PACKAGE INSERT SCHEDULING STATUS Schedule 4 PROPRIETARY NAME AND DOSAGE FORM MOTILIUM 1 mg/ml suspension COMPOSITION Each ml contains 1 mg domperidone, with 0,18 % m/v methylparaben and 0,02 % m/v propylparaben as preservatives. List of excipients: Sodium saccharin, microcrystalline cellulose and sodium carboxy-methylcellulose, sorbitol liquid non-crystallising, methylparahydroxybenzoate, propylparahydroxy-benzoate, sodium hydroxide, polysorbate, purified water. PHARMACOLOGICAL CLASSIFICATION A 5.7.2 Anti-emetics and anti-vertigo preparations CCDS Oct 2013 & CCDS June 2014 Page 1 of 37
PHARMACOLOGICAL ACTION Pharmacodynamic properties Domperidone is a dopamine-receptor blocking agent. Its action on the dopaminereceptors in the chemo-emetic trigger zone produces an anti-emetic effect. Domperidone does not cross the blood-brain barrier to any appreciable degree and so exerts relatively little effect on cerebral dopaminergic receptors. Domperidone has been shown to increase antroduodenal motility and gastric emptying. There is no effect on gastric secretion. Effect on QT/QTc interval and cardiac electrophysiology In accordance with ICH-E14 guidelines, a thorough QT study was performed in healthy subjects. This study included a placebo, active comparator and positive control and was conducted using recommended and supra-therapeutic doses (10 and 20 mg administered 4 times a day). This study found a maximal difference of QTc between domperidone and placebo in LS-means in the change from baseline of 3,4 msec for 20 mg domperidone administered 4 times a day on Day 4, and the 2-sided 90 % CI (1,0 5,9 msec) did not exceed 10 msec. The QT prolongation observed in this study when domperidone was administered according to the recommended dosing regimen is not clinically relevant. This lack of clinical relevance is corroborated by pharmacokinetics and QTc interval data from two older studies which involved a 5-day treatment of 20 mg and 40 mg domperidone administered 4 times a day. ECGs were recorded prior to the study, on Day 5 at 1 hour (approximately at t max ) after the morning dose, and 3 days later. In both studies, no CCDS Oct 2013 & CCDS June 2014 Page 2 of 37
difference between QTc after active treatment and placebo was observed. It was therefore concluded that domperidone administration of 80 and 160 mg daily doses had no clinically significant effect on QTc in healthy subjects. Pharmacokinetic properties Absorption In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 60 minutes after dosing. The key pharmacokinetic parameters after a single or multiple doses (administered 4 times a day) of 10 mg domperidone base tablets to healthy subjects are presented in the table below. The C max and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. Key domperidone pharmacokinetic parameters after a single or multiple doses (administered 4 times a day) of 10 mg domperidone base tablets to healthy subjects PK parameter Mean Domperidone 10 mg administered four times a day Day 1 Day 4 n 40 40 C min, ng/ml NA 5,26 (CV: 31,1 %) C max, ng/ml 11,6 (CV: 50,8 %) 17,3 (CV: 35,4 %) t max, h a 1,02 (range: 0,52 5,02) 1,02 (range: 0,50 4,03) AUC 5h, ng.h/ml 20,4 (CV: 34,4 %) 47,8 (CV: 30,5 %) a median (range) CCDS Oct 2013 & CCDS June 2014 Page 3 of 37
The absolute bio-availability of oral domperidone is low (approximately 15 %) due to firstpass hepatic and intestinal metabolism. Distribution Domperidone is 91-93 % bound to plasma proteins. The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency. Metabolism Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N- dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation. Excretion Urinary and faecal excretion amount to 31 % and 66 % of the oral dose, respectively. The proportion of medicine excreted unchanged is small (approximately 1 % of urinary and 10 % of faecal excretion). CCDS Oct 2013 & CCDS June 2014 Page 4 of 37
Special Populations Hepatic impairment In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and C max of domperidone is 2,9- and 1,5-fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25 %, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on C max and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied (see CONTRA-INDICATIONS). Renal impairment In patients with severe renal insufficiency (serum creatinine more than 6 mg/100 ml, i.e. more than 0,6 mmol/l) the elimination half-life of domperidone was increased from 7,4 to 20,8 hours, but plasma medicine levels are lower than in subjects with normal renal function. Very little unchanged medicine (approximately 1 %) is excreted via the kidneys. (see DOSAGE AND DIRECTIONS FOR USE). Paediatric patients Based on limited pharmacokinetic data, domperidone plasma concentrations in preterm neonates were consistent with those reported in adults. INDICATIONS MOTILIUM 1 mg/ml suspension is indicated for: CCDS Oct 2013 & CCDS June 2014 Page 5 of 37
Short-term management of delayed gastric emptying of functional origin with gastrooesophageal reflux and/or dyspepsia. Control of nausea and vomiting of central or local origin. As an anti-emetic in patients receiving cytostatic and radiation therapy. Facilitation of radiological examination of the upper gastro-intestinal tract. CONTRA-INDICATIONS MOTILIUM is contra-indicated in the following situations: Known hypersensitivity to domperidone or any of its excipients. Prolactin-releasing pituitary tumour (prolactinoma). Co-administration with other potent CYP3A4 inhibitors which have been shown to cause QT interval prolongation such as fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, clarithromycin, erythromycin, azithromycin, roxithromycin, amiodarone, telithromycin, amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir and quinolones (see WARNINGS AND SPECIAL PRECAUTIONS and INTERACTIONS). Co-administration with medicines known to induce Torsades de Pointes and/or prolong the QT interval e.g. cisapride, class 1A antidysrythmics. Hypokalaemia, hypomagnesaemia. Bradycardia or heart block. Pre-existing cardiac disease. Known congenital long QT interval or family history thereof. CCDS Oct 2013 & CCDS June 2014 Page 6 of 37
Whenever stimulation of gastric motility might be dangerous, e.g. in the presence of gastro-intestinal haemorrhage, mechanical obstruction or perforation. In patients with moderate or severe hepatic impairment (see Pharmacokinetic properties). WARNINGS AND SPECIAL PRECAUTIONS Cardiac effects Epidemiological studies have shown that MOTILIUM is associated with an increased risk of serious ventricular dysrhythmias or sudden cardiac death (see SIDE-EFFECTS). These studies suggested that this increased risk may be higher in patients older than 60 years of age or in patients taking oral doses greater than 30 mg per day. Therefore, MOTILIUM should be used with caution in older patients. Medicine interaction potential The main metabolic pathway of domperidone is through CYP3A4. In vitro and human data show that the concomitant use of medicines that significantly inhibit this enzyme may result in increased plasma levels of domperidone. Co-administration of MOTILIUM with potent CYP3A4 inhibitors which have been shown to cause QT interval prolongation is contraindicated (see CONTRA-INDICATIONS). Caution should be exercised when MOTILIUM is co-administered with potent CYP3A4 inhibitors which have not been shown to cause QT interval prolongation, and patients should be monitored closely for signs and symptoms of adverse reactions (see SIDE- EFFECTS). CCDS Oct 2013 & CCDS June 2014 Page 7 of 37
Caution should be exercised when MOTILIUM is co-administered with medicines which have been shown to cause QT interval prolongation and patients should be monitored closely for signs or symptoms of cardiovascular adverse reactions (see SIDE-EFFECTS). Examples include: Anti-arrhythmias class IA (e.g. disopyramide, quinidine). Anti-arrhythmias class III (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol). Certain antipsychotics (e.g. haloperidol, pimozide, sertindole). Certain antidepressants (e.g. citalopram, escitalopram). Certain antibiotics (e.g. levofloxacin, moxifloxacin and quinolones). Certain antifungal medicines (e.g. pentamidine). Certain antimalarial medicines (e.g. halofantrine). Certain gastro-intestinal medicines (e.g. dolasetron). Certain medicines in cancer (e.g. toremifene, vandetanib). Certain other medicines (e.g. bepridil, methadone). The above list is representative and not exhaustive. Domperidone base Antacids and anti-secretory medicines should not be taken simultaneously with oral formulations of MOTILIUM as they lower the oral bioavailability of MOTILIUM. When used concomitantly, MOTILIUM should be taken before meals and antacids or anti-secretory medicines after meals. Excipients CCDS Oct 2013 & CCDS June 2014 Page 8 of 37
MOTILIUM oral suspension contains sorbitol and may be unsuitable for patients with sorbitol intolerance. Effects on ability to drive and use machines Dizziness and somnolence have been observed following use of MOTILIUM (see SIDE-EFFECTS). Therefore, patients should be advised not to drive or use machinery or engage in other activities requiring mental alertness and coordination until they have established how MOTILIUM affects them. INTERACTIONS The main metabolic pathway of domperidone is through CYP3A4. In vitro and human data show that the concomitant use of medicines that significantly inhibit this enzyme may result in increased plasma levels of domperidone. When MOTILIUM was co-administered with potent CYP3A4 inhibitors which have been shown to cause QT interval prolongation, clinically relevant changes in QT intervals were observed. Therefore, co-administration of MOTILIUM with certain medicines is contraindicated (see CONTRA-INDICATIONS). Caution should be exercised when MOTILIUM is co-administered with potent CYP3A4 inhibitors which have not been shown to cause QT interval prolongation or medicines which have been shown to cause QT interval prolongation (see WARNINGS AND SPECIAL PRECAUTIONS). CCDS Oct 2013 & CCDS June 2014 Page 9 of 37
Concomitant administration of anti-cholinergic medicines (e.g. dextromethorphan, diphenhydramine) may antagonise the anti-dyspeptic effects of MOTILIUM. Since MOTILIUM has gastro-kinetic effects, it could influence the absorption of concomitant orally administered medicines, particularly those with sustained release or enteric coated formulations. However, in patients already stabilised on digoxin or paracetamol, concomitant administration of MOTILIUM did not influence the blood levels of these medicines. MOTILIUM may also be given with: Neuroleptics, the action of which it does not potentiate Dopaminergic agonists (bromocriptine, L-dopa), whose unwanted peripheral effects such as digestive disorders, nausea and vomiting it suppresses without counteracting their central properties. Reduced gastric acidity impairs the absorption of MOTILIUM. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. As MOTILIUM interferes with serum prolactin levels, it may interfere with other hypoprolactinaemic agents and with some diagnostic tests. PREGNANCY AND LACTATION The safety of use during pregnancy and lactation has not been established. CCDS Oct 2013 & CCDS June 2014 Page 10 of 37
Domperidone is excreted in human breast milk therefore breast feeding is not recommended for mothers who are taking MOTILIUM suspension. DOSAGE AND DIRECTIONS FOR USE It is recommended to take oral MOTILUM 15 30 minutes before meals. If taken after meals, absorption of the medicine is somewhat delayed. Adults and adolescents 12 years of age and weighing 35 kg, and children weighing 35 kg The dose of MOTILIUM suspension should be the lowest effective dose for the individual situation (typically 30 mg/day) with a maximum daily oral dose of 40 mg. Usually, the maximum treatment duration should not exceed one week for the treatment of acute nausea and vomiting. If nausea and vomiting persists for longer than one week, patients should consult their medical practitioners. For other indications, the initial duration of treatment is up to four weeks. If treatment exceeds four weeks, patients should be re-evaluated and the need for continued treatment reassessed. Formulation (domperidone per unit) Oral suspension (1 mg/ml) Dosage 10 ml three to four times per day Maximum dose per day 40 mg (40 ml of 1 mg/ml oral suspension) Infants and children < 12 years of age and weighing < 35 kg, and adults and adolescents weighing < 35 kg. CCDS Oct 2013 & CCDS June 2014 Page 11 of 37
The dose of MOTILIUM suspension should be the lowest effective dose. The total daily dose is dependent on body weight (see table below). Since metabolic functions and the blood-brain barrier are not fully developed in the first months of life, the risk of neurological side effects is higher in young children (see SIDE-EFFECTS). Overdosing may cause nervous system disorders in children (see KNOWN SYMPTOMS OF OVERDOSE AND PARTICULARS OF ITS TREATMENT). The dose should be determined accurately based on body weight and not exceed the recommended maximum individual and daily dose in neonates, infants, toddlers and children. Usually, the maximum treatment duration should not exceed one week for the treatment of acute nausea and vomiting. For other indications, the initial duration of treatment is up to four weeks. If treatment exceeds four weeks, patients should be re-evaluated and the need for continued treatment reassessed. Film-coated tablets are unsuitable for use in children, adults and adolescents weighing less than 35 kg. Formulation (domperidone per unit) Oral suspension (1 mg/ml) Dosage 0,25 mg/kg three to four times per day Maximum dose per day 35 mg (1 mg/kg but no more than 35 ml) Renal impairment Since the elimination half-life of domperidone is prolonged in severe renal impairment (serum creatinine > 6 mg/100 ml, i.e. > 0,6 mmol/l), the dosing frequency of MOTILIUM should be reduced to once or twice daily, depending on the severity of the impairment, and the dose may need to be reduced. Patients with severe renal impairment should be reviewed regularly. CCDS Oct 2013 & CCDS June 2014 Page 12 of 37
Hepatic impairment MOTILIUM is contraindicated for patients with moderate (Child-Pugh 7 to 9) or severe (Child-Pugh > 9) hepatic impairment (see CONTRA-INDICATIONS). Dose adjustment is not required for patients with mild (Child-Pugh 5 to 6) hepatic impairment (see Pharmacokinetic properties). Directions for use Mix the contents of the bottle completely using a gentle tilting motion to avoid the formation of foam. Directions for opening the bottle: The bottle comes with a child-proof cap, and should be opened as follows: - Push the plastic screw cap down while turning it counter clockwise. - Remove the unscrewed cap. SIDE EFFECTS Clinical Trial Data The adverse reactions are ranked by frequency, using the following convention: 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), including isolated reports. Psychiatric disorders Common: Depression, anxiety, libido decreased/loss of libido. CCDS Oct 2013 & CCDS June 2014 Page 13 of 37
Nervous system disorders Common: Headache, somnolence, akathisia. Gastro-intestinal disorders Common: Diarrhoea. Immune system disorders Uncommon: Hypersensitivity. Skin and subcutaneous tissue disorders Common: Rash, pruritus. Uncommon: Urticaria. Reproductive system and breast disorders Common: Breast enlargement/ gynaecomastia, breast tenderness, galactorrhoea, amenorrhoea, breast pain, menstruation irregular, lactation disorder. Uncommon: Breast discharge, breast swelling. CCDS Oct 2013 & CCDS June 2014 Page 14 of 37
General disorders and administration site conditions Common: Asthenia. Dry mouth has also been reported. Post-marketing In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported post-marketing: Immune System Disorders Anaphylactic reaction (including anaphylactic shock). Psychiatric Disorders Agitation, nervousness. Nervous System Disorders Dizziness, extrapyramidal disorder, convulsion. Cardiac Disorders Sudden cardiac death, serious ventricular dysrhythmias (see WARNINGS AND SPECIAL PRECAUTIONS). Skin and Subcutaneous Tissue Disorders CCDS Oct 2013 & CCDS June 2014 Page 15 of 37
Angioedema. Renal and Urinary Disorders Urinary retention. Investigations Liver function test abnormal, blood prolactin increased. Paediatric population Extrapyramidal disorder occurs in neonates and infants. Central nervous system-related effects of convulsion, agitation and somnolence have also been reported in infants and children. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Symptoms and signs Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions. Treatment There is no specific antidote to domperidone, but in the event of overdosage, gastric lavage as well as the administration of activated charcoal may be useful. Symptomatic and supportive measures are recommended. Anticholinergic or anti-parkinson medicines may be helpful in controlling the extrapyramidal reactions. CCDS Oct 2013 & CCDS June 2014 Page 16 of 37
IDENTIFICATION White suspension with a sweet taste. PRESENTATION 100 ml amber glass bottles. STORAGE INSTRUCTIONS Store at or below 25 o C. Protect from light. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBER V/5.7.2/19 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, CCDS Oct 2013 & CCDS June 2014 Page 17 of 37
21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) 518 7000 www.janssen.co.za Nam. Reg. No.: 04/5.7.1/0277 NS 2 Botswana Reg. No.: B9315430 S3 Zimbabwe Reg. No.: 90/16.4/2379 PIM DATE OF PUBLICATION OF THIS PACKAGE INSERT 02 April 2015 CCDS Oct 2013 & CCDS June 2014 Page 18 of 37
VOUBILJET SKEDULERINGSTATUS Skedule 4 EIENDOMSNAAM EN DOSEERVORM MOTILIUM 1 mg/ml suspensie SAMESTELLING Elke ml bevat 1 mg domperidoon, met 0,18 % m/v metielparabeen en 0,02 % m/v propielparabeen as preserveermiddels. Lys van mengmiddels: Natriumsakkarien, mikrokristallyne sellulose en natriumkarboksimetielsellulose, sorbitol nie-kristalliserende vloeistof, metielparahidroksiebensoaat, propielparahidroksiebensoaat, natriumhidroksied, polisorbaat, gesuiwerde water. FARMAKOLOGIESE KLASSIFIKASIE A 5.7.2 Anti-emetika en antivertigopreparate FARMAKOLOGIESE WERKING CCDS Oct 2013 & CCDS June 2014 Page 19 of 37
Farmakodinamiese eienskappe Domperidoon is 'n dopamienreseptor blokkeerder. Die werking daarvan op die dopamienreseptore in die chemo-emetiese snellerarea veroorsaak 'n anti-emetiese effek. Daar vind geen noemenswaardige kruising van domperidoon deur die bloedbreinskans plaas nie en derhalwe oefen dit weinig effek op die dopaminergiese reseptore van die serebrum uit. Daar is aangetoon dat domperidoon die motiliteit van die dunderm en maaglediging verhoog. Daar is geen effek op maagafskeiding nie. Effek op QT/QTc-interval en kardiale elektrofisiologie In ooreenstemming met ICH-E14 riglyne, is 'n deeglike QT-studie uitgevoer in gesonde persone. Hierdie studie het 'n plasebo, 'n aktiewe vergelyker en 'n positiewe kontrole ingesluit en daar is gebruik gemaak van die aanbevole en supra-terapeutiese dosisse (10 en 20 mg, 4 keer per dag toegedien). Hierdie studie het aangetoon dat daar 'n maksimale verskil van QTc is tussen domperidoon en plasebo in kleinste kwadraat-gemiddelde in die verandering vanaf basislyn van 3,4 msek vir 20 mg domperidoon, 4 keer per dag toegedien, op Dag 4. Die 2-kantige 90 % VI (1,0-5,9 msek) het nie 10 msek oorskry nie. Die QT-verlenging wat in hierdie studie waargeneem is toe domperidoon volgens die aanbevole doseringsregimen toegedien is, is nie klinies relevant nie. Hierdie gebrek aan kliniese relevansie word gestaaf deur die farmakokinetiese en QTcinterval data uit twee ouer studies wat 'n 5-dag behandeling van 20 mg en 40 mg domperidoon, 4 keer per dag toegedien, behels het. EKGs is voor die studie, op Dag 5 by CCDS Oct 2013 & CCDS June 2014 Page 20 of 37
1 uur (ongeveer by t maks ) na die oggenddosis en 3 dae later, opgeneem. In beide studies is daar geen verskil tussen die QTc na aktiewe behandeling en plasebo waargeneem nie. Die gevolgtrekking was dus dat die toediening van daaglikse dosisse van 80 en 160 mg domperidoon geen klinies beduidende uitwerking op QTc by gesonde persone het nie. Farmakokinetiese eienskappe Absorpsie By vastende persone word domperidoon vinnig na orale toediening geabsorbeer, met piekplasmakonsentrasies teen ongeveer 60 minute na dosering. Die hooffarmakokinetiese parameters na 'n enkele dosis of veelvuldige dosisse (4 keer per dag toegedien) van 10 mg domperidoonbasis tablette aan gesonde persone word in die tabel hieronder weergegee. Die K maks en AOK waardes van domperidoon het proporsioneel met die dosis in die 10 mg tot 20 mg dosisreeks toegeneem. Hoof-farmakokinetiese parameters na 'n enkele dosis of veelvuldige dosisse (4 keer per dag toegedien) van 10 mg domperidoonbasis tablette aan gesonde persone PK-parameter Gemiddelde Domperidoon 10 mg, vier keer per dag toegedien Dag 1 Dag 4 n 40 40 K min, ng/ml nvt 5,26 (VK: 31,1 %) K max, ng/ml 11,6 (VK: 50,8 %) 17,3 (VK: 35,4 %) t maks, h a 1,02 (reeks: 0,52 5,02) 1,02 (reeks: 0,50 4,03) AOK 5h, ng.h/ml 20,4 (VK: 34,4 %) 47,8 (VK: 30,5 %) a mediaan (reeks) CCDS Oct 2013 & CCDS June 2014 Page 21 of 37
Die absolute biobeskikbaarheid van orale domperidoon is laag (ongeveer 15 %) weens die eerstedeurgang hepatiese en intestinale metabolisme. Verspreiding Domperidoon word 91-93 % aan plasmaproteïene gebind. Die plasmahalfleeftyd na 'n enkele mondelike dosis is 7-9 uur in gesonde indiwidue maar is effens langer by pasiënte met erge nierversaking. Metabolisme Domperidoon ondergaan snelle en uitgebreide hepatiese metabolisme deur hidroksilasie en N-dealkilering. In vitro metabolisme eksperimente met diagnostiese inhibeerders het bekend gemaak dat CYP3A4 n belangrike vorm van sitochroom P-450 is en betrokke is in die N-dealkilering van domperidoon, terwyl CYP3A4, CYP1A2 en CYP2E1 betrokke is by die aromatiese hidroksilasie van domperidoon. Uitskeiding Daar word onderskeidelik 31 % en 66 % van die mondelike dosis urinêr en fekaal uitgeskei. Die gedeelte van die medisyne wat onveranderd uitgeskei word is klein (ongeveer 1 % van die urinêre en 10 % van die fekale uitskeiding). CCDS Oct 2013 & CCDS June 2014 Page 22 of 37
Spesiale populasies Swak lewerfunksie By persone met matige lewerontoereikendheid (Pugh-telling 7-9, Child-Pugh gradering B), is die AOK en K maks van domperidoon onderskeidelik 2,9- en 1,5 keer hoër as by gesonde persone. Die vrye gedeelte neem 25 % toe en die terminale eliminasiehalfleeftyd is verleng vanaf 15 tot 23 uur. Persone met ligte lewerontoereikendheid toon ietwat laer sistemiese blootstelling as gesonde persone, op grond van die K maks en die AOK, sonder verandering in proteïenbinding of terminale halfleeftyd. Persone met ernstige lewerontoereikendheid is nie bestudeer nie (sien KONTRA-INDIKASIES). Swak nierfunksie By pasiënte met ernstige swak nierfunksie (serumkreatinien> 6 mg/100 ml, dus > 0,6 mmol/l) is die halfleeftyd van domperidoon van 7,4 tot 20,8 uur verleng, maar die plasmageneesmiddelkonsentrasie is laer as by pasiënte met 'n normale nierfunksie. Baie min geneesmiddel (ongeveer 1 %) word in onveranderde vorm deur die niere uitgeskei (sien DOSIS EN GEBRUIKSAANWYSINGS). Pediatriese pasiënte Gebaseer op beperkte farmakokinetiese data is die plasmakonsentrasies van domperidoon in vroeggebore neonate in ooreenstemming met dié wat by volwassenes aangemeld is. CCDS Oct 2013 & CCDS June 2014 Page 23 of 37
INDIKASIES MOTILIUM 1 mg/ml suspensie word aangedui vir: Korttermyn behandeling van vertraagde maaglediging van funksionele oorsprong met gastro-esofageale refluks en/of dispepsie. Beheer van naarheid en braking van sentrale of plaaslike oorsprong. As 'n anti-emetiese middel by pasiënte wat sitostatika gebruik en stralingsterapie ontvang. Om radiologiese ondersoeke van die boonste gastro-intestinale kanaal te vergemaklik. KONTRA-INDIKASIES MOTILIUM word teenaangedui by die volgende toestande: Bekende hipersensitiwiteit vir domperidoon of enige van die bestanddele daarvan. Prolaktienvrystellende hipofisêre tumor (prolaktinoom). Gesamentlike toediening met ander kragtige CYP3A4- remmers waarvan aangetoon is dat hulle QT-interval verlenging veroorsaak soos flukonasool, itrakonasool, ketokonasool, vorikonasool, posakonasool, klaritromisien, eritromisien, asitromisien, roksitromisien, amiodaroon, telitromisien, amprenavir, atasanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, sakinavir en kinolone (sien WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS en INTERAKSIES). Gesamentlike toediening met medisyne bekend vir induksie van Torsades de Pointes en/of wat die QT interval verleng, bv.sisapried, klas 1A-anti-disritmiese middels. Hipokalemie, hipomagnesemie. CCDS Oct 2013 & CCDS June 2014 Page 24 of 37
Bradikardie of hartblok. Reeds bestaande hartsiekte. Bekende kongenitale lang-qt interval of familiegeskiedenis daarvan. Wanneer stimulering van maagbeweeglikheid gevaarlik kan wees, bv. in die teenwoordigheid van gastro-intestinale bloeding, meganiese obstruksie of perforasie. By pasiënte met matige tot ernstige lewerinkorting (sien Farmakokinetiese eienskappe). WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS Uitwerking op die hart Epidemiologiese studies het getoon dat MOTILIUM in verband gebring kan word met 'n hoër risiko op ernstige ventrikelaritmie of skielike hartdood (sien NEWE-EFFEKTE). Hierdie studies het daarop gedui dat die risiko hoër kan wees by pasiënte ouer as 60 jaar of by pasiënte wat dosisse neem van meer as 30 mg per dag. Daarom moet MOTILIUM met omsigtigheid gebruik word by ouer pasiënte. Moontlike interaksies met medisyne Domperidoon word hoofsaaklik deur CYP3A4 gemetaboliseer. In vitro en menslike data wys daarop dat gelyktydige gebruik van medisynes wat hierdie ensiem sterk rem, die plasmakonsentrasie van domperidoon kan laat styg. Gesamentlike toediening van MOTILIUM met kragtige CYP3A4- remmers waarvan aangetoon is dat dit QT-interval verlenging veroorsaak, is teenaangedui (sien KONTRA-INDIKASIES). CCDS Oct 2013 & CCDS June 2014 Page 25 of 37
Versigtigheid moet uitgeoefen word wanneer MOTILIUM toegedien word saam met kragtige CYP3A4-remmers waarvan daar nie QT-interval verlenging aangetoon is nie en pasiënte moet noukeurig gemoniteer word vir tekens en simptome van ongunstige reaksies (sien NEWE-EFFEKTE). Versigtigheid moet uitgeoefen word wanneer MOTILIUM toegedien word saam met medisynes waarvan daar QT-interval verlenging aangetoon is en pasiënte moet noukeurig gemoniteer word vir tekens en simptome van ongunstige reaksies (sien NEWE- EFFEKTE). Voorbeelde sluit in: Antidisritmiese middels klas IA (bv. disopiramied, kinidien) Antidisritmiese middels klas III (bv. amiodaroon, dofetilied, dronedaroon, ibutilied, sotalol). Sekere antipsigotika (bv. haloperidol, pimosied, sertindool). Sekere antidepressante (bv. sitalopraam, essitalopraam). Sekere antibiotika (bv. levofloksasien, moksifloksasien en kinolone). Sekere swamweermiddels (bv. pentamidien). Sekere antimalariamiddels (bv. halofantrien). Sekere gastro-intestinale medisyne (bv. dolasetron). Sekere medisynes vir kanker (bv. toremifeen, vandetanib). Sekere ander medisynes (bv. bepridil, metadoon). Die bogenoemde lys is verteenwoordigend en nie volledig nie. Domperidoonbasis Teensuurmiddels en anti-sekretoriese medisyne moet nie saam met mondelike formulerings van MOTILIUM geneem word nie aangesien hulle die orale CCDS Oct 2013 & CCDS June 2014 Page 26 of 37
biobeskikbaarheid van MOTILIUM verminder. Wanneer albei gebruik word, moet MOTILIUM voor etes geneem word en teensuurmiddels of anti-sekretoriese medisyne na etes. Mengmiddels MOTILIUM orale suspensie bevat sorbitol en kan moontlik nie geskik wees vir pasiënte met sorbitol intoleransie nie. Effek op die vermoë om te bestuur en masjinerie te gebruik Duiseligheid en slaperigheid is waargeneem na gebruik van MOTILIUM (sien NEWE-EFFEKTE). Pasiënte moet gevolglik aangeraai word om nie te bestuur of masjinerie te gebruik, of betrokke te raak by ander aktiwiteite wat verstandelike wakkerheid en koördinasie verg nie, totdat hulle weet hoe MOTILIUM hulle beïnvloed. INTERAKSIES Domperidoon word hoofsaaklik deur CYP3A4 gemetaboliseer. In vitro en menslike data wys daarop dat gelyktydige gebruik van medisynes wat hierdie ensiem sterk rem, die plasmakonsentrasie van domperidoon kan laat styg. Toe MOTILIUM toegedien is saam met kragtige CYP3A4-remmers waarvan aangetoon is dat hulle die QT-interval verleng, is klinies relevante veranderinge in QT-intervalle waargeneem. Gevolglik is gesamentlike toediening van MOTILIUM met sekere medisyne teenaangedui (sien KONTRA-INDIKASIES). CCDS Oct 2013 & CCDS June 2014 Page 27 of 37
Versigtig moet uitgeoefen word wanneer MOTILIUM toegedien word saam met kragtige CYP3A4-remmers waarvan nie aangetoon is dat hulle die QT-interval verleng nie, of medisyne waarvan reeds aangetoon is dat hulle die QT-interval verleng (sien WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS). Gelyktydige toediening van anticholinergiese medisynes (bv. dekstrometorfaan, difenhidramien) kan die anti-dispeptiese effekte van MOTILIUM antagoniseer. Aangesien MOTILIUM n gastrokinetiese uitwerking het, kan dit die absorpsie van ander medisyne wat gelyktydig mondelik toegedien word beïnvloed, veral die wat stadig vrygestel word of enteriesbedekte formulerings. By pasiënte wat reeds op digoksien of parasetamol gestabiliseer is, het gepaardgaande toediening van MOTILIUM egter nie die bloedvlakke van hierdie medisynes beïnvloed nie. MOTILIUM kan ook gegee word met: Neuroleptika; die werking hiervan word nie gepotensieer nie. Dopaminergiese agoniste (broomkriptien, L-dopa), waarvan die ongewenste perifere effekte soos verteringsteurnisse, naarheid en braking onderdruk word sonder om hul sentrale eienskappe teen te werk. Verminderde maagsuur belemmer die absorpsie van MOTILIUM. Mondelike biobeskikbaarheid word verminder deur voorafgaande toediening van simetidien en natriumbikarbonaat. CCDS Oct 2013 & CCDS June 2014 Page 28 of 37
Omdat MOTILIUM die serumprolaktienvlakke beïnvloed, kan dit moontlik inmeng met ander hipoprolaktinemiese medisynes en sommige diagnostiese toetse. SWANGERSKAP EN LAKTASIE Die veiligheid van gebruik tydens swangerskap en borsvoeding is nie bepaal nie. Domperidoon word in menslike borsmelk uitgeskei, daarom word borsvoeding nie aanbeveel vir moeders wat MOTILIUM suspensie neem nie. DOSIS EN GEBRUIKSAANWYSINGS Dit word aanbeveel dat mondelike MOTILIUM 15 30 minute voor maaltye geneem word. Indien dit na maaltye geneem word, is die absorpsie van die medisyne ietwat vertraag. Volwassenes en adolessente 12 jaar oud, wat 35 kg weeg en kinders wat 35 kg weeg Die dosis van MOTILIUM suspensie moet die laagste doeltreffende dosis vir die individuele situasie wees (tipies 30 mg/dag), met 'n maksimum daaglikse orale dosis van 40 mg. Gewoonlik moet die maksimum duur van behandeling nie meer as een week wees vir die behandeling van akute naarheid en braking nie. As naarheid en braking vir langer as 'n week aanhou, moet pasiënte hul mediese praktisyns raadpleeg. Vir ander indikasies is die aanvanklike duur van behandeling tot vier weke. Indien die behandeling vier CCDS Oct 2013 & CCDS June 2014 Page 29 of 37
weke oorskry, moet pasiënte herevalueer word en die behoefte vir voortgesette behandeling heroorweeg word. Formulering (domperidoon per eenheid) Orale suspensie (1 mg/ml) Dosis 10 ml drie tot vier keer per dag Maksimum dosis per dag 40 mg (40 ml van 'n 1 mg/ml orale suspensie) Babas en kinders < 12 jaar oud en wat < 35 kg weeg en volwassenes en adolessente wat < 35 kg weeg Die dosis van die MOTILIUM suspensie moet die laagste doeltreffende dosis wees. Die totale daaglikse dosis is afhanklik van die liggaamsgewig (sien tabel hieronder). Aangesien die metaboliese funksies en die bloedbreinskans nie volledig ontwikkel is binne die eerste lewensmaande nie, is die risiko van neurologiese newe-effekte hoër by jong kinders (sien NEWE-EFFEKTE). Oordosering kan senuweestelsel versteurings by kinders veroorsaak (sien BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN). Die dosis moet akkuraat volgens die liggaamsgewig bepaal word en moet nie die aanbevole maksimum individuele en daaglikse dosis by pasgeborenes, babas, kleuters en kinders oorskry nie. Gewoonlik moet die maksimum duur van behandeling nie meer as een week wees vir die behandeling van akute naarheid en braking nie. Vir ander indikasies is die aanvanklike duur van behandeling tot vier weke. Indien die behandeling vier weke oorskry, moet pasiënte herevalueer word en die behoefte vir voortgesette behandeling heroorweeg word. Die filmbedekte tablette is nie geskik vir gebruik by kinders, volwassenes en adolessente wat minder as 35 kg weeg nie. CCDS Oct 2013 & CCDS June 2014 Page 30 of 37
Formulering (domperidoon per eenheid) Orale suspensie (1 mg/ml) Dosis 0,25 mg/kg drie tot vier keer per dag Maksimum dosis per dag 35 mg (1 mg/kg maar nie meer as 35 ml nie) Swak nierfunksie Aangesien die eliminasie-halfleeftyd van domperidoon langer duur by ernstige verswakte nierfunksie (serumkreatinien > 6 mg/100 ml, d.i. > 0,6 mmol/l), moet die frekwensie van dosering van MOTILIUM verminder word na een- tot tweemaal per dag, afhangende van hoe ernstig die inkorting is, en die dosis sal moontlik verlaag moet word. Pasiënte met ernstig verswakte nierfunksie moet gereeld nagegaan word. Swak lewerfunksie MOTILIUM is teenaangedui vir pasiënte met matige (Child-Pugh 7 tot 9) of ernstige (Child- Pugh > 9) aangetaste lewerfunksie (sien KONTRA-INDIKASIES). Dosisaanpassing is nie nodig vir pasiënte met lig aangetaste (Child-Pugh 5 tot 6) lewerfunksie nie (sien Farmakokinetiese eienskappe). Gebruiksaanwysings Meng die inhoud van die bottel deeglik deur dit sagkens te kantel om die voorkoms van skuim te vermy. Aanwysings om die bottel oop te maak: Die bottel word voorsien met ʼn kind-bestande doppie, en moet soos volg oopgemaak word: CCDS Oct 2013 & CCDS June 2014 Page 31 of 37
- Druk die plastiese skroefdoppie ondertoe af terwyl dit antikloksgewys gedraai word. - Verwyder die losgedraaide doppie. NEWE-EFFEKTE Kliniese proewe data Die ongunstige geneesmiddelreaksies is volgens voorkomsfrekwensie ingedeel, in ooreenstemming met die volgende gebruik: 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), insluitende enkele berigte. Psigiatriese siektes Algemeen: Depressie, angs, afname/verlies van libido. Senuweestelselsiektes Algemeen: Hoofpyn, lomerigheid, akatisie. Gastro-intestinale siektes Algemeen: Diarree. Immuunstelselsiekte Ongewoon: CCDS Oct 2013 & CCDS June 2014 Page 32 of 37
Hipersensitiwiteit Vel- en onderhuidse weefselsiektes Algemeen: Uitslag, pruritus. Ongewoon: Urtikaria. Voortplantingstelsel- en borssiektes Algemeen: Borsvergroting/ginekomastie, borsteerheid, galaktorree, amenoree, borspyn, ongereelde menstruasie, laktasie afwyking. Ongewoon: Borsafskeiding, borste geswel. Algemene siektes en toestande by die plek van toediening Algemeen: Astenie. Droë mond is ook aangemeld. Nabemarking Bykomend tot die ongunstige newe-effekte wat gedurende kliniese proewe aangemeld is en hierbo gelys word, is die volgende newe-effekte na bemarking aangemeld: CCDS Oct 2013 & CCDS June 2014 Page 33 of 37
Immuunstelselsiekte Anafilaktiese reaksie (insluitende anafilaktiese skok). Psigiatriese siektes Agitasie, senuweeagtigheid. Senuweestelselsiektes Duiseligheid, ekstrapiramidale newe-effekte, konvulsies. Hartsiektes Skielike hartstilstand, ernstige ventrikulêre disritmieë (sien WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS). Vel- en onderhuidse weefselsiektes Angio-edeem Nier- en urienwegsiektes Urienretensie Ondersoeke Lewerfunksietoets abnormaal, toename in bloedprolaktienvlakke. Pediatriese bevolking CCDS Oct 2013 & CCDS June 2014 Page 34 of 37
Ekstrapiramidale versteurings kom hoofsaaklik voor by neonate en babas. Ander sentrale senuweestelsel-verwante effekte soos konvulsies, onrustigheid en lomerigheid is ook by babas en kinders aangemeld. BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN Tekens en simptome Oordosering is hoofsaaklik by babas en kinders aangemeld. Simptome van oordosering kan opgewondenheid, veranderde bewussyn, konvulsies, disoriëntasie, lomerigheid en ekstrapiramidale reaksies insluit. Behandeling Daar bestaan geen spesifieke teenmiddel vir domperidoon nie, maar maagspoeling asook die toediening van geaktiveerde houtskool kan in die geval van oordosering van nut wees. Simptomatiese en ondersteunende stappe word aanbeveel. Anticholinergiese of anti- Parkinson medisyne kan van nut wees by die beheer van ekstrapiramidale reaksies. IDENTIFIKASIE 'n Wit suspensie met ʼn soet smaak. AANBIEDING 100 ml bruin glasbottels. CCDS Oct 2013 & CCDS June 2014 Page 35 of 37
BERGINGSAANWYSINGS Bewaar by of benede 25 º C. Beskerm teen lig. HOU BUITE BEREIK VAN KINDERS. REGISTRASIENOMMER V/5.7.2/19 NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIESERTIFIKAAT JANSSEN PHARMACEUTICA (PTY) LTD. (Reg No.: 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) 518 7000 Nam. Reg. No.: 04/5.7.1/0277 NS 2 CCDS Oct 2013 & CCDS June 2014 Page 36 of 37
Botswana Reg. No.: B9315430 S3 Zimbabwe Reg. No.: 90/16.4/2379 PIM DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET 02 April 2015 CCDS Oct 2013 & CCDS June 2014 Page 37 of 37