Risperidone-Chanelle

Risperidone.

Each ml contains 1 mg of risperidone.
Excipients/Inactive Ingredients: Tartaric acid (E334), Benzoic acid (E210), Hydrochloric acid concentrated for pH adjustment, Purified water.

Pharmacotherapeutic group: Other antipsychotics. ATC code: N05AX08.
Pharmacology: Pharmacodynamics: Mechanism of action: Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for both serotonergic 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, an activity which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical neuroleptics. Balanced central serotonin and dopamine antagonism may reduce the tendency to cause extrapyramidal side effects, and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Pharmacokinetics: Risperidone is metabolised to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone (see Biotransformation and Elimination as follows).
Absorption: Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) compared with a solution. The absorption is not affected by food and thus Risperidone can be given with or without meals. Steady-state of 9-hydroxy-risperidone is reached within 4-5 days of dosing.
Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 l/kg. In plasma, risperidone is bound to albumin and alpha₁-acid glycoprotein. The plasma protein binding of risperidone is 90%, that of 9-hydroxyrisperidone is 77%.
Biotransformation and elimination: Risperidone 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 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 dose. The remainder is inactive metabolites. After oral administration to psychotic patients, risperidone is eliminated with a half-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours.
Linearity: Risperidone plasma concentrations are dose-proportional within the therapeutic dose range.
Elderly, hepatic and renal impairment: A single-dose study 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. Higher active antipsychotic fraction plasma concentrations and a reduced clearance of the active antipsychotic fraction by on average 60% were observed in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by about 35%.
Paediatric patients: The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children are similar to those in adults.
Gender, race and smoking habits: A population pharmacokinetic analysis revealed no apparent effect of gender, race or smoking habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Toxicology: Preclinical safety data: In (sub)chronic toxicity studies, in which dosing was started in sexually immature rats and dogs, dose dependant effects were present in male and female genital tract and mammary gland. These effects were related to the increased serum prolactin levels, resulting from the dopamine D2-receptor blocking activity of risperidone. In addition, tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Risperidone was not teratogenic in rat and rabbit. In rat reproduction studies with risperidone, adverse effects were seen on mating behaviour of the parents, and on the birth weight and survival of the offspring. In rats, intrauterine exposure to risperidone was associated with cognitive deficits in adulthood. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring. Risperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolactinaemia. The relevance of these tumour findings in rodents in terms of human risk is unknown. In vitro and in vivo, animal models show that at high doses risperidone may cause QT interval prolongation, which has been associated with a theoretically increased risk of torsade de pointes in patients.

Risperidone is indicated for the treatment of schizophrenia. Risperidone alleviates affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia. Risperidone is also effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
Risperidone is indicated as adjunctive therapy to mood stabilizers for the treatment of manic episodes associated with bipolar disorders. These episodes are characterized by symptoms such as elevated, expansive or irritable mood, inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility, or poor judgment, including disruptive or aggressive behaviors.
Risperidone is indicated for the short-term treatment of persistent aggression in patients with moderate to severe dementia of the Alzheimer's type unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.
Risperidone is indicated in the treatment of conduct and other disruptive behavior disorders in children (over 5 years), adolescents and adults with subaverage intellectual functioning or mental retardation in whom destructive behaviors (e.g. aggression, impulsivity and self-injurious behaviors) are prominent.

1 ml of Risperidone Oral Solution contains 1 mg risperidone. The liquid may be diluted with mineral water, orange juice or black coffee (see Cautions for Usage).
Schizophrenia: Adults: Risperidone may be given once daily or twice daily.
Patients should start with 2 mg/day risperidone. The dosage may be increased on the second day to 4 mg. Subsequently, the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.
Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and may cause increased incidence of extrapyramidal symptoms. Safety of doses above 16 mg/day has not been evaluated, and are therefore not recommended.
Elderly: A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily.
Paediatric population: Risperidone is not recommended for use in children below age 18 with schizophrenia due to a lack of data on efficacy.
Manic episodes in bipolar mania: Adults: Risperidone should be administered once daily, starting with 2 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. Risperidone can be administered in flexible doses over a range of 1 to 6 mg per day to optimize each patient's level of efficacy and tolerability. Daily doses over 6 mg risperidone have not been investigated in patients with manic episodes. The physician who elects to use risperidone for periods extending beyond 12 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an ongoing basis.
Paediatric population: Risperidone is not recommended for use in children below age 18 with bipolar mania due to a lack of data on efficacy.
Persistent aggression in patients with moderate to severe Alzheimer's dementia: A starting dose of 0.25 mg twice daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg twice daily, not more frequently than every other day, if needed. The optimum dose is 0.5 mg twice daily for most patients. Some patients, however, may benefit from doses up to 1 mg twice daily.
There is no data to support treatment beyond 12 weeks in patients with moderate to severe dementia of the Alzheimer type with agitation, aggression or psychotic symptoms. During treatment, patients must be evaluated frequently and regularly, and the need for continuing treatment reassessed.
Conduct disorders: Children and adolescents from 5 to 18 years of age: Patients weighing more than 50 kg: A starting dose of 0.5 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.5 mg once daily not more frequently than every other day, if needed. The optimum dose is 1 mg once daily for most patients. Some patients, however, may benefit from 0.5 mg once daily while others may require 1.5 mg once daily.
Patients weighing less than 50 kg: A starting dose of 0.25 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg once daily not more frequently than every other day, if needed. The optimum dose is 0.5 mg once daily for most patients, although some patients may benefit from 0.25 mg once daily while others may require 0.75 mg once daily.
As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an on-going basis.
Risperidone is not recommended in children less than 5 years of age, as there is no experience in children less than 5 years of age with this disorder.
Renal and hepatic impairment: Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than in adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.
Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal or hepatic impairment.
Risperidone should be used with caution in these groups of patients.
Method of administration: Risperidone is for oral use. Food does not affect the absorption of risperidone.
Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic medicines (see Adverse Reactions). Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported.
Switching from other antipsychotics: When medically appropriate, gradual discontinuation of the previous treatment while risperidone therapy is initiated is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medicines should be re-evaluated periodically.

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-prolongation and convulsions have been reported. Torsade de Pointes has been reported in association with combined overdose of risperidone and paroxetine.
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. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered only when drug intake was less than one hour before. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to risperidone. 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 medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Risperidone is contraindicated in patients with a known hypersensitivity to risperidone or any other ingredients in the product.

Cerebrovascular Adverse Events (CVAE): 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.
Risperidone 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 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.
Risperidone 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 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, hypovolaemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see Dosage & Administration). A dose reduction should be considered if hypotension occurs.
Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS): Medicines with dopamine receptor antagonist 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 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 have been reported to occur with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In such an 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 risperidone, 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: Hyperglycemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported in patients treated with atypical antipsychotics, including risperidone. 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 risperidone should be monitored for symptoms of hyperglycemia and diabetes mellitus. 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.
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 risperidone 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.
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. Risperidone 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: Risperidone 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 risperidone 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 risperidone 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.
Effects on ability to drive and use machines: Risperidone 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.
Use in Children: Children and adolescents: 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.
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 have not been adequately studied.
Because of the potential effects of prolonged hyperprolactinemia 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.
During treatment with risperidone regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.
For specific posology recommendations in children and adolescents see Dosage & Administration.
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 Risperidon Oral Solution and preventive measures undertaken.
Use in the Elderly: Elderly patients with dementia: Overall Mortality: Elderly patients with dementia treated with atypical antipsychotic drugs have 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).
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 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 medication with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Pregnancy: There are no adequate data from the use of risperidone in pregnant women. Neonates exposed to antipsychotics (including Risperidone) 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. Consequently newborns should be monitored carefully.
Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. Therefore, risperidone should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.
Lactation: In animal studies, risperidone and 9-hydroxyrisperidone 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 reactions in breast-feeding infants. Therefore, women receiving risperidone should not breast-feed.

The most frequently reported adverse drug reactions (ADRs) (incidence ≥10%) are: Parkinsonism, headache, and insomnia.
The following are all the ADRs that were reported in clinical trials and postmarketing. The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available clinical trial data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse Drug Reactions by System Organ Class and Frequency: Investigations: Common: Blood prolactin increased^a, Weight increased.
Uncommon: Electrocardiogram QT prolonged, Electrocardiogram abnormal, Blood glucose increased, Transaminases increased, White blood cell count decreased, Body temperature increased, Eosinophil count increased, Haemoglobin decreased, Blood creatine phosphokinase increased.
Rare: Body temperature decreased.
Cardiac disorders: Common: Tachycardia.
Uncommon: Atrioventricular block, Bundle branch block, Atrial fibrillation, Sinus, Bradycardia, Palpitations.
Blood and lymphatic system disorders: Uncommon: Anaemia, Thrombocytopenia.
Rare: Granulocytopenia.
Not known: Agranulocytosis.
Nervous system disorders: Very common: Parkinsonism^b, Headache.
Common: Akathisia^b, Dizziness, Tremor^b, Dystonia^b, Somnolence, Sedation, Lethargy, Dyskinesia^b.
Uncommon: Unresponsive to stimuli, Loss of consciousness, Syncope, Depressed level of consciousness, Cerebrovascular accident, Transient ischaemic attack, Dysarthria, Disturbance in attention, Hypersomnia, Dizziness postural, Balance disorder, Tardive dyskinesia, Speech disorder, Coordination abnormal, Hypoaesthesia.
Rare: Neuroleptic malignant syndrome, Diabetic coma, Cerebrovascular disorder, Cerebral ischaemia, Movement disorder.
Eye disorders: Common: Vision blurred.
Uncommon: Conjunctivitis, Ocular hyperaemia, Eye discharge, Eye swelling, Dry eye, Lacrimation increased, Photophobia.
Rare: Visual acuity reduced, Eye rolling, Glaucoma.
Ear and labyrinth disorders: Uncommon: Ear pain, Tinnitus.
Respiratory, thoracic and mediastinal disorders: Common: Dyspnoea, Epistaxis, Cough, Nasal congestion, Pharyngolaryngeal pain.
Uncommon: Wheezing, Pneumonia aspiration, Pulmonary congestion, Respiratory disorder, Rales, Respiratory tract congestion, Dysphonia.
Rare: Sleep apnea syndrome, Hyperventilation.
Gastrointestinal disorders: Common: Vomiting, Diarrhoea, Constipation, Nausea, Abdominal pain, Dyspepsia, Dry mouth, Stomach discomfort.
Uncommon: Dysphagia, Gastritis, Faecal incontinence, Faecaloma.
Rare: Intestinal obstruction, Pancreatitis, Lip swelling, Cheilitis.
Renal and urinary disorders: Common: Enuresis.
Uncommon: Dysuria, Urinary incontinence, Pollakiuria.
Skin and subcutaneous tissue disorders: Common: Rash, Erythema.
Uncommon: Angioedema, Skin lesion, Skin disorder, Pruritus, Acne, Skin discolouration, Alopecia, Seborrhoeic dermatitis, Dry skin, Hyperkeratosis
Rare: Dandruff.
Musculoskeletal and connective tissue disorders: Common: Arthralgia, Back pain, Pain in extremity.
Uncommon: Muscular weakness, Myalgia, Neck pain, Joint swelling, Posture abnormal, Joint stiffness, Musculoskeletal chest pain.
Rare: Rhabdomyolysis.
Endocrine disorders: Rare: Inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders: Common: Increased appetite, Decreased appetite.
Uncommon: Anorexia, Polydipsia.
Very rare: Diabetic ketoacidosis.
Not known: Water intoxication.
Infections and infestations: Common: Pneumonia, Influenza, Bronchitis, Upper respiratory tract infection, Urinary tract infection.
Uncommon: Sinusitis, Viral infection, Ear infection, Tonsillitis, Cellulitis, Otitis media, Eye infection, Localised infection, Acarodermatitis, Respiratory tract infection, Cystitis, Onychomycosis.
Rare: Otitis media chronic.
Vascular disorders: Uncommon: Hypotension, Orthostatic hypotension, Flushing.
Not known: Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs.
General disorders and administration site conditions: Common: Pyrexia, Fatigue, Peripheral oedema, Asthenia, Chest pain.
Uncommon: Face oedema, Gait disturbance, Feeling abnormal, Sluggishness, Influenza like illness, Thirst, Chest discomfort, Chills.
Rare: Generalised oedema, Hypothermia, Drug withdrawal syndrome, Peripheral coldness.
Immune system disorders: Uncommon: Hypersensitivity.
Rare: Drug hypersensitivity.
Not known: Anaphylactic reaction.
Hepatobiliary disorders: Rare: Jaundice.
Reproductive system and breast disorders: Uncommon: Amenorrhoea, Sexual dysfunction, Erectile dysfunction, Ejaculation disorder, Galactorrhoea, Gynaecomastia, Menstrual disorder, Vaginal discharge.
Not known: Priapism.
Psychiatric disorders: Very common: Insomnia.
Common: Anxiety, Agitation, Sleep disorder.
Uncommon: Confusional state, Mania, Libido decreased, Listless, Nervousness.
Rare: Anorgasmia, Blunted affect.
Pregnancy, puerperium and perinatal conditions: Not known: Drug withdrawal syndrome neonatal (see Use in Pregnancy & Lactation).
^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.
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.
Weight gain: The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for risperidone (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥7% at endpoint was comparable in the risperidone (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%).
In a population of children and adolescents with conduct and other disruptive behaviour disorders, in long term studies, weight increased by a mean of 7.3 kg after 12 months of treatment. The expected weight gain for normal children between 5-12 years of age is 3 to 5 kg per year. From 12-16 years of age, this magnitude of gaining 3 to 5 kg per year is maintained for girls, while boys gain approximately 5 kg per year.
Additional information on special populations: Adverse drug reactions that were reported with higher incidence in elderly patients with dementia or paediatric patients than in adult populations are described as follows: Elderly patients with dementia: Transient ischaemic attack and cerebrovascular accident were ADRs reported in clinical trials with a frequency of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, the following ADRs were reported with a frequency ≥5% in elderly patients with dementia and with at least twice the frequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy, and cough.
Paediatric patients: The following ADRs were reported with a frequency ≥5% in paediatric patients (5 to 17 years) and with at least twice the frequency seen in clinical trials in adults: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infection, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhoea, and enuresis.

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 antidepressant (i.e. amitriptyline), tetracyclic antidepressants (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 risperidone to affect other medicinal products: Risperidone it 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.
Risperidone 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.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium, valproate, digoxin or topiramate.
Potential for other medicinal products to affect risperidone: Carbamazepine has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be 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-glycoprotein (P-gp) inducers are initiated or discontinued, the physician should re-evaluate the dosing of risperidone.
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 risperidone.
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 increased 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 Precautions regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
Concomitant use of oral risperidone 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.

Incompatibilities: This medicinal product must not be mixed with other products except those mentioned in Special precautions for disposal as follows. This medicinal product is incompatible with tea.
Special precautions for disposal: If necessary, Risperidone Oral Solution may be diluted with mineral water, orange juice or black coffee. When diluted in this way, it is recommended that it is used immediately in order to avoid the risk of inadvertent consumption.
Instructions for Use/Handling: A special dosing pipette is supplied with each pack of Risperidone Oral Solution.
Instructions for using the pipette with Risperidone Oral Solution: 1. Remove the child-proof cap from the bottle by pushing down on the cap while turning it anti-clockwise.
2. Place the bottle on a flat surface.
3. Insert the pipette into the solution in the bottle.
4. While holding the lower ring, pull the top ring upwards until the mark that matches the number of mg or ml to be taken is just visible.
5. Holding the lower ring, remove the whole pipette from the bottle.
6. To empty the pipette, push down on the top ring while still holding the lower ring.
7. The contents of the pipette may be emptied directly into the mouth or into a drink of mineral water, orange juice or black coffee.
8. Rinse the pipette with water.
9. Replace the child-proof cap on the bottle by screwing it down clockwise until it locks fully.

Shelf life: Unopened: 3 years.
Opened: 4 months.
Once diluted with mineral water, orange juice or black coffee the product is stable for up to 4 hours below 25°C, although it is recommended that once diluted in this way Risperidone Oral Solution is used immediately in order to avoid risk of inadvertent consumption.
Unopened: Store at or below 30°C in the original package. Do not freeze.
Opened: Store at or below 25°C. Do not freeze.

Antipsychotics

N05AX08 - risperidone ; Belongs to the class of other antipsychotics.

POM