
Elderly patients with dementiaRISPERDAL 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 dementiaIn 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 67-100). 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 furosemideIn 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 hypotensionDue 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.
Leukopenia, neutropenia, and agranulocytosisEvents of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including RISPERDAL CONSTA. 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 leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of RISPERDAL CONSTA 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 RISPERDAL CONSTA 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.
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 bodiesPhysicians 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 mellitusHyperglycaemia, 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 gainSignificant weight gain has been reported with RISPERDAL CONSTA use. Weight should be monitored regularly.
HyperprolactinaemiaHyperprolactinaemia is a common side-effect of treatment with RISPERDAL CONSTA. 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, galactorrhea).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 prolongationQT 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.
SeizuresRISPERDAL CONSTA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
PriapismPriapism may occur with RISPERDAL CONSTA treatment due to its alpha-adrenergic blocking effects.
Body temperature regulationDisruption 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 thromboembolismCases 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.
Intraoperative Floppy Iris SyndromeIntraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including RISPERDAL CONSTA (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.
Antiemetic effectAn 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 or hepatic impairmentAlthough 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).AdministrationCare must be taken to avoid inadvertent injection of RISPERDAL CONSTA into a blood vessel.ExcipientsThis medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially 'sodium-free'.
Drugs known to prolong the QT intervalAs with other antipsychotics, caution is advised when prescribing risperidone with medicinal products known to prolong the QT interval, such as antiarrhythmics (e.g., quinidine, dysopiramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (i.e., amitriptyline), tetracyclic antidepressants (i.e., maprotiline), some antihistamines, other antipsychotics, some antimalarials (i.e., quinine 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.
Centrally-Acting Drugs and AlcoholRisperidone 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.
Levodopa and Dopamine AgonistsRISPERDAL 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.
Drugs with Hypotensive EffectClinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment.
PaliperidoneConcomitant use of oral RISPERDAL with paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive active antipsychotic fraction exposure.
Pharmacokinetic-related InteractionsFood does not affect the absorption of RISPERDAL.Risperidone is mainly metabolized through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.
Strong CYP2D6 InhibitorsCo-administration of RISPERDAL with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g., paroxetine, see below). It is expected that other CYP 2D6 inhibitors, such as quinidine, may affect the plasma concentrations of risperidone in a similar way. When concomitant paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL.
CYP3A4 and/or P-gp InhibitorsCo-administration of RISPERDAL with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL.
CYP3A4 and/or P-gp InducersCo-administration of RISPERDAL with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.
Highly Protein-bound DrugsWhen RISPERDAL is taken together with highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosage.
Paediatric PopulationInteraction studies have only been performed in adults. The relevance of the results from these studies in paediatric patients is unknown.The combined use of psychostimulants (e.g., methylphenidate) with RISPERDAL in children and adolescents did not alter the pharmacokinetics and efficacy of RISPERDAL.
ExamplesExamples of drugs that may potentially interact or that were shown not to interact with risperidone are listed below:
Effect of other medicinal products on the pharmacokinetics of risperidoneAntibacterials:• Erythromycin, a moderate CYP3A4 inhibitor and P-gp inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction.• Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentrations of the active antipsychotic fraction.Anticholinesterases:• Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.Antiepileptics:• Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be observed with e.g. phenytoin and phenobarbital which also induce CYP 3A4 hepatic enzyme, as well as P-glycoprotein.• Topiramate modestly reduced the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.Antifungals:• Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.• Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200mg/day increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxyrisperidone.Antipsychotics:• Phenothiazines may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.Antivirals:• Protease inhibitors: No formal study data are available; however, since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction. Beta blockers: • Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.Calcium channel blockers:• Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases the plasma concentration of risperidone and the active antipsychotic fraction.Gastrointestinal drugs:• H2-receptor antagonists: Cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.SSRIs and Tricyclic antidepressants:• Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but less so of the active antipsychotic fraction. • Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentrations of risperidone, but, at dosages up to 20 mg/day, less so of the active antipsychotic fraction. However, higher doses of paroxetine may elevate concentrations of the risperidone active antipsychotic fraction. • Tricyclic antidepressants 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.• Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.
Effect of risperidone on the pharmacokinetics of other medicinal productsAntiepileptics:• Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate.Antipsychotics:• Aripiprazole, a CYP2D6 and CYP3A4 substrate: Risperidone tablets or injections did not affect the pharmacokinetics of the sum of aripiprazole and its active metabolite, dehydroaripiprazole.Digitalis glycosides:• Risperidone does not show a clinically relevant effect on the pharmacokinetics of digoxin.Lithium:• Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium.
Concomitant use of risperidone with furosemide• See section 4.4 regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
PregnancyThere are no adequate data from the use of risperidone in pregnant women. 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. Neonates exposed to antipsychotics (including RISPERDAL CONSTA) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.RISPERDAL CONSTA should not be used during pregnancy unless clearly necessary.
Breast-feedingIn 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.
FertilityAs with other drugs that antagonize dopamine D2 receptors, RISPERDAL CONSTA elevates prolactin level. 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.There were no relevant effects observed in the non-clinical studies.
|System Organ Class||Adverse Drug Reaction|
|Very common||Common||Uncommon||Rare||Very Rare|
|Infections and infestations||upper respiratory tract infection||pneumonia, bronchitis, sinusitis, urinary tract infection, influenza||respiratory tract infection, cystitis, ear infection, eye infection, tonsillitis, onychomycosis, cellulitis, infection, localised infection, viral infection, acarodermatitis, subcutaneous abscess|
|Blood and lymphatic system disorders||anaemia||white blood cell count decreased, thrombocytopenia, haematocrit decreased||agranulocytosisc, neutropenia, eosinophil count increased|
|Immune system disorders||hypersensitivity||anaphylactic reactionc|
|Endocrine disorders||hyperprolactinaemiaa||glucose urine present||inappropriate antidiuretic hormone secretion|
|Metabolism and nutrition disorders||hyperglycaemia, weight increased, increased appetite, weight decreased, decreased appetite||diabetes mellitusb, anorexia, blood triglycerides increased, blood cholesterol increased||water intoxicationc, hypoglycemia, hyperinsulinaemiac, polydipsia||diabetic ketoacidosis|
|Psychiatric disorders||insomniad, depression, anxiety||sleep disorder, agitation, libido decreased||mania, confusional state, anorgasmia, nervousness, nightmare||blunted affect|
|Nervous system disorders||parkinsonismd, headache||sedation/ somnolence, akathisiad, dystoniad, dizziness, dyskinesiad, tremor||tardive dyskinesia, cerebral ischaemia, loss of consciousness, convulsiond, syncope, psychomotor hyperactivity, balance disorder, coordination abnormal, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paraesthesia||neuroleptic malignant syndrome, cerebrovascular disorder, unresponsive to stimuli, depressed level of consciousness, diabetic coma, head titubation|
|Eye disorders||vision blurred||conjunctivitis, dry eye, lacrimation increased, ocular hyperaemia||retinal artery occlusion, glaucoma, eye movement disorder, eye rolling, photophobia, eyelid margin crusting, floppy iris syndrome (intraoperative)c|
|Ear and labyrinth disorders||vertigo, tinnitus, ear pain|
|Cardiac disorders||tachycardia||atrial fibrillation, atrioventricular block, conduction disorder, electrocardiogram QT prolonged, bradycardia, electrocardiogram abnormal, palpitations||sinus arrhythmia|
|Vascular disorders||hypotension, hypertension||orthostatic hypotension||pulmonary embolism, venous thrombosis, flushing|
|Respiratory, thoracic and mediastinal disorders||dyspnoea, pharyngolaryngeal pain, cough, nasal congestion||hyperventilation , respiratory tract congestion, wheezing, epistaxis||sleep apnoea syndrome, pneumonia aspiration, pulmonary congestion, rales, dysphonia, respiratory disorder|
|Gastrointestinal disorders||abdominal pain, abdominal discomfort, vomiting, nausea, constipation, gastroenteritis, diarrhoea, dyspepsia, dry mouth, toothache||faecal incontinence, dysphagia, flatulence||pancreatitis, intestinal obstruction, swollen tongue, faecaloma, cheilitis||ileus|
|Skin and subcutaneous tissue disorders||rash||pruritus, alopecia, eczema, dry skin, erythema, skin discolouration, acne, seborrhoeic dermatitis||drug eruption, urticaria, hyperkeratosis, dandruff, skin disorder, skin lesion||angioedema|
|Musculoskeletal and connective tissue disorders||muscle spasms, musculoskeletal pain, back pain, arthralgia||blood creatine phosphokinase increased, joint stiffness, joint swelling, muscular weakness, neck pain||rhabdomyolysis, posture abnormal|
|Renal and urinary disorders||urinary incontinence||pollakiuria, urinary retention, dysuria|
|Pregnancy, puerperium, and neonatal conditions||drug withdrawal syndrome neonatalc|
|Reproductive system and breast disorders||erectile dysfunction, amenorrhoea, galactorrhoea||ejaculation disorder, menstruation delayed, menstrual disorderd, gynaecomastia, sexual dysfunction, breast pain, breast discomfort, vaginal discharge||priapismc, breast engorgement, breast enlargement, breast discharge|
|General disorders and administration site conditions||oedemad, pyrexia, chest pain, asthenia, fatigue, pain, injection site reaction||face oedema, chills, body temperature increased, gait abnormal, thirst, chest discomfort, malaise, feeling abnormal, indurationc||hypothermia, body temperature decreased, peripheral coldness, drug withdrawal syndrome, discomfort|
|Hepatobiliary disorders||transaminases increased, gamma- glutamyltransferas increased||hepatic enzyme increased||jaundice|
|Injury, poisoning and procedural complications||fall||procedural pain|
Undesirable effects noted with paliperidone formulationsPaliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. In addition to the above adverse reactions, the following adverse reaction has been noted with the use of paliperidone products and can be expected to occur with RISPERDAL CONSTA.Cardiac disorders : Postural orthostatic tachycardia syndrome
Anaphylactic reactionRarely, cases of anaphylactic reaction after injection with RISPERDAL CONSTA have been reported during postmarketing experience in patients who have previously tolerated oral risperidone.
Class effectsAs 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 thromboembolismCases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic drugs (frequency unknown).
Weight gainIn 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 ≥ 7% of body weight at endpoint. In the 1-year, open-label study of RISPERDAL CONSTA, changes in body weight in individual patients were generally within ±7% from baseline; 25% of patients had an increase in body weight of ≥ 7%.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
SymptomsIn 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-prolongation and convulsions have been reported. Torsade de Pointes has been reported in association with combined overdose of oral RISPERDAL and paroxetine.In case of acute overdose, the possibility of multiple drug involvement should be considered.
TreatmentEstablish 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.
Mechanism of actionRisperidone 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. Although risperidone is a potent D2 antagonist, that is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical antipsychotics. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Clinical efficacyThe effectiveness of RISPERDAL CONSTA (25 mg and 50 mg) in the management of the manifestations of psychotic disorders (schizophrenia/schizoaffective disorder) was established in one 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.In a 12-week comparative trial in stable patients with schizophrenia, RISPERDAL CONSTA was shown to be as effective as the oral tablet formulation. The long-term (50 weeks) safety and efficacy of RISPERDAL CONSTA was also evaluated in an open-label trial of stable psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia or schizoaffective disorder. Over time efficacy was maintained with RISPERDAL CONSTA (Figure 1).Figure 1. Mean in total PANSS score over time (LOCF) in patients with schizophrenia.
AbsorptionThe absorption of risperidone from RISPERDAL CONSTA is complete.After a single intramuscular injection with RISPERDAL CONSTA, the release profile consists of a small initial release of risperidone (<1% of the dose), followed by a lag time of 3 weeks. The main release of risperidone starts from Week 3 onwards, is maintained from 4 to 6 weeks, and subsides by Week 7. Oral antipsychotic supplementation should therefore be given during the first 3 weeks of RISPERDAL CONSTA treatment (see section 4.2).The combination of the release profile and the dosage regimen (intramuscular injection every two weeks) results in sustained therapeutic plasma concentrations. Therapeutic plasma concentrations remain until 4 to 6 weeks after the last RISPERDAL CONSTA injection.After repeated intramuscular injections with 25 or 50 mg RISPERDAL CONSTA every two weeks, median trough and peak plasma concentrations of the active antipsychotic fraction fluctuated between 9.9-19.2 ng/ml and 17.9-45.5 ng/ml respectively. No accumulation of risperidone was observed during long term use (12 months) in patients who were injected with 2550 mg every two weeks.The above studies were conducted with gluteal intramuscular injection. Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.
DistributionRisperidone is rapidly distributed. The volume of distribution is 1-2 l/kg. In plasma, risperidone is bound to albumin and alpha-1-acid glycoprotein. The plasma protein binding of risperidone is 90%; that of the active metabolite 9-hydroxy-risperidone is 77%.
Biotransformation and eliminationRisperidone is metabolised by CYP 2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. CYP 2D6 is subject to genetic polymorphism. Extensive CYP 2D6 metabolisers convert risperidone rapidly into 9-hydroxy-risperidone, whereas poor CYP 2D6 metabolisers convert it much more slowly. Although extensive metabolisers have lower risperidone and higher 9-hydroxy-risperidone concentrations than poor metabolisers, the pharmacokinetics of risperidone and 9-hydroxy-risperidone combined (i.e., the active antipsychotic fraction), after single and multiple doses, are similar in extensive and poor metabolisers of CYP 2D6. Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human liver microsomes showed that risperidone at clinically relevant concentration does not substantially inhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including CYP 1A2, CYP 2A6, CYP 2C8/9/10, CYP 2D6, CYP 2E1, CYP 3A4, and CYP 3A5. One week after oral risperidone administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxy-risperidone represent 35-45% of the orally administered dose. The remainder is inactive metabolites. The elimination phase is complete approximately 7 to 8 weeks after the last RISPERDAL CONSTA injection.
LinearityThe pharmacokinetics of risperidone are linear in the dose range of 25-50 mg injected every 2 weeks.
Elderly, hepatic and renal impairmentA single-dose PK-study with oral risperidone showed on average a 43% higher active antipsychotic fraction plasma concentrations, a 38% longer half-life and a reduced clearance of the active antipsychotic fraction by 30% in the elderly. In adults with moderate renal disease the clearance of the active moiety was ~48% of the clearance in young healthy adults. In adults with severe renal disease the clearance of the active moiety was ~31% of the clearance in young healthy adults. The half-life of the active moiety was 16.7 h in young adults, 24.9 h in adults with moderate renal disease (or ~1.5 times as long as in young adults), and 28.8 h in those with severe renal disease (or ~1.7 times as long as in young adults). Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by 37.1%.The oral clearance and the elimination half-life of risperidone and of the active moiety in adults with moderate and severe liver impairment were not significantly different from those parameters in young healthy adults.
Pharmacokinetic/pharmacodynamic relationshipThere was no relationship between the plasma concentrations of the active antipsychotic fraction and the change in total PANSS (Positive And Negative Syndrome Scale) and total ESRS (Extrapyramidal Symptom Rating Scale) scores across the assessment visits in any of the phase-III trials where efficacy and safety was examined.
Gender, race and smoking habitsA population pharmacokinetic analysis revealed no apparent effect of gender, race or smoking habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.
SolventPolysorbate 20 Carmellose sodium Disodium hydrogen phosphate dihydrate Citric acid anhydrousSodium chloride Sodium hydroxide Water for injection.
Needle-Free Vial Access Device• One vial containing powder for prolonged-release suspension for injection • One West-Medimop Vial Adapter® for reconstitution (referred as Vial Adapter) • One prefilled syringe containing the solvent for RISPERDAL CONSTA • Two Terumo SurGuard®3 needles for intramuscular injection (a 21G UTW 1-inch (0.8 mm x 25 mm) safety needle with needle protection device for deltoid administration and a 20G TW 2-inch (0.9 mm x 51 mm) safety needle with needle protection device for gluteal administration).
Instructions for Needle-Free Vial Access Device
|RISPERDAL CONSTA requires close attention to the step-by-step 'Instructions for Use' to help ensure successful administration and help avoid difficulties in the use of the kit.RISPERDAL CONSTA extended release microspheres in the vial must be reconstituted only in the solvent in the syringe supplied in the dose pack, and must be administered with only the appropriate needle supplied in the dose pack for gluteal (2-inch (50 mm) needle) or deltoid (1-inch (25 mm) needle) administration. Do not substitute any components in the dose pack. To assure that the intended dose of risperidone is delivered, the full contents from the vial must be administered. Administration of partial contents may not deliver the intended dose of risperidone. It is recommended to administer immediately after reconstitution.|
Do not touch the spike tip of the access device at any time.3. It is very important that the SmartSite® Needle-Free Vial Access Device be placed on the vial correctly or the diluent could leak upon transfer to the vial.Place the vial on a hard surface. Hold the base of the vial. Orient the SmartSite® Needle-Free Vial Access Device vertically over the vial so that the spike tip is at the center of the vial's rubber stopper. With a straight downward push, press the spike tip of the SmartSite® Needle-Free Vial Access Device through the center of the vial's rubber stopper until the device securely snaps onto the vial top.Correct Incorrect 4. Hold the base of the vial and swab the syringe connection point (blue circle) of the SmartSite® Needle-Free Vial Access Device with an alcohol wipe and allow to dry prior to attaching the syringe to the SmartSite® Needle-Free Vial Access Device. 5. The prefilled syringe has a white tip consisting of 2 parts: a white collar and a smooth white cap. To open the syringe, hold the syringe by the white collar and snap off the smooth white cap (DO NOT TWIST OR CUT OFF THE WHITE CAP). Remove the white cap together with the rubber tip cap inside. For all syringe assembly steps, hold the syringe only by the white collar located at the tip of the syringe. Holding the white collar will help to prevent the white collar from getting detached and ensure a good connection to the syringe. Be careful not to overtighten components when assembling. Overtightening connections may cause syringe component parts to loosen from the syringe body. 6. While holding the white collar of the syringe, insert and press the syringe tip into the blue circle of the SmartSite® Needle-Free Vial Access Deviceand twist in a clockwise motion to secure the connection of the syringe to the SmartSite® Needle-Free Vial Access Device (avoid over tightening). Hold the skirt of the vial access device during attachment to prevent it from spinning.Keep the syringe and the SmartSite® Needle-Free Vial Access Devicealigned.7. Inject the entire contents of the syringe containing the solvent into the vial. 8. Shake the vial VIGOROUSLY while holding the plunger rod down with the thumb for a minimum of 10 seconds to ensure a homogeneous suspension. When properly mixed, the suspension appears uniform, thick, and milky in colour. The microspheres will be visible in liquid, but no dry microspheres remain.
|DO NOT STORE THE VIAL AFTER RECONSTITUTION OR THE SUSPENSION MAY SETTLE.|
|14. RESUSPENSION OF RISPERDAL CONSTA WILL BE NECESSARY PRIOR TO ADMINISTRATION, AS SETTLING WILL OCCUR OVER TIME ONCE PRODUCT IS RECONSITITUTED. RESUSPEND THE MICROSPHERES IN THE SYRINGE BY SHAKING VIGOROUSLY.|
DO NOT ADMINISTER INTRAVENOUSLY.
|WARNING: To avoid a needle stick injury with a contaminated needle: • Do not use free hand to press the Needle-Pro safety device over the needle. • Do not intentionally disengage the Needle-Pro safety device. • Do not attempt to straighten the needle or engage Needle-Pro safety device if the needle is bent or damaged. • Do not mishandle the Needle-Pro safety device as it may cause the needle to protrude from the Needle-Pro safety device.|
50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG
+44 (0)1494 567 568
+44 (0) 1494 567 445
+44 (0)1494 567 567
+44 (0)800 731 8450
+44 (0)800 731 5550