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1 PACKAGE INSERT SCHEDULING STATUS Schedule 5 PROPRIETARY NAME AND DOSAGE FORM RISPERDAL 1 mg/ml oral solution COMPOSITION Each ml contains risperidone 1 mg. Preservatives: Benzoic acid 0,2 % m/v The solution also contains tartaric acid, benzoic acid, sodium hydroxide and purified water. PHARMACOLOGICAL CLASSIFICATION A Central nervous system depressants. Miscellaneous structures. PHARMACOLOGICAL ACTION Pharmacodynamics: Risperidone is an antipsychotic of the benzisoxazol derivatives. It is a selective monoaminergic antagonist. Risperidone has affinity for serotonin-5-ht 2, dopamine-d 2, H 1 - histamine, α 1 - and α 2 -adrenergic receptors. Risperidone has no affinity for cholinergic receptors. It is a dopamine D 2 -antagonist. Pharmacokinetics: Risperidone is completely absorbed after oral administration. Peak plasma concentrations are attained within 1 to 2 hours. Food does not affect the absorption of risperidone. Risperidone is metabolised by cytochrome CYP2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone. Risperidone and 9-hydroxy-risperidone form the active antipsychotic fraction. CCDS Jan 2013 Page 1 of 38

2 After oral administration to psychotic patients, risperidone's half-life is about 3 hours. The elimination half-life of 9-hydroxy-risperidone and the active antipsychotic fraction is 24 hours. Steady state is reached within 1 day for risperidone in most patients and 4-5 days for 9-hydroxy-risperidone. Risperidone plasma concentration is dose-proportional within the therapeutic dose-range. Risperidone is bound to albumin and alpha 1 -acid glycoprotein. Plasma protein binding of risperidone is 88 % and 77 % for 9-hydroxy-risperidone. One week after administration, 70 % of the dose is excreted in the urine and 14 % in the faeces. In urine, risperidone and 9-hydroxy-risperidone represent % of the dose. A single dose study showed higher active plasma concentrations and a reduced clearance of the active antipsychotic fraction by 30 % in the elderly and 50 % in patients with moderate renal insufficiency. In patients with severe renal insufficiency the clearance was one third that of normal. The plasma concentrations of risperidone were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by about 35 %. The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active moiety in children are similar to those in adults. INDICATIONS RISPERDAL is indicated for the treatment of: Acute and chronic schizophrenic psychoses and related psychosis in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness) and/or the negative symptoms (such as blunted affect, emotional and social CCDS Jan 2013 Page 2 of 38

3 withdrawal, poverty of speech) are prominent. RISPERDAL also alleviates affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia. In patients who have shown an initial treatment response, RISPERDAL is also effective in maintaining the clinical improvement. Mania in bipolar disorder. These episodes are characterised 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 behaviours. Conduct and other disruptive behaviour disorders in children (aged 5 12 years), with subaverage intellectual functioning or mental retardation in whom destructive behaviours (e.g. aggression, impulsivity and self-injurious behaviours) are prominent. CONTRA-INDICATIONS RISPERDAL is contra-indicated in patients with known sensitivity to any of the components of the medicine. Conduct and other disruptive behaviour disorders in children: RISPERDAL is contra-indicated in children under 5 years of age as efficacy and safety in these children have not been demonstrated. Parkinson s disease and Lewy Body Dementia (see WARNINGS) WARNINGS and SPECIAL PRECAUTIONS Elderly Patients with Dementia (See Interactions ) Overall Mortality Elderly patients with dementia treated with atypical antipsychotic medicines have an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic medicines, including RISPERDAL. In placebo-controlled trials with oral CCDS Jan 2013 Page 3 of 38

4 RISPERDAL in this population, the incidence of mortality was 4,0 % for RISPERDAL-treated patients compared to 3,1 % for placebo-treated patients. The mean age (range) of patients who died was 86 years (range ). Concomitant use with furosemide (see INTERACTIONS) In RISPERDAL placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide and RISPERDAL (7,3 %; mean age 89 years, range 75-97) when compared to patients treated with RISPERDAL 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 RISPERDAL was observed in two of the four clinical trials. 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 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 RISPERDAL. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia. Cerebrovascular Adverse Events (CAE) In placebo-controlled clinical trials in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischaemic attacks), including fatalities, in patients treated with RISPERDAL compared to patients receiving placebo (mean age 85 years; range years). Orthostatic Hypotension Due to the alpha-blocking activity of RISPERDAL, (orthostatic) hypotension can occur, especially during the initial dose-titration period. RISPERDAL should be used with caution in CCDS Jan 2013 Page 4 of 38

5 patients with known cardiovascular disease, and the dosage should be gradually titrated as recommended. A dose reduction should be considered if hypotension occurs. Leukopenia, Neutropenia, and Agranulocytosis Events of leucopenia, neutropenia and agranulocytosis have been reported with RISPERDAL. Agranulocytosis has been reported during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a medicine-induced leukopenia/neutropenia should be monitored during therapy and discontinuation of RISPERDAL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1 X 10 9 /L) should discontinue RISPERDAL and have their WBC followed until recovery. Venous thromboembolism Cases of venous thromboembolism (VTE) have been reported with RISPERDAL. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with RISPERDAL and preventive measures undertaken. Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS) RISPERDAL has been associated with the induction of tardive dyskinesia (TD) characterised by potentially irreversible rhythmical involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk CCDS Jan 2013 Page 5 of 38

6 factor for the development of tardive dyskinesia.td appears to be most prominent in the elderly especially elderly females. If signs and symptoms of tardive dyskinesia appear, the discontinuation of RISPERDAL should be considered. Neuroleptic Malignant Syndrome (NMS) Neuroleptic Malignant Syndrome, a potentially fatal symptom complex, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels has been reported to occur in association with RISPERDAL. Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, RISPERDAL, should be discontinued. Parkinson s disease/lewy Body dementia and NMS Patients with Parkinson s disease or Dementia with Lewy Bodies (DLB) have an increased risk of Neuroleptic Malignant Syndrome (NMS) as well as having an increased sensitivity to antipsychotic medications (see CONTRA-INDICATIONS). Manifestation of this increased sensitivity can include confusion, obtundation and postural instability with frequent falls, in addition to extrapyramidal symptoms. In addition, in clinical trials, elderly patients have a higher mortality than placebo treated elderly patients. (see CONTRA-INDICATIONS). Hyperglycaemia and diabetes mellitus Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with RISPERDAL. Patients with an established diagnosis of diabetes mellitus who are starting on RISPERDAL medications should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with RISPERDAL medications should be monitored for symptoms of hyperglycaemia including CCDS Jan 2013 Page 6 of 38

7 polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with RISPERDAL medications should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when RISPERDAL medications were discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL. Weight gain Significant weight gain has been reported. Monitoring weight gain is advisable when RISPERDAL is being used. Patients may be advised to refrain from excessive eating in view of the possibility of weight gain. QT Interval Caution should be exercised when RISPERDAL is prescribed in patients with a history of cardiac dysrhythmias, in patients with congenital long QT syndrome, and in concomitant use with medicines known to prolong the QT interval. Priapism Medicines with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with RISPERDAL during postmarketing surveillance (see SIDE-EFFECTS). Body Temperature Regulation Disruption of the body s ability to reduce core body temperature may occur. Appropriate care is advised when prescribing RISPERDAL to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. CCDS Jan 2013 Page 7 of 38

8 Antiemetic Effect An antiemetic effect was observed in preclinical studies with risperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reye s syndrome, and brain tumor. Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including RISPERDAL. IFIS may increase the risk of eye complications during and after the operation. Current or past use of RISPERDAL should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping RISPERDAL prior to cataract surgery has not been established and must be weighed against the risk of stopping RISPERDAL therapy. Seizures RISPERDAL should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Ability to drive or use machinery RISPERDAL may impair mental alertness. Patients should therefore be advised not to drive or operate machinery until their individual susceptibility is known. INTERACTIONS The risk of using RISPERDAL in combination with other medicines has not been systematically evaluated. Given the primary CNS depressive effects of RISPERDAL, it CCDS Jan 2013 Page 8 of 38

9 should be used with caution in combination with alcohol and other centrally acting medicines. RISPERDAL may antagonise the effect of levodopa and other dopamine agonists. Clinically significant hypotension has been observed postmarketing with concomitant use of RISPERDAL and antihypertensive treatment. (see WARNINGS) Caution is advised when prescribing RISPERDAL with medicines known to prolong the QT interval.(see WARNINGS ) Carbamazepine has been shown to decrease the plasma levels of the active antipsychotic fraction of risperidone. Similar effects may be observed with other CYP3A4 hepatic enzyme inducers. On discontinuation of carbamazepine or other hepatic enzyme inducers, the dosage of RISPERDAL should be re-evaluated and, if necessary, decreased. Fluoxetine and paroxetine, CYP2D6 inhibitors, increase the plasma concentration of risperidone but less so of the active anti-psychotic fraction. When concomitant fluoxetine or paroxetine is initiated or discontinued, the dosing of RISPERDAL should be re-evaluated. Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32 % increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active antipsychotic fraction. 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. CCDS Jan 2013 Page 9 of 38

10 Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentration of risperidone but not that 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 CYP3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction. The cholinesterase inhibitors, galantamine and donepezil, do not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction. When RISPERDAL is taken together with other highly protein-bound medicines (e.g. diazepam, warfarin, digoxin, imipramine and propranolol), there is no clinically relevant displacement of either agent from the plasma proteins. RISPERDAL does not show a clinically relevant effect on the pharmacokinetics of lithium, valproate, digoxin or topiramate. There is increased mortality in elderly patients with dementia concomitantly receiving furosemide and RISPERDAL. (see WARNINGS ) Food does not affect the absorption of RISPERDAL. PREGNANCY AND LACTATION The safety of RISPERDAL in pregnancy and lactating women has not been established. CCDS Jan 2013 Page 10 of 38

11 Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed. No teratogenic effect of risperidone was noted in any study. Neonates exposed to antipsychotic medicines (including RISPERDAL) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in the neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Therefore, RISPERDAL should only be used during pregnancy if the benefits outweigh the risks. 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. Therefore, women receiving RISPERDAL should not breastfeed. DOSAGE AND DIRECTIONS FOR USE Schizophrenia Switching from other antipsychotics to RISPERDAL: When medically appropriate, gradual discontinuation of the previous treatment, while RISPERDAL therapy is initiated, is recommended. Also if medically appropriate, when switching patients from depot antipsychotics, initiate RISPERDAL therapy in place of the next scheduled injection. The need for continuing existing anti-parkinsons medications should be re-evaluated periodically. Adults: RISPERDAL may be given once or twice daily. CCDS Jan 2013 Page 11 of 38

12 Patients should start with 2 mg/day RISPERDAL. The dosage may be increased on the second day to 4 mg/day. From then on, the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses of between 4 mg/day and 8 mg/day. Doses above 6 mg/day (when administered twice daily) were associated with more extrapyramidal symptoms and other adverse effects and are not generally recommended. In some patients, particularly with first episode acute psychosis, a slower titration phase and a lower starting and maintenance dose may be appropriate. Doses above 10 mg/day have not been shown to be superior in efficacy to lower doses and may cause an increased incidence of side-effects such as extrapyramidal symptoms. Dosages above 10 mg/day should only be considered if the benefits outweigh the risk. The maximum total daily dose is 16 mg/day. A benzodiazepine may be added to RISPERDAL if additional sedation is required. Elderly patients and patients with renal and hepatic impairment. 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 1-2 mg twice daily. Children: Not for children under 15 years as efficacy and safety in children under the age of 15 years have not been demonstrated in schizophrenia. Mania in bipolar disorders RISPERDAL should be administered on a once daily schedule, starting with 2 or 3 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in CCDS Jan 2013 Page 12 of 38

13 dosage increments of 1 mg per day. Efficacy was demonstrated in flexible doses over a range of 1 to 6 mg per day. The continued use of RISPERDAL must be evaluated and justified on an ongoing basis. Experience is lacking in bipolar mania in children and adolescents less than 18 years of age. Conduct and other Disruptive Behaviour Disorders (DBD) in children 5-12 years of age Subjects < 50 kg: A starting dose of 0,01 mg / kg once daily is recommended. This dosage can be individually adjusted by increments of 0,01 mg / kg once daily not more frequently than every other day, if needed. The recommended maintenance dose is 0,02 0,04 mg/kg once daily. The mean dose is 0,03 mg/kg once daily. The continued use of RISPERDAL must be evaluated and justified on an ongoing basis. Experience is lacking in children aged less than 5 years. Renal and liver impairment Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than normal adults. 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. RISPERDAL should be used with caution in these groups of patients. DIRECTIONS FOR OPENING THE BOTTLE AND USING THE PIPETTE To open the bottle and use the pipette: CCDS Jan 2013 Page 13 of 38

14 Fig. 1: The bottle comes with a child resistant cap, and should be opened as follows: - Push the plastic screw cap down while turning it counter clockwise. - Remove the unscrewed cap. Fig. 2: Insert the pipette into the bottle. While holding the bottom ring, pull the top ring up to the mark that corresponds to the number of milliliters or milligrams you need to give. Fig.3: Holding the bottom ring, remove the entire pipette from the bottle. Empty the pipette into any nonalcoholic drink, except for tea, by sliding the upper ring down. Close the bottle. Rinse the pipette with some water. SIDE-EFFECTS Adverse drug reactions (ADR s) reported during clinical trials: ADR s are listed below by system organ class and frequency. Frequencies are defined as: Very common ( 1/10); common ( 1/100, <1/10); uncommon ( 1/1 000, < 1/100); rare ( 1/10 000, < 1/1 000); very rare (< 1/10 000) Investigations: Common: Increased blood prolactin, Increased weight CCDS Jan 2013 Page 14 of 38

15 Uncommon: Abnormal electrocardiogram, increased blood glucose, increased transaminases, decreased white blood cell count, increased body temperature, increased eosinophil count, decreased haemoglobin, increased blood creatine phosphokinase Rare: Decreased body temperature Cardiac disorders: Common: Uncommon: Tachycardia Atrioventricular block, bundle branch block, sinus bradycardia, palpitations Blood and lymphatic system disorders: Uncommon: Rare: Anaemia, neutropenia Granulocytopenia Nervous system disorders Very common: Parkinsonism, headache Common: Akathisia, dizziness, tremor, dystonia, somnolence, sedation, lethargy, dyskinesia 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, head intubation Rare: Neuroleptic malignant syndrome, diabetic coma, cerebrovascular disorder,cerebral ischaemia, movement disorder Eye disorder Common: Uncommon: Vision blurred Conjunctivitis, ocular hyperaemia, eye discharge, eye swelling, dry eye, CCDS Jan 2013 Page 15 of 38

16 lacrimation increased, photophobia Rare: Visual acuity reduced, eye rolling, glaucoma Ear and labyrinth disorders: Uncommon: Ear pain, tinnitus Respiratory, thoracic and mediastinal disorders Common: Uncommon: Dyspnoea, epistaxis, cough, nasal congestion, pharyngolaryngeal pain Wheezing, pneumonia aspiration, pulmonary congestion, respiratory disorder, rales, respiratory tract congestion, dysphonia Rare: Hyperventilation Gastrointestinal disorders Common: Vomiting, diarrhoea, constipation, nausea, abdominal pain, dyspepsia, dry mouth, stomach discomfort Uncommon: Rare: Dysphagia, gastritis, faecal incontinence, faecaloma Lip swelling, cheilitis Renal and urinary disorders Common: Uncommon: : Enuresis Dysuria, urinary incontinence, pollakiuria Skin and subcutaneous tissue disorders Common: Uncommon: Rash, erythema Skin lesion, skin disorder, pruritus, acne, skin discolouration, seborrhoeic dermatitis, dry skin, hyperkeratosis Rare: Dandruff Musculoskeletal and connective tissue disorders Common: Uncommon: Arthralgia, back pain, pain in extremity Muscular weakness, myalgia, neck pain, joint swelling, posture abnormal, joint stiffness, musculoskeletal chest pain Rare: Rhabdomyolysis CCDS Jan 2013 Page 16 of 38

17 Metabolism and nutrition disorders Common: Uncommon: Increased appetite, decreased appetite Anorexia, polydipsia 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 General disorders and administration site conditions Common: Uncommon: Pyrexia, fatigue, peripheral oedema, asthenia, chest pain Face oedema, gait disturbance, feeling abnormal, sluggishness, influenza like illness, thirst, chest discomfort, chills Rare: Generalised oedema, drug withdrawal syndrome, peripheral coldness Immune system disorders Uncommon: Rare: Hypersensitivity Drug hypersensitivity Reproductive system and breast disorders Uncommon: Amenorrhoea, sexual dysfunction, erectile dysfunction, ejaculation Psychiatric disorders disorder, galactorrhoea, gynaecomastia, menstrual disorder, vaginal discharge Very Common: Common: Insomnia Anxiety, agitation, sleep disorder CCDS Jan 2013 Page 17 of 38

18 Uncommon: Rare: Confusional state, decreased libido, listless, nervousness Anorgasmia, blunted affect Adverse drug reactions reported post-marketing: Investigations: Electrocardiogram QT prolongation Cardiac disorders: Atrial fibrillation Blood and lymphatic system disorders: Thrombocytopenia, agranulocytosis Respiratory, thoracic and mediastinal disorders: Sleep apnoea syndrome Gastro-intestinal disorders: Intestinal obstruction, pancreatitis Paralytic Ileus Renal and urinary disorders: Urinary retention Skin and subcutaneous tissue disorder: Angioedema, alopecia Endocrine disorder: Inappropriate antidiuretic hormone secretion Metabolism and nutrition disorder: Diabetic ketoacidosis, water intoxication, diabetes Mellitus, hypoglycaemia, blood cholesterol increased, blood triglycerides increased Immune system disorder: Anaphylactic reaction Psychiatric disorder: Mania CCDS Jan 2013 Page 18 of 38

19 Nervous System Disorder Dysgeusia Eye Disorders Floppy iris syndrome (intraoperative) Hepatobiliary disorders: Jaundice Reproductive system and breast disorders: Priapism Pregnancy, Puerperium and Perinatal Conditions Drug withdrawal syndrome neonatal General disorders: Hypothermia KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Reported signs and symptoms have been those resulting from an exaggeration of the medicine's known pharmacological effects. Symptoms of acute overdosage include drowsiness, sedation, hypotension, tachycardia 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 the case of acute overdosage, the possibility of multiple medicine 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. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible dysrhythmias CCDS Jan 2013 Page 19 of 38

20 Since there is no known antidote if accidental poisoning or overdosage is suspected, 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. IDENTIFICATION A clear, colourless solution PRESENTATION RISPERDAL 1 mg/ml is supplied in 30 ml amber glass bottle with 3 ml pipette. STORAGE INSTRUCTIONS Store at or below 25 ºC. Do not freeze. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBER 30/2.6.5/0215 Nam. Reg. No.: 04/2.6.5/0257 NS 3 CCDS Jan 2013 Page 20 of 38

21 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION JANSSEN PHARMACEUTICA (PTY) LTD (Reg. No. 1980/011122/07) Building 6, Country Club Estate 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATE OF PUBLICATION OF THE PACKAGE INSERT 28 November 2014 CCDS Jan 2013 Page 21 of 38

22 SKEDULERINGSTATUS Skedule 5 EIENDOMSNAAM EN DOSEERVORM RISPERDAL 1 mg/ml orale oplossing SAMESTELLING Elke ml bevat 1 mg risperidoon. Preserveermiddel: Bensoësuur 0,2 % m/v. Die oplossing bevat ook wynsteensuur, bensoësuur, natrium hidroksied en suiwer water FARMAKOLOGIESE KLASSIFIKASIE A Sentrale senuweestelselonderdrukkers. Diverse strukture. FARMAKOLOGIESE WERKING Farmakodinamiese eienskappe RISPERDAL (risperidoon) is ʼn antipsigotiese middel van die bensisoksasoolderivate. Dit is ʼn selektiewe mono-aminergiese antagonis. Risperidoon toon ʼn affiniteit vir serotonien-5ht 2, dopamien-d 2, H 1 -histamien en α 1 - en α 2 -adrenergiese reseptore. Risperidoon besit geen affiniteit vir cholinergiese reseptore nie. Dit is ʼn kragtige D 2 -antagonis. Farmakokinetiese eienskappe Risperidoon word volledig geabsorbeer na orale toediening. Piek plasmakonsentrasies word binne 1 tot 2 ure bereik. Voedsel beïnvloed nie die absorpsie van risperidoon nie. Risperidoon word deur sitochroom CYP2D6 na 9-hidroksierisperidoon gemetaboliseer wat ʼn soortgelyke farmakologiese aktiwiteit as risperidoon het. Risperidoon en 9-hidroksierisperidoon vorm die aktiewe antipsigotiese fraksie. CCDS Jan 2013 Page 22 of 38

23 Die halfleeftyd van risperidoon is ongeveer 3 uur na orale toediening aan psigotiese pasiënte. Die eliminasiehalfleeftyd van 9-hidroksierisperidoon en die aktiewe antipsigotiese fraksie is 24 uur. Vastevlak vir risperidoon word in meeste pasiënte binne 1 dag bereik en 4-5 dae vir 9-hidroksierisperidoon. Plasmakonsentrasies van risperidoon is dosisverwant binne die terapeutiese dosisreikwydte. Risperidoon bind aan albumien en α1-glikoproteïen. Die binding van risperidoon aan plasmaproteïen is 88 % en die van 9-hidroksierisperidoon is 77 %. Een week na toediening word 70 % van die dosis een week na toediening in die urien en 14 % in die stoelgang uitgeskei. In die urien verteenwoordig risperidoon en 9-hidroksierisperidoon % van die dosis. n Enkeldosis studie het hoër aktiewe plasmakonsentrasies en ʼn afname in die suiwering van die aktiewe antipsigotiese fraksie van 30 % in bejaardes en 50 % in pasiënte met matig ontoereikende nierfunksie getoon. In pasiënte met erg ontoereikende nierfunksie was die suiwering een derde van normaal. Die plasmakonsentrasies van risperidoon was normaal in pasiënte met ontoereikende lewerfunksie. Die gemiddelde vrye fraksie van risperidoon in plasma was egter 35 % hoër. Die farmakokinetika van risperidoon, 9-hidroksierisperidoon en die aktiewe antipsigotiese fraksie in kinders was soortgelyk aan dié in volwassenes. INDIKASIES RISPERDAL word aangedui vir die behandeling van: Akute en chroniese skisofreniese psigose en verwante psigose, waar positiewe simptome (soos hallusinasies, waanvoorstellings, gedagte versteurings, vyandelikheid, verdagtheid) en/of negatiewe simptome (soos afgestomptheid, emosionele en sosiale onttrekking, spraak onbevoegdheid) prominent is. RISPERDAL verlig ook die emosionele simptome (soos depressie, skuldgevoelens, angs) wat met skisofrenie gepaard gaan. By pasiënte wat ʼn respons getoon het na die aanvanklike behandeling, sal RISPERDAL ook effektief wees in die instandhouding van die kliniese verbetering. Manie by bipolêre versteuring. Hierdie episodes word gekenmerk deur simptome soos opgewonde, uitbundige of prikkelbare gemoedstoestand, opgeblase eiedunk, verminderde behoefte aan slaap, beklemtoonde spraak, jagende gedagtes, afleibaarheid, swak oordeel, insluitende steurende of aggressiewe optrede. CCDS Jan 2013 Page 23 of 38

24 Gedragsafwykings en ander ontwrigtende optredes by 5 12 jarige kinders, met ondergemiddelde intellektuele funksionering of verstandelike vertraging, by wie vernietigende gedrag (bv. aggressie, impulsiwiteit en selfvernietigingsgedrag) opvallend is. KONTRA-INDIKASIES RISPERDAL word teenaangedui by pasiënte met n bekende gevoeligheid vir die medisyne. Gedragsafwykings en ander ontwrigtende optredes by kinders: Nie vir kinders jonger as 5 jaar nie, aangesien die doeltreffendheid en veiligheid by kinders jonger as 5 jaar nog nie aangetoon is nie. Parkinson se siekte en Lewyliggaam demensie (sien WAARSKUWINGS ). WAARSKUWINGS EN SPESIALE VOORSORGMAATRËELS Bejaarde pasiënte met demensie (Sien INTERAKSIES ) Algehele mortaliteit In vergelyking met ʼn plasebo in ʼn meta-ontleding van 17 beheerde proewe met atipiese antipsigotiese middels, insluitende RISPERDAL, het bejaarde pasiënte met demensie ʼn toename in mortaliteit getoon. In plasebobeheerde proewe met mondelikse RISPERDAL in hierdie populasie, was die insidens van mortaliteit 4,0 % vir RISPERDAL-behandelde pasiënte in vergelyking met 3,1 % vir plasebobehandelde pasiënte. Die gemiddelde ouderdom (reikwydte) van pasiënte wat gesterf het was 86 jaar (reikwydte ). Gelyktydige gebruik saam met furosemied (Sien INTERAKSIES ) In die mondelikse RISPERDAL plasebobeheerde studies in bejaarde pasiënte met demensie, is ʼn groter insidens van mortaliteit in pasiënte wat met furosemied plus RISPERDAL behandel is (7,3 %; gemiddelde ouderdom 89 jaar, reikwydte 75 97) waargeneem, in vergelyking met behandel met RISPERDAL alleen (3,1 %; gemiddelde 84 jaar, reikwydte 70 96) of furosemied alleen (4,1 %; gemiddelde ouderdom 80 jaar, reikwydte 67 90). Die toename in mortaliteit in pasiënte wat met furosemied en RISPERDAL behandel is, is in twee van die vier kliniese proewe waargeneem. Daar is geen patofisiologiese meganisme geïdentifiseer om hierdie bevinding te verklaar nie, en daar is ook nie ʼn konsistente patroon vir die oorsaak van dood waargeneem nie. Desnieteenstaande behoort sorg aan die dag gelê te word en behoort die risiko en voordele van hierdie kombinasie oorweeg te word voordat daar besluit word om dit te CCDS Jan 2013 Page 24 of 38

25 gebruik. Daar was geen toename in die insidens van mortaliteit onder pasiënte wat ander diuretika as meegaande medikasie saam met RISPERDAL geneem het nie. Ongeag die behandeling is dehidrasie ʼn algehele risikofaktor vir mortaliteit en behoort daarom noukeurig in bejaarde pasiënte met demensie vermy te word. Serebrovaskulêre newe-effekte (SNE) In plasebobeheerde proewe in bejaarde pasiënte met demensie, was daar ʼn groter insidens van serebrovaskulêre newe-effekte, (serebrovaskulêre toevalle en verbygaande iskemiese aanvalle), insluitende fataliteite (gemiddelde ouderdom 85 jaar; reikwydte 73 97), in pasiënte wat met RISPERDAL behandel is, teenoor pasiënte wat ʼn plasebo ontvang het. Ortostatiese hipotensie As gevolg van die alfa-blokkerende werksaamheid van RISPERDAL kan (ortostatiese) hipotensie voorkom, veral tydens die aanvanklike dosistitrasie tydperk. RISPERDAL moet met omsigtigheid gebruik word by pasiënte met bekende kardiovaskulêre siekte en die dosis moet geleidelik getitreer word, soos aanbeveel. n Dosisvermindering moet oorweeg word indien hipotensie voorkom. Leukopenie, neutropenie en agranulositose Voorvalle van leukopenie, neutropenie en agranulositose is met RISPERDAL aangemeld. Agranulositose is met na-bemarkingsbewaking aangemeld. Pasiënte met n geskiedenis van n klinies-beduidende lae witbloedseltelling (WBT), of leukopenie/neutropenie veroorsaak deur medisyne, moet gedurende die behandeling gemoniteer word en staking van RISPERDAL moet oorweeg by die eerste tekens van n klinies- beduidende afname in WBT wanneer ander oorsaaklike faktore afwesig is. Pasiënte met klinies beduidende neutropenie moet deeglik gemoniteer word vir koors of ander simptome of tekens van infeksie en moet sonder versuim behandel word indien sulke simptome of tekens voorkom. Pasiënte met beduidende neutropenie (absolute neutrofieltelling < 1 X 10 9 /L) moet RISPERDAL staak en hulle WBS moet nagegaan word totdat hulle herstel het. Veneuse tromboëmbolisme Gevalle van veneuse tromboëmbolisme (VTE) is met RISPERDAL aangemeld. Aangesien pasiënte wat met antipsigotika behandel word dikwels presenteer met verworwe risikofaktore CCDS Jan 2013 Page 25 of 38

26 vir VTE, moet alle moontlike risikofaktore vir VTE voor en tydens behandeling met RISPERDAL bepaal word en voorkomende maatreëls onderneem word. Tardiewe diskinesie/ekstrapiramidale simptome (TD/EPS) RISPERDAL is geassosieer met die induksie van tardiewe diskinesie (TD), gekenmerk deur moontlik onomkeerbare ritmiese onwillekeurige bewegings, veral van die tong en/of gesig. Daar is aangemeld dat die voorkoms van ekstrapiramidale simptome n risikofaktor is vir die ontwikkeling van tardiewe diskinesie. TD kom skynbaar meer prominent voor by bejaardes, veral by vroue. Indien tekens en simptome van tardiewe diskinesie voorkom, moet die staking van RISPERDAL oorweeg word. Neuroleptiese Maligne Sindroom (NMS) Die voorkoms van Neuroleptiese Maligne Sindroom, n potensieel noodlottige simptoomkompleks, gekenmerk deur hipertermie, spierstyfheid, outonome onstabiliteit, veranderde bewussyn en verhoogde serum kreatinienfosfokinasevlakke is in assosiasie met RISPERDAL aangemeld. Addisionele tekens kan insluit verhoogde kreatinienfosfokinasevlakke, mioglobienurie (rabdomiolise) en akute nierversaking. In hierdie geval moet RISPERDAL gestaak word. Parkinson s se siekte/ Lewy liggaam demensie en NMS Pasiënte met Parkinson se siekte of Demensie met Lewyliggame (DLL) is onderworpe aan n hoër risiko vir Neuroleptiese Maligne Sindroom, asook verhoogde sensitiwiteit vir antipsigotiese medikasies.(sien KONTRA-INDIKASIES). Die manifestering van hierdie toename in sensitiwiteit kan bo en behalwe ekstrapiramidale simptome, ook verwardheid, afstomping, posturale onstabiliteit, waartydens die pasiënt dikwels val, insluit. Daarbenewens het bejaarde pasiënte in kliniese proewe n hoër mortaliteit getoon as plasebo-behandelde pasiënte. Hiperglukemie en diabetes mellitus: Hiperglukemie, in sommige gevalle ekstreem en geassosieer met keto-asidose of hiperosmolare koma of dood, is in pasiënte wat met atipiese antipsigotiese middels, insluitende RISPERDAL behandel is, aangemeld. Pasiënte met ʼn bevestigde diagnose van diabetes mellitus en wie op RISPERDAL begin word, behoort gereeld vir verergering van glukosebeheer gemonitor te word. Pasiënte met risikofaktore vir diabetes mellitus (bv. Vetsug, familiegeskiedenis van diabetes mellitus) wat behandeling met RISPERDAL begin, behoort vir simptome van hiperglukemie, insluitende CCDS Jan 2013 Page 26 of 38

27 polidipsie, poliurie, polifagie en swakheid gemonitor te word. Pasiënte wat simptome van hiperglukemie gedurende die behandeling met RISPERDAL ontwikkel, behoort n vastende glukosetoets te ondergaan. In sommige gevalle het die hiperglukemie met staking van RISPERDAL verdwyn: sommige pasiënte het egter voortsetting van hul antidiabetiese behandeling, ten spyte van onttrekking van die verdagte middel, vereis. Gewigstoename Beduidende gewigstoename is aangemeld. Die monitering van gewigstoename word aanbeveel wanneer RISPERDAL gebruik word. Pasiënte kan aangeraai word om hulle nie te ooreet nie, as gevolg van die moontlikheid van gewigstoename. QT Interval Versigtigheid moet aan die dag gelê word wanneer RISPERDAL voorgeskryf word aan pasiënte met n geskiedenis van hart disritmie, by pasiënte met kongenitale lang QT sindroom en met gelyktydige gebruik met medisyne, bekend om die QT interval te verleng. Priapisme Daar is berig dat medisyne met alfa-adrenergiese blokkerende uitwerking priapisme induseer. Priapisme is aangemeld met RISPERDAL tydens nabemarkingstoesig (sien NEWE-EFFEKTE). Liggaamstemperatuurbeheer Versteuring in die vermoë van die liggaam om die kern-liggaamstemperatuur te verlaag kan voorkom. Gepaste versorging word aangeraai wanneer RISPERDAL voorgeskryf word aan pasiënte wat toestande sal ervaar wat kan bydra tot n verhoging in kernliggaamstemperatuur, bv. strawwe oefening, blootstelling aan buitensporige hitte, gepaardgaande medikasie ontvang met anticholinergiese werking, of onderhewig aan dehidrasie. Antiëmetiese werking n Antiëmetiese uitwerking is waargeneem in prekliniese navorsingstudies met risperidoon. Hierdie effek, indien dit by die mens voorkom, kan die tekens en simptome van oordosering met sekere medisyne of toestande soos inwendige obstruksie, Reyesindroom en breintumor verbloem. Intra-operatiewe slap-iris-sindroom CCDS Jan 2013 Page 27 of 38

28 Intra-operatiewe slap-iris-sindroom (ISIS) is tydens katarakoperasies waargeneem by pasiënte wat met medisyne met alfa-1a-adrenergiese antagonistiese uitwerking, insluitende RISPERDAL, behandel is (sien NEWE-EFFEKTE). ISIS kan die risiko van oogkomplikasies tydens en na die operasie verhoog. Huidige of vorige gebruik van RISPERDAL moet voor die operasie aan die oogchirurg bekend gemaak word. Die moontlike voordele om RISPERDAL behandeling voor die katarakoperasie te staak, is nie vasgestel nie en moet opgeweeg word aan die risiko om die RISPERDAL behandeling te staak. Toevalle RISPERDAL moet met omsigtigheid gebruik word by pasiënte met n geskeidenis van toevalle of ander toestande wat moontlik die konvulsiedrempel kan verlaag. Vermoë om te bestuur of masjinerie te bedryf: RISPERDAL kan verstandelike wakkerheid aantas. Gevolglik moet pasiënte aangeraai word om nie te bestuur of masjinerie te hanteer totdat hulle individuele vatbaarheid bekend is nie. INTERAKSIES Die risiko van die gebruik van RISPERDAL in kombinasie met ander middels is nie sistematies geëvalueer nie. Met inagname van die primêre SSS depressiewe effekte van RISPERDAL, behoort dit met sorg gebruik te word in kombinasie met alkohol en ander sentraalwerkende medisyne. RISPERDAL kan die effek van levodopa en ander dopamien agoniste antagoniseer. Klinies-beduidende hipotensie is waargeneem na bemarking met die gelyktydige gebruik van RISPERDAL en antihipertensiewe behandeling. Versigtigheid word aangeraai wanneer RISPERDAL saam met middels voorgeskryf word wat bekend is om die QT interval te verleng. (Sien WAARSKUWINGS ) Dit is aangetoon dat karbamasepien die plasmavlakke van die aktiewe antipsigotiese fraksie van risperidoon verlaag. Soortgelyke effekte mag met ander lewerensieminduseerders waargeneem word. Met staking van karbamasepien of ander lewerensieminduseerders moet die RISPERDAL dosis geherevalueer en indien nodig, verminder te word. Fluoksetien en paroksetien, CYP2D6- inhibeerders, verhoog die plasmakonsentrasie van risperidoon, maar tot n mindere mate die aktiewe antipsigotiese fraksie. Wanneer CCDS Jan 2013 Page 28 of 38

29 gesamentlik toegediende fluoksetien of paroksetien geïnisieer of onttrek word, moet die geneesheer die dosering van RISPERDAL herevalueer. Venlafaksien, 150 mg/dag onder bestendige toestande toegedien, het die CYP2D6- bemiddelde metabolisme van risperidoon (as n enkele 1 mg orale dosis toegedien) tot die 9-hidroksierisperidoon aktiewe metaboliet daarvan, effens inhibeer, met n gevolglike toename van 32 % in risperidoon-aok. Gesamentlike toediening van venlafaksien het egter nie die farmakokinetiese profiel van die totale aktiewe antipsigotiese fraksie beduidend verander nie. Topiramaat het die biobeskikbaarheid van risperidoon matig verminder, maar nie dié van die aktiewe antipsigotiese fraksie nie. Daarom is dit onwaarskynlik dat hierdie interaksie van kliniese belang is. Fenotiasiene, trisikliese antidepressante en sommige betablokkeerders kan die plasmakonsentrasie van risperidoon laat toeneem, maar nie dié van die aktiewe antipsigotiese fraksie nie. Amitriptilien affekteer nie die farmakokinetika van risperidoon of die aktiewe antipsigotiese fraksie nie. Simetidien en ranitidien het die biobeskikbaarheid van risperidoon verhoog, maar het die antipsigotiese fraksie slegs tot n geringe mate beïnvloed. Eritromisien, n CYP3A4 inhibeerder, verander nie die farmakokinetika van risperidoon en die aktiewe antipsigotiese fraksie nie. Die cholienesterase inhibeerders, galantamien en donepesil, toon nie n klinies beduidende effek op die farmakokinetika van risperidoon en die aktiewe antipsigotiese fraksie nie. Wanneer RISPERDAL saam met ander hoogs proteïengebonde geneesmiddels geneem word (bv. diasepam, warfarien, digitoksien, imipramien en propranolol), is daar geen klinies relevante verplasing van enige van hierdie middels vanaf die plasmaproteïene nie. RISPERDAL toon nie n klinies relevante effek op die farmakokinetika van litium, valproaat, digoksien of topiramaat nie. Daar is n verhoogde mortaliteit by bejaarde pasiënte met demensie, wat furosemied en RISPERDAL gesamentlik ontvang. CCDS Jan 2013 Page 29 of 38

30 Voedsel beïnvloed nie die absorpsie van RISPERDAL nie. SWANGERSKAP EN LAKTASIE Die veiligheid van RISPERDAL tydens swangerskap en by vroue wat borsvoed is nie bepaal nie. Alhoewel risperidoon nie in proefdiere direkte reproduktiewe toksisiteit getoon het nie, is sommige indirekte, prolaktien- en SSS- bemiddelde effekte waargeneem. Daar is geen risperidoon verwante teratogeniese effek in enige navorsingstudie bemerk nie. Pasgeborenes wat blootgestel word aan antipsigotiese medisyne (insluitende RISPERDAL ) tydens die derde trimester van swangerskap is aan n risiko vir ekstrapiramidale en/of onttrekkingsimptome na geboorte onderwerp, dit kan wissel in erns. Hierdie simptome in die pasgeborene kan insluit onrustigheid, hipertonie, hipotonie, bewing, lomerigheid, respiratoriese nood, of voedingsteurnis. Daarom behoort RISPERDAL slegs in swangerskap gebruik te word indien die voordele voordelig teen die risiko s opweeg. In dierestudies word risperidoon en 9-hidroksierisperidoon in die melk uitgeskei. Dit is aangetoon dat risperidoon en 9-hidroksierisperidoon ook in menslike borsmelk uitgeskei word. Daarom behoort vroue wat RISPERDAL ontvang, nie hul babas te borsvoed nie. DOSIS EN GEBRUIKSAANWYSINGS Skisofrenie Verandering van ander antipsigotika na RISPERDAL: Daar word aanbeveel dat die vorige behandeling geleidelik verminder word, indien dit medies toepaslik is, terwyl RISPERDAL behandeling geïnisieer word. Ook, indien medies geskik, wanneer pasiënte van depot antipsigotika na RISPERDAL verander word, inisieer RISPERDAL terapie in die plek van die volgende beplande inspuiting. Die behoefte om voort te gaan met behandeling met bestaande anti-parkinsonistiese medisynes, behoort periodiek herevalueer te word. Volwassenes: RISPERDAL kan een of twee maal per dag toegedien word. Pasiënte moet met 2 mg RISPERDAL per dag begin. Die dosis kan op die tweede dag na CCDS Jan 2013 Page 30 of 38

31 4 mg/dag verhoog word. Daarna kan die dosis onveranderd gehou word, of indien nodig na gelang van die individu aangepas word. Meeste pasiënte sal baat vind by n daaglikse dosering van tussen 4 mg/dag en 8 mg/dag. Dosisse bokant 6 mg/dag (wanneer twee maal per dag toegedien word) is geassosieer met meer ekstrapiramidale simptome en ander newe effekte en word nie algemeen aanbeveel nie. By sommige pasiënte, veral tydens die eerste akute psigotiese episode, mag n stadiger titrasie fase en n laer aanvangs- en instandhoudingsdosis meer geskik wees. Daar is aangetoon dat dosisse van meer as 10 mg/dag nie meer doeltreffend as die laer dosisse is nie en mag n verhoogde voorkoms van newe-effekte soos ekstrapiramidale simptome veroorsaak. Doserings bo 10 mg/dag behoort alleenlik oorweeg te word indien die voordele die nadele oortref. Die maksimum totale daaglikse dosis is 16 mg/dag. n Bensodiasepien kan saam met RISPERDAL toegedien word indien addisionele kalmering verlang word. Bejaarde pasiënte en pasiënte met nier- en lewerinkorting n Aanvangsdosis van 0,5 mg twee keer per dag word aanbeveel. Hierdie dosis kan individueel aangepas word met inkremente van 0,5 mg twee keer per dag tot 1-2 mg twee keer per dag. Kinders: Nie vir kinders jonger as 15 jaar nie, aangesien die effektiwiteit en veiligheid in kinders jonger as 15 jaar nog nie in skisofrenie bevestig is nie. Bipolêre manie RISPERDAL moet toegedien word volgens n een-keer daaglikse skedule, beginnende met 2 of 3 mg. Dosis aanpassings, indien aangedui, moet met intervalle van nie minder as 24 uur en met dosis inkremente van 1 mg per dag geskied. Doeltreffendheid was aangetoon in aanpasbare dosisse binne die dosis reikwydte van 1 tot 6 mg per dag. Die voortgesette gebruik van RISPERDAL moet deurlopend geëvalueer en regverdig word. Daar is nie voldoende ondervinding met bipolêre manie by kinders en adolessente jonger as 18 jaar oud nie. CCDS Jan 2013 Page 31 of 38

32 Gedragsafwykings en ander ontwrigtende optredes by kinders 5 12 jaar oud Pasiënte < 50 kg: n Aanvangsdosis van 0,01 mg/kg een keer daagliks word aanbeveel. Die dosis kan, indien nodig, individueel aangepas word met inkremente van 0,01 mg/kg een keer per dag, nie meer dikwels as elke tweede dag nie. Die aanbevole instandhoudingsdosis is 0,02 0,04 mg/kg een keer per dag. Die gemiddelde dosis is 0,03 mg/kg een keer daagliks. Die aanhoudende gebruik van RISPERDAL moet op n deurlopende basis geëvalueer en regverdig word. Ondervinding ontbreek by kinders jonger as 5 jaar. Belemmerde nier- en lewerfunksie Pasiënte met beperkte nierfunksie het n swakker vermoë as normale pasiënte om die aktiewe antipsigotiese fraksie te elimineer. Pasiënte met belemmerde lewerfunksie toon toenames in plasmakonsentrasie van die vry fraksie van risperidoon. Ongeag die indikasie, behoort die aanvanklike en daaropvolgende dosering gehalveer te word en titrasie van die dosis stadiger plaas te vind by pasiënte met belemmerde nier- en lewerfunksie. RISPERDAL behoort met sorg gebruik te word by hierdie groep pasiënte. AANWYSINGS VIR DIE OOPMAAK VAN DIE BOTTEL EN DIE GEBRUIK VAN DIE PIPET Om die bottel oop te maak en die pipet te gebruik: CCDS Jan 2013 Page 32 of 38

33 Fig. 1: Die bottel het n kinder-bestande prop en moet as volg oopgemaak word: - druk die plastiek skroefprop afwaarts terwyl dit antikloksgewys gedraai word. - Verwyder die skroefprop. Fig. 2: Plaas die pipet in die bottel. Terwyl die onderste ring vasgehou word, trek die boonste ring tot op n vlak wat ooreenstem met die aantal milliliter of milligram wat toegedien moet word. Fig.3: Terwyl die onderste ring vasgehou word, verwyder die volledige pipet uit die bottel. Ledig die inhoud van die pipet in enige nie-alkoholiese drankie, behalwe tee, deur die boonste ring af te laat gly na onder. Maak die bottel weer toe en spoel die pipet met water uit. NEWE-EFFEKTE Ongunstige geneesmiddelreaksies (OGR) wat tydens kliniese proewe aangemeld is: Ongunstige geneesmiddelreaksies word hieronder gelys volgens orgaansisteemklas en frekwensie. Frekwensies word gedefinieer as: Baie algemeen (> 1/10); algemeen (> 1/100, < 1/10); ongewoon (> 1/1 000, <1/100); seldsaam (> 1/10 000, < 1/1 000); baie seldsaam (< 1/10 000). Ondersoeke: Algemeen: Bloed- prolaktien verhoog, gewig toename Ongewoon: Abnormale elektrokardiogram, bloed-glukose verhoog, transaminase verhoog, witbloedseltelling verminder, liggaamstemperatuur verhoog, eosinofieltelling verhoog, hemoglobien verminder, bloedkreatinienfosfokinase verhoog Seldsaam: Liggaamstemperatuur verlaag. Hartsiektes: Gewoon: Tagikardie. CCDS Jan 2013 Page 33 of 38