英文药名:Trobalt(retigabine filmcoated tablets) 中文药名:瑞替加滨片 生产厂家:葛兰素史克
Description of selected adverse reactions Adverse reactions related to voiding dysfunction, including urinary retention, were reported in 5% of retigabine-treated patients in the pooled safety dataset (see section 4.4). The majority of events occurred in the first 8 weeks of treatment, and there was no apparent dose-relationship. In retigabine-treated patients in the pooled dataset, confusional state was reported in 9% of patients, hallucinations in 2% of patients and psychotic disorders in 1% of patients (see section 4.4). The majority of adverse reactions occurred in the first 8 weeks of treatment, and there was an apparent dose-relationship for confusional state only. Adverse event data from clinical trial subjects showed a rate of event of discolouration of the nails, lips, skin and/or mucosa per patient year of exposure of 3.6%. The cumulative incidences of an event at 1 year, 2 years, 3 years, 4 years and 5 years of exposure are approximately 1%, 1.8%, 4.4%, 10.2% and 16.7% respectively. Approximately 30-40% of clinical trial subjects who were being treated with retigabine and underwent a skin and/or ophthalmological examination had findings of discolouration of nails, lips, skin and/or mucosa or non-retinal ocular pigmentation, and approximately 15-30% of clinical trial subjects who were being treated with retigabine and underwent an ophthalmological examination had retinal pigmentation findings. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Ireland HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie. United Kingdom the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Symptoms and signs There is limited experience of overdose with retigabine. Retigabine overdoses in excess of 2,500 mg/day were reported during clinical studies. In addition to adverse reactions seen at therapeutic doses, symptoms of retigabine overdose included agitation, aggressive behaviour and irritability. There were no reported sequelae. In a study in volunteers, cardiac arrhythmia (cardiac arrest/asystole or ventricular tachycardia) occurred in two subjects within 3 hours of receiving a single 900 mg retigabine dose. The arrhythmias spontaneously resolved, and both volunteers recovered without sequelae. Management In the event of overdose, it is recommended that the patient is given appropriate supportive therapy as clinically indicated, including electrocardiogram (ECG) monitoring. Further management should be as recommended by the national poisons centre, where available. Haemodialysis has been shown to reduce the plasma concentrations of retigabine and NAMR by approximately 50%. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX21. Mechanism of action Potassium channels are one of the voltage-gated ion channels found in neuronal cells and are important determinants of neuronal activity. In vitro studies indicate that retigabine acts primarily through opening neuronal potassium channels (KCNQ2 [Kv7.2] and KCNQ3 [Kv7.3]). This stabilises the resting membrane potential and controls the sub-threshold electrical excitability in neurons, thus preventing the initiation of epileptiform action potential bursts. Mutations in the KCNQ channels underlie several human inheritable disorders, including epilepsy (KCNQ2 and 3). The mechanism of action of retigabine on potassium channels has been well documented, however other mechanisms by which retigabine may assert an antiepileptic effect have yet to be fully elucidated. In a range of seizure models, retigabine increased the threshold for seizure induction produced by maximal electroshock, pentylenetetrazol, picrotoxin and N-methyl-D-aspartate (NMDA). Retigabine also displayed inhibitory properties in multiple kindling models, for example, in the fully kindled state and in some cases during the kindling development. In addition, retigabine was effective in preventing status epilepticus seizures in rodents with cobalt-induced epileptogenic lesions, and inhibiting tonic extensor seizures in genetically susceptible mice. The relevance of these models to human epilepsy, however, is not known. Pharmacodynamic effects In rats, retigabine increased the sleep time induced by thiopental sodium from approximately 4 min to 53 min, and the propofol-induced sleep time from approximately 8 min to 12 min. There was no effect on sleep time induced by halothane or methohexital sodium. Trobalt may increase the duration of anesthesia induced by some anaesthetics (for example thiopental sodium). Clinical efficacy of adjunctive retigabine therapy in partial onset seizures Three multicentre, randomized, double-blind, placebo-controlled studies in a total of 1239 adult patients have been conducted to assess the efficacy of retigabine as adjunctive therapy of partial onset seizures, with or without secondary generalisation. All patients enrolled were to have had seizures that were not adequately controlled with 1 to 3 concomitant antiepileptic drugs, and more than 75% of all patients were taking ≥2 concurrent antiepileptic drugs. Across all studies, patients had a mean duration of epilepsy of 22 years and a median baseline seizure frequency ranging from 8 to 12 per 28 days. Patients were randomized to placebo or retigabine at 600, 900 or 1,200 mg/day (see Table 1). During an 8-week baseline period, patients had to experience ≥4 partial onset seizures per 28 days. Patients could not be seizure-free for ≥21 days. The duration of the maintenance phase was 8 or 12 weeks. The primary efficacy endpoints were: - percentage change in the 28-day total partial seizure frequency from baseline to the double-blind phase (titration and maintenance phases combined) in all three studies - responder rate (defined as the percentage of patients with a ≥50% reduction in 28-day total partial seizure frequency) from baseline to the maintenance phase (Studies 301 and 302 only). Retigabine was effective in adjunctive treatment of adults with partial onset seizures in three clinical studies (Table 1). Retigabine was statistically significantly superior to placebo at 600 mg/day (one study), 900 mg/day (two studies) and 1,200 mg/day (two studies). The studies were not designed to evaluate specific combinations of antiepileptic drugs. Consequently, the efficacy and safety of retigabine when taken concomitantly with antiepileptic drugs that were less commonly used as background treatment in the clinical studies, including levetiracetam, has not been definitely shown. Table 1. Summary of percentage changes in 28-day total partial seizure frequency and responder rates
~ Dose not studied In open-label extensions of the three placebo-controlled studies, persistence of efficacy was maintained over an evaluation period of at least 12 months (365 patients). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Trobalt in paediatric patients aged 0 to below 2 years with Lennox Gastaut Syndrome (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Trobalt in paediatric patients aged 2 to below 18 years with Lennox Gastaut Syndrome, and in paediatric patients aged 0 to below 18 years with partial onset seizures (see section 4.2 for information on paediatric use) . 5.2 Pharmacokinetic properties Absorption After both single and multiple oral doses, retigabine is rapidly absorbed with median tmax values generally between 0.5 and 2 hours. Absolute oral bioavailability of retigabine relative to an intravenous dose is approximately 60%. Administration of retigabine with a high fat meal resulted in no change in the overall extent of retigabine absorption, but food reduced the between-subject variability in Cmax (23%) compared to the fasted state (41%), and led to an increase in Cmax (38%). The effect of food on Cmax under usual clinical conditions is not expected to be clinically relevant. Therefore Trobalt may be taken with or without food. Distribution Retigabine is approximately 80% bound to plasma protein over the concentration range of 0.1 to 2 µg/ml. The steady state volume of distribution of retigabine is 2 to 3 l/kg following intravenous dosing. Biotransformation Retigabine is extensively metabolised in humans. A substantial fraction of the retigabine dose is converted to inactive N-glucuronides. Retigabine is also metabolised to an N-acetyl metabolite (NAMR) that is also subsequently glucuronidated. NAMR has antiepileptic activity, but is less potent than retigabine in animal seizure models. There is no evidence for hepatic oxidative metabolism of retigabine or NAMR by cytochrome P450 enzymes. Therefore co-administration with inhibitors or inducers of cytochrome P450 enzymes is unlikely to affect the pharmacokinetics of retigabine or NAMR. In vitro studies using human liver microsomes showed little or no potential for retigabine to inhibit the major cytochrome P450 isoenzymes (including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5). In addition, retigabine and NAMR did not induce CYP1A2 or CYP3A4/5 in human primary hepatocytes. Therefore retigabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms. Elimination Elimination of retigabine occurs via a combination of hepatic metabolism and renal excretion. A total of approximately 84% of the dose is recovered in the urine, including the N-acetyl metabolite (18%), N-glucuronides of the parent active substance and of the N-acetyl metabolite (24%), or parent active substance (36%). Only 14% of retigabine is excreted in the faeces. Retigabine has a plasma half-life of approximately 6 to 10 hours. The total clearance of retigabine from plasma following intravenous dosing is typically 0.4 to 0.6 l/h/kg. Linearity Retigabine pharmacokinetics are essentially linear over the single dose range of 25 to 600 mg in healthy volunteers and up to 1,200 mg daily in patients with epilepsy, with no unexpected accumulation following repeated administration. Special patient populations Renal impairment In a single dose study, retigabine AUC was increased by approximately 30% in volunteers with mild renal impairment (creatinine clearance 50 to 80 ml/min) and by approximately 100% in volunteers with moderate to severe renal impairment (creatinine clearance <50 ml/min), relative to healthy volunteers. Adjustment of the Trobalt dose is recommended in patients with moderate to severe renal impairment but no adjustment of the Trobalt dose is recommended in patients with mild renal impairment (see section 4.2). In a single dose study in healthy volunteers and subjects with end stage renal disease, the retigabine AUC was increased by approximately 100% in the subjects with end stage renal disease relative to healthy volunteers. In a second single dose study in subjects with end stage renal disease receiving chronic haemodialysis (n= 8), initiation of dialysis at approximately 4 hours after a single dose of retigabine (100 mg) resulted in a median reduction in retigabine plasma concentrations of 52% from the start to end of dialysis. The percentage decrease in plasma concentration during dialysis ranged from 34% to 60% except for one subject who had a 17% reduction. Hepatic impairment In a single dose study, there were no clinically significant effects on retigabine AUC in volunteers with mild hepatic impairment (Child-Pugh score 5 to 6). The retigabine AUC was increased by approximately 50% in volunteers with moderate hepatic impairment (Child-Pugh score 7 to 9) and by approximately 100% in volunteers with severe hepatic impairment (Child-Pugh score >9), relative to healthy volunteers. Adjustment of the Trobalt dose is recommended in patients with moderate or severe hepatic impairment (see section 4.2). Body weight In a population pharmacokinetic analysis, retigabine clearance increased with increasing body surface area. However, this increase is not considered to be clinically meaningful, and since retigabine is titrated according to individual patient response and tolerability, dose-adjustments are not required on the basis of body weight. Older people (65 years of age and above) In a single-dose study, retigabine was eliminated more slowly by healthy older volunteers (66 to 82 years of age) relative to healthy young adult volunteers, resulting in a higher AUC (approximately 40 to 50%) and longer terminal half-life (30%) (see section 4.2). Gender The results of a single dose study showed that in young adult volunteers, retigabine Cmax was approximately 65% higher in females than in males, and in older volunteers (66 to 82 years of age), retigabine Cmax was approximately 75% higher in females compared with males. When Cmax was normalized for weight, the values were approximately 30% higher in young females than in males and 40% higher in older females compared with males. However, there was no apparent gender difference in weight-normalized clearance, and since retigabine is titrated according to individual patient response and tolerability, dose-adjustments are not required on the basis of gender. Race A post-hoc analysis across multiple healthy volunteer studies demonstrated a 20% reduction in retigabine clearance in healthy black volunteers relative to healthy Caucasian volunteers. However, this effect is not considered clinically significant, therefore no adjustment of the Trobalt dose is recommended. Paediatric population The pharmacokinetics of retigabine in children below 12 years of age have not been investigated. An open-label, multiple dose pharmacokinetic, safety and tolerability study in five subjects aged between 12 years to less than 18 years with partial onset seizures determined that the pharmacokinetics of retigabine in adolescents were consistent with the pharmacokinetics of retigabine in adults. However, efficacy and safety of retigabine have not been determined in adolescents. 5.3 Preclinical safety data Maximum doses in repeat dose toxicity studies were limited by the exaggerated pharmacologic effects of retigabine (including ataxia, hypokinesia and tremor). At no observed effect levels, animal exposure in these studies was generally less than that reached in humans at recommended clinical doses. Distension of the gall bladder was seen in studies with dogs, but there was no evidence of cholestasis or other signs of gall bladder dysfunction, and bile ejection volume was unchanged. The gall bladder distension in the dog resulted in focal compression of the liver. No signs of gall bladder dysfunction were seen clinically. Preclinical data reveal no special hazard for humans based on studies of genotoxicity or carcinogenic potential. Reproductive toxicology Retigabine had no effect on fertility or general reproductive performance. In rats, retigabine and/or its metabolites crossed the placenta resulting in tissue concentrations that were similar in dams and foetuses. There was no evidence of teratogenicity following administration of retigabine to pregnant animals during the period of organogenesis. In a study of peri- and post-natal development in rats, retigabine was associated with increased perinatal mortality following administration during pregnancy. In addition, there was a delay in auditory startle response development. These findings were apparent at exposure levels lower than those obtained with clinically recommended doses and were accompanied by maternal toxicities (including ataxia, hypokinesia, tremor and reduced body weight gain). The maternal toxicities interfered with higher dosing of the dams and hence deduction of safety margins with regard to human therapy. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Croscarmellose sodium Hypromellose Magnesium stearate Microcrystalline cellulose. Film-coating 50 mg tablets: Polyvinyl alcohol Titanium dioxide (E171) Talc (E553b) Indigo carmine aluminium lake (E132) Carmine (E120). Lecithin (SOY) Xanthan gum 100 mg tablets: Polyvinyl alcohol Titanium dioxide (E171) Talc (E553b) Indigo carmine aluminium lake (E132) Iron oxide yellow (E172). Lecithin (SOY) Xanthan gum 200 mg tablets: Polyvinyl alcohol Titanium dioxide (E171) Talc (E553b) Iron oxide yellow (E172). Lecithin (SOY) Xanthan gum 300 mg tablets: Polyvinyl alcohol Titanium dioxide (E171) Talc (E553b) Indigo carmine aluminium lake (E132) Iron oxide yellow (E172). Lecithin (SOY) Xanthan gum 400 mg tablets: Polyvinyl alcohol Titanium dioxide (E171) Talc (E553b) Indigo carmine aluminium lake (E132) Carmine (E120). Lecithin (SOY) Xanthan gum 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions 6.5 Nature and contents of container 50 mg tablets (maintenance packs): Opaque PVC-PVDC-aluminium foil blisters. Packs containing 21 or 84 film-coated tablets. 100 mg tablets (maintenance packs): Opaque PVC-PVDC-aluminium foil blisters. Packs containing 21 or 84 film-coated tablets. 200 mg tablets: Opaque PVC-PVDC-aluminium foil blisters. Pack containing 84 film-coated tablets; multi-pack comprising 168 (2 x 84) film-coated tablets. 300 mg tablets: Opaque PVC-PVDC-aluminium foil blisters. Pack containing 84 film-coated tablets; multi-pack comprising 168 (2 x 84) film-coated tablets. 400 mg tablets: Opaque PVC-PVDC-aluminium foil blisters. Pack containing 84 film-coated tablets; multi-pack comprising 168 (2 x 84) film-coated tablets. Treatment initiation pack Outer carton containing opaque PVC-PVDC-aluminium foil blisters Each pack contains: - 105 film-coated tablets (presented as five blisters of 21 x 50 mg film-coated tablets) - a detachable posology card 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Glaxo Group Limited 980 Great West Road, Brentford, Middlesex, TW8 9GS United Kingdom 8. Marketing authorisation number(s) EU/1/11/681/001 – Trobalt 50 mg – 21 film-coated tablets EU/1/11/681/002 – Trobalt 50 mg – 84 film-coated tablets EU/1/11/681/004 – Trobalt 100 mg – 21 film-coated tablets EU/1/11/681/005 – Trobalt 100 mg – 84 film-coated tablets EU/1/11/681/007 – Trobalt 200 mg – 84 film-coated tablets EU/1/11/681/008 – Trobalt 200 mg – 168 (2 x 84) film-coated tablets (multipack) EU/1/11/681/009 – Trobalt 300 mg – 84 film-coated tablets EU/1/11/681/010 – Trobalt 300 mg – 168 (2 x 84) film-coated tablets (multipack) EU/1/11/681/011 – Trobalt 400 mg – 84 film-coated tablets EU/1/11/681/012 – Trobalt 400 mg – 168 (2 x 84) film-coated tablets (multipack) EU/1/11/681/014 – Trobalt Intiation Pack – 105 x 50 mg film-coated tablets 9. Date of first authorisation/renewal of the authorisation 28 March 2011 10. Date of revision of the text 9 April 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. |
Trobalt(retigabine filmcoated tablets)简介:
英文药名:Trobalt(retigabine filmcoated tablets)
中文药名:瑞替加滨片
生产厂家:葛兰素史克药品介绍Trobalt(retigabine)获欧盟正式批准成人癫痫近日,欧盟已批准的Trobalt(retigabine,瑞替加滨 ... 责任编辑:admin
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