英文药名：TECFIDERA(dimethyl fumarate delayed-release capsules）
In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush (7% versus 2%) was increased in patients treated with Tecfidera compared to placebo, respectively. Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth, redness, itching, and burning sensation). Flushing events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing, these events may continue to occur intermittently throughout treatment with Tecfidera. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfidera discontinued due to flushing. The incidence of serious flushing, which may be characterised by generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with Tecfidera (see sections 4.2, 4.4 and 4.5).
The incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%], upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%] and dyspepsia [5% versus 3%]) was increased in patients treated with Tecfidera compared to placebo, respectively. Gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience gastrointestinal events, these events may continue to occur intermittently throughout treatment with Tecfidera. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with Tecfidera discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with Tecfidera (see section 4.2).
In placebo-controlled studies, elevations of hepatic transaminases were observed. The majority of patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (ULN). The increased incidence of elevations of hepatic transaminases in patients treated with Tecfidera relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase ≥3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2% of patients treated with Tecfidera. There were no elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with Tecfidera or placebo.
In placebo-controlled studies, the incidence of proteinuria was higher in patients treated with Tecfidera (9%) compared to placebo (7%). The overall incidence of renal and urinary adverse events was similar for Tecfidera and placebo-treated patients. There were no reports of serious renal failure. On urinalysis, the percentage of patients with protein values of 1+ or greater was similar for Tecfidera (43%) and placebo-treated patients (40%). Typically, laboratory observations of proteinuria were not progressive. Compared to patients treated with placebo, estimated glomerular filtration rate (eGFR) was observed to increase in patients treated with Tecfidera, including those patients with 2 consecutive occurrences of proteinuria (≥1+).
In the placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count <0.2x109/l was observed in 1 patient treated with Tecfidera and in no patients treated with placebo. The incidence of infections (58% versus 60%) and serious infections (2% versus 2%) was similar in patients treated with placebo or Tecfidera. An increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8x109/l or <0.5x109/l. A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in patients treated with Tecfidera (45%) compared to placebo (10%). No untoward clinical consequences were observed in clinical trials.
Levels of 1,25-dihydroxyvitamin D decreased in Tecfidera treated patients relative to placebo (median percentage decrease from baseline at 2 years of 25% versus 15%, respectively) and levels of parathyroid hormone (PTH) increased in Tecfidera treated patients relative to placebo (median percentage increase from baseline at 2 years of 29% versus 15%, respectively). Mean values for both parameters remained within normal range.
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 the national reporting system:
Yellow Card Scheme
HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
No cases of overdose have been reported.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX09
Mechanism of action
The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear to be primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]).
Effects on the immune system
In preclinical and clinical studies, Tecfidera demonstrated anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite of dimethyl fumarate, significantly reduced immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studies with psoriasis patients, dimethyl fumarate affected lymphocyte phenotypes through a down-regulation of pro-inflammatory cytokine profiles (TH1, TH17), and biased towards anti-inflammatory production (TH2). Dimethyl fumarate demonstrated therapeutic activity in multiple models of inflammatory and neuroinflammatory injury. In Phase 3 studies, upon treatment with Tecfidera mean lymphocyte counts decreased on average by approximately 30% of their baseline value over the first year with a subsequent plateau.
Effect on cardiovascular system
Single doses of 240 mg or 360 mg Tecfidera did not have any effect on the QTc interval when compared to placebo in a QTc study.
Clinical efficacy and safety
Two, 2-year, randomised, double-blind, placebo controlled studies [Study 1 (DEFINE) with 1234 subjects and Study 2 (CONFIRM) with 1417 subjects] of subjects with relapsing-remitting multiple sclerosis (RRMS) were performed. Subjects with progressive forms of MS were not included in these studies. Efficacy (see table below) and safety were demonstrated in subjects with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least 1 relapse during the year prior to randomisation, or, within 6 weeks of randomisation had a brain Magnetic Resonance Imaging (MRI) demonstrating at least one gadolinium-enhancing (Gd+) lesion. Study 2 contained a rater-blinded (i.e. study physician/ investigator assessing the response to study treatment was blinded) reference comparator of glatiramer acetate.
In Study 1, patients had the following median baseline characteristics: age 39 years, disease duration 7.0 years, EDSS score 2.0. In addition, 16% of patients had an EDSS score >3.5, 28% had ≥2 relapses in the prior year and 42% had previously received other approved MS treatments. In the MRI cohort 36% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 1.4).
In Study 2, patients had the following median baseline characteristics: age 37 years, disease duration 6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score >3.5, 32% had ≥2 relapses in the prior year and 30% had previously received other approved MS treatments. In the MRI cohort 45% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 2.4).
Compared to placebo, subjects treated with Tecfidera had a clinically meaningful and statistically significant reduction on: the primary endpoint in Study 1, proportion of subjects relapsed at 2 years; and the primary endpoint in Study 2, annualised relapse rate at 2 years.
The annualised relapse rate for glatiramer acetate and placebo was 0.286 and 0.401 respectively in Study 2, corresponding to a reduction of 29% (p=0.013), which is consistent with approved prescribing information.
*P-value < 0.05; **P-value < 0.01; ***P-value < 0.0001; #not statistically significant
Efficacy in patients with high disease activity:
Consistent treatment effect on relapses in a subgroup of patients with high disease activity was observed, whilst the effect on time to 3-month sustained disability progression was not clearly established. Due to the design of the studies, high disease activity was defined as follows:
- Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions on brain MRI (n=42 in DEFINE; n=51 in CONFIRM) or,
- Patients who have failed to respond to a full and adequate course (at least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years (n=177 in DEFINE; n=141 in CONFIRM).
The European Medicines Agency has deferred the obligation to submit the results of studies with Tecfidera in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Orally administered Tecfidera (dimethyl fumarate) undergoes rapid presystemic hydrolysis by esterases and is converted to its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate is not quantifiable in plasma following oral administration of Tecfidera. Therefore, all pharmacokinetic analyses related to dimethyl fumarate were performed with plasma monomethyl fumarate concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.
The Tmax of monomethyl fumarate is 2 to 2.5 hours. As Tecfidera gastro-resistant hard capsules contain microtablets, which are protected by an enteric coating, absorption does not commence until they leave the stomach (generally less than 1 hour). Following 240 mg twice a day administered with food, the median peak (Cmax) was 1.72 mg/l and overall (AUC) exposure was 8.02 h.mg/l in subjects with multiple sclerosis. Overall, Cmax and AUC increased approximately dose- proportionally in the dose range studied (120 mg to 360 mg). In subjects with multiple sclerosis, two 240 mg doses were administered 4 hours apart as part of a three times a day dosing regimen. This resulted in a minimal accumulation of exposure yielding an increase in the median Cmax of 12% compared to the twice daily dosing (1.72 mg/l for twice daily compared to 1.93 mg/l for three times daily) with no safety implications.
Food does not have a clinically significant effect on exposure of dimethyl fumarate. However, Tecfidera should be taken with food due to improved tolerability with respect to flushing or gastrointestinal adverse events (see section 4.2).
The apparent volume of distribution following oral administration of 240 mg Tecfidera varies between 60 L and 90 L. Human plasma protein binding of monomethyl fumarate generally ranges between 27% and 40%.
In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted as unchanged dimethyl fumarate in urine. It is initially metabolised by esterases, which are ubiquitous in the gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Further metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system. A single 240 mg 14C-dimethyl fumarate dose study identified glucose as the predominant metabolite in human plasma. Other circulating metabolites included fumaric acid, citric acid and monomethyl fumarate. The downstream metabolism of fumaric acid occurs through the tricarboxylic acid cycle, with exhalation of CO2 serving as a primary route of elimination.
Exhalation of CO2 is the primary route of dimethyl fumarate elimination accounting for 60% of the dose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the dose respectively.
The terminal half-life of monomethyl fumarate is short (approximately 1 hour) and no circulating monomethyl fumarate is present at 24 hours in the majority of individuals. Accumulation of parent drug or monomethyl fumarate does not occur with multiple doses of dimethyl fumarate at the therapeutic regimen.
Dimethyl fumarate exposure increases in an approximately dose proportional manner with single and multiple doses in the 120 mg to 360 mg dose range studied.
Pharmacokinetics in special patient groups
Based on the results of Analysis of Variance (ANOVA), body weight is the main covariate of exposure (by Cmax and AUC) in relapsing remitting multiple sclerosis (RRMS) subjects, but did not affect safety and efficacy measures evaluated in the clinical studies.
Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethyl fumarate. The pharmacokinetics in patients aged 65 and over has not been studied.
The pharmacokinetics in patients below the age of 18 has not been studied.
Since the renal pathway is a secondary route of elimination for dimethyl fumarate accounting for less than 16% of the dose administered, evaluation of pharmacokinetics in individuals with renal impairment was not conducted.
As dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without the involvement of the CYP450 system, evaluation of phamacokinetics in individuals with hepatic impairment was not conducted.
5.3 Preclinical safety data
The adverse reactions described in the Toxicology and Reproduction toxicity sections below were not observed in clinical studies, but were seen in animals at exposure levels similar to clinical exposure levels.
Dimethyl fumarate and mono-methylfumarate were negative in a battery of in vitro assays (Ames, chromosomal aberration in mammalian cells). Dimethyl fumarate was negative in the in vivo micronucleus assay in the rat.
Carcinogenicity studies of dimethyl fumarate were conducted for up to 2 years in mice and rats. Dimethyl fumarate was administered orally at doses of 25, 75, 200 and 400 mg/kg/day in mice, and at doses of 25, 50, 100, and 150 mg/kg/day in rats. In mice, the incidence of renal tubular carcinoma was increased at 75 mg/kg/day, at equivalent exposure (AUC) to the recommended human dose. In rats, the incidence of renal tubular carcinoma was increased at 100 mg/kg/day, approximately 3 times higher exposure than the recommended human dose. The relevance of these findings to human risk is unknown.
The incidence of squamous cell papilloma and carcinoma in the nonglandular stomach (forestomach) was increased at equivalent exposure to the recommended human dose in mice and below exposure to the recommended human dose in rats (based on AUC). The forestomach in rodents does not have a human counterpart.
Nonclinical studies in rodent, rabbits, and monkeys were conducted with a dimethyl fumarate suspension (dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) administered by oral gavage. The chronic dog study was conducted with oral administration of the dimethyl fumarate capsule.
Kidney changes were observed after repeated oral administration of dimethyl fumarate in mice, rats, dogs, and monkeys. Renal tubule epithelial regeneration, suggestive of injury, was observed in all species. Renal tubular hyperplasia was observed in rats with life time dosing (2-year study). Cortical atrophy was observed in dogs and monkeys, and single cell necrosis and interstitial fibrosis were observed in monkeys that received daily oral doses of dimethyl fumarate for 12 months, at 6 times the recommended dose based on AUC. The relevance of these findings to humans is not known.
In the testes, degeneration of the seminiferous epithelium was seen in rats and dogs. The findings were observed at approximately the recommended dose in rats and 6 times the recommended dose in dogs (AUC basis). The relevance of these findings to humans is not known.
Findings in the forestomach of mice and rats consisted of squamous epithelial hyperplasia and hyperkeratosis; inflammation; and squamous cell papilloma and carcinoma in studies of 3 months or longer in duration. The forestomach of mice and rats does not have a human counterpart.
Oral administration of dimethyl fumarate to male rats at 75, 250, and 375 mg/kg/day prior to and during mating had no effects on male fertility up to the highest dose tested (at least 2 times the recommended dose on an AUC basis). Oral administration of dimethyl fumarate to female rats at 25, 100, and 250 mg/kg/day prior to and during mating, and continuing to Day 7 of gestation, induced reduction in the number of estrous stages per 14 days and increased the number of animals with prolonged diestrus at the highest dose tested (11 times the recommended dose on an AUC basis). However, these changes did not affect fertility or the number of viable fetuses produced.
Dimethyl fumarate has been shown to cross the placental membrane into fetal blood in rats and rabbits, with ratios of fetal to maternal plasma concentrations of 0.48 to 0.64 and 0.1 respectively. No malformations were observed at any dose of dimethyl fumarate in rats or rabbits. Administration of dimethyl fumarate at oral doses of 25, 100, and 250 mg/kg/day to pregnant rats during the period of organogenesis resulted in maternal adverse effects at 4 times the recommended dose on an AUC basis, and low fetal weight and delayed ossification (metatarsals and hindlimb phalanges) at 11 times the recommended dose on an AUC basis. The lower fetal weight and delayed ossification were considered secondary to maternal toxicity (reduced body weight and food consumption).
Oral administration of dimethyl fumarate at 25, 75, and 150 mg/kg/day to pregnant rabbits during organogenesis had no effect on embryo-fetal development and resulted in reduced maternal body weight at 7 times the recommended dose and increased abortion at 16 times the recommended dose, on an AUC basis.
Oral administration of dimethyl fumarate at 25, 100, and 250 mg/kg/day to rats during pregnancy and lactation resulted in lower body weights in the F1 offspring, and delays in sexual maturation in F1 males at 11 times the recommended dose on an AUC basis. There were no effects on fertility in the F1 offspring. The lower offspring body weight was considered secondary to maternal toxicity.
6. Pharmaceutical particulars
6.1 List of excipients
Silica, hydrophobic colloidal
Methacrylic acid – methyl methacrylate copolymer (1:1)
Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30%
Titanium dioxide (E171)
Brilliant Blue FCF (E133)
Yellow iron oxide (E172)
Capsule print (black ink)
Black iron oxide (E172)
6.3 Shelf life
240 mg gastro-resistant hard capsules: 3 years
6.4 Special precautions for storage
Do not store above 30°C.
Keep the blisters in the outer carton in order to protect from light.
6.5 Nature and contents of container
240 mg capsules: 56 or 168 capsules in PVC/PE/PVDC-PVC aluminium blister packs.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Biogen Idec Ltd
70 Norden Road
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 30 January 2014
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
TECFIDERA(dimethyl fumarate gastro-resistant hard capsules）
简介：英文药名：TECFIDERA(dimethyl fumarate delayed-release capsules） 中文药名：富马酸二甲酯缓释胶囊 生产厂家：德国[Biogen Idec]药品介绍富马酸二甲酯缓释胶囊由Biogen Idec公司开发，2013年3月27 ...