英文药名：Fampyr（Fampridin prolonged-release tablets） 中文药名：氨吡啶缓释片 生产厂家：Biogen 药品介绍 2010年7月25日,欧盟委员会批准Fampyra(氨吡啶缓释片)上市。用于改善多发性硬化症成人患者的行走状态. fampridine缓释剂是4_氨基吡啶(4_AP)的一种缓释剂型，由Aeorda公司开发的，用于治疗慢性脊髓损伤(SCI)。该公司已开始了两项Ⅲ期临床试验，将在美国和加拿大的70家以上的SCI医疗中心共观察360例患者，用以评价该药在治疗与慢性SCI有关的中度至重度强直状态时的安全性及疗效。 fampridine能加强受损伤神经的传导，是第1个用来恢复SCI患者一些神经学功能的化合物。氨吡啶缓释制剂为一口服剂型，每天服2次。它能通过阻滞无髓鞘神经轴突暴露的钾通道而恢复神经传导功能。在一项双盲、安慰剂对照的试验中，10mg的氨吡啶缓释制剂能改善一些SCI患者的中枢性运动传导功能，这可能是该药使损伤部位的传导缺陷得以改善及增强了大脑皮层的兴奋性所致。 在一项开放标签、为期4周的试验中，对l6例慢性SCI患者评价了fampridine缓释剂多种口服剂量的药代动力学与安全性。患者在l周分别服用l0，l5，20或25mg(bid)。结果表明该药吸收较慢，于2．6～3．2h达到血浆峰值浓度，其平均血浆清除半衰期为5．5～7．5h。该药一般都能被患者良好耐受，且不良反应也都为轻中度，有2名患者因不良反应而停止用药。 对l3例长期存在SCI的患者和l3名志愿者的试验中，观察了单次口服10mg氨吡啶缓释制剂后的心率及其变化情况。结果发现基础心率较慢的SCI患者的心率变化能力低于志愿者，而服药后增加到对照组的水平。一项双盲、设平行组的试验证实，该药25mg(bid)被患者良好耐受，且能明显改善肠道功能及SubjectGlobal的印象计分。 对新生大鼠所做的一些实验显示，在神经损伤之前以氨吡啶缓释制剂处理运动神经末梢能预防运动神经元死亡。在碾压坐骨神经前3d以该药处理比目鱼肌和趾长伸肌能促进其神经支配的恢复，而未处理组则否。该药能以浓度依赖方式增加I型星形细胞、神经元和骨骼肌胞质中游离钙的浓度，并使钙进入星形细胞及肌肉细胞的量增高7倍，但对神经元无此作用。 总之，氨吡啶缓释制剂能改善慢性SCI或多发性硬化症患者的神经学功能。先前的一些临床试验已表明，该缓释剂能减轻强直状态，改善性功能及对肠道与膀胱的控制能力。 包装规格 10mgx28 10mgx56 厂家：德国Biogen Fampyra 10 mg prolonged-release tablets 1. Name of the medicinal product Fampyra 10 mg prolonged-release tablets 2. Qualitative and quantitative composition Each prolonged-release tablet contains 10 mg of fampridine. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Prolonged-release tablet. An off-white, film coated, oval biconvex 13 x 8 mm tablet with flat edge debossed with A10 on one side. 4. Clinical particulars 4.1 Therapeutic indications Fampyra is indicated for the improvement of walking in adult patients with multiple sclerosis with walking disability (EDSS 4-7). 4.2 Posology and method of administration Treatment with Fampyra is restricted to prescription and supervision by physicians experienced in the management of MS. Posology The recommended dose is one 10 mg tablet, twice daily, taken 12 hours apart (one tablet in the morning and one tablet in the evening). Fampyra should not be administered more frequently or at higher doses than recommended (see section 4.4). The tablets should be taken without food (see section 5.2). Starting and Evaluating Fampyra Treatment • Initial prescription should be limited to 2 weeks of therapy as clinical benefits should generally be identified within 2-weeks after starting Fampyra • A timed walking test, e.g. the Timed 25 Foot Walk (T25FW), is recommended to evaluate improvement after two weeks. If no improvement is observed, Fampyra should be discontinued • Fampyra should be discontinued if benefit is not reported by patients. Re-Evaluating Fampyra Treatment If decline in walking ability is observed physicians should consider an interruption to treatment in order to reassess the benefits of Fampyra (see above). The re-evaluation should include withdrawal of Fampyra and performing the walking test. Fampyra should be discontinued if patients no longer receive walking benefit. Missed Dose The usual dosing regime should always be followed. A double dose should not be taken if a dose is missed. Older people Renal function should be checked in older people before starting treatment with Fampyra. Monitoring renal function to detect any renal impairment is recommended in older people (see section 4.4). Patients with renal impairment Fampyra is contraindicated in patients with mild, moderate and severe renal impairment (creatinine clearances <80 ml/min) (see section 4.3). Patients with hepatic impairment No dose adjustment is required for patients with hepatic impairment. Paediatric population The safety and efficacy of Fampyra in children aged 0 to 18 years have not been established. No data are available. Method of Administration Fampyra is for oral use. The tablet must be swallowed whole. It must not be divided, crushed, dissolved, sucked or chewed. 4.3 Contraindications Hypersensitivity to fampridine or to any of the excipients listed in section 6.1. Concurrent treatment with other medicinal products containing fampridine (4-aminopyridine). Patients with prior history or current presentation of seizure. Patients with mild, moderate or severe renal impairment (creatinine clearances <80 ml/min). Concomitant use of Fampyra with medicinal products that are inhibitors of Organic Cation Transporter 2 (OCT2) for example, cimetidine. 4.4 Special warnings and precautions for use Seizure risk Treatment with fampridine increases seizure risk (see section 4.8). Fampyra should be administered with caution in the presence of any factors which may lower seizure threshold. Fampyra should be discontinued in patients who experience a seizure while on treatment. Renal impairment Fampyra is primarily excreted unchanged by the kidneys. Patients with renal impairment have higher plasma concentrations which are associated with increased adverse reactions, in particular neurological effects. Determining renal function before treatment and its regular monitoring during treatment is recommended in all patients (particularly in older people in whom renal function might be reduced). Creatinine clearance can be estimated using the Cockroft-Gault formula. Fampyra should not be administered to patients with renal impairment (creatinine clearance <80 ml/min) (see section 4.3). Caution is required when Fampyra is prescribed concurrently with medicinal products that are substrates of OCT2 for example, carvedilol, propanolol and metformin. Hypersensitivity Reactions In post-marketing experience, serious hypersensitivity reactions (including anaphylactic reaction) have been reported, the majority of these cases occurred within the first week of treatment. Particular attention should be given to patients with a previous history of allergic reactions. If an anaphylactic or other serious allergic reaction occurs, Fampyra should be discontinued and not restarted. Other warnings and precautions Fampyra should be administered with caution to patients with cardiovascular symptoms of rhythm and sinoatrial or atrioventricular conduction cardiac disorders (these effects are seen in overdose). There is limited safety information in these patients. The increased incidence of dizziness and balance disorder seen with Fampyra may result in an increased risk of falls. Therefore, patients should use walking aids as needed. In clinical studies low white blood cell counts were seen in 2.1% of Fampyra patients versus 1.9% of patients on placebo. Infections were seen in the clinical studies as stated below. An increased infection rate and impairment of the immune response cannot be excluded. Placebo-Controlled Studies 202/203/204 System Organ Class Preferred Term Placebo (N=238) Fampyra 10 mg BID (N=400) TEAEs* with Incidence ≥1% in Fampyra vs Placebo Infections and Infestations (202/203/204) 59 (24.8%) 124 (31.0%) 6.2% Gastroenteritis viral 4 (1.7%) 6 (1.5%) - Influenza 0 (0%) 6 (1.5%) 1.5% Nasopharyngitis 4 (1.7%) 14 (3.5%) 1.8% Pneumonia 1 (0.4%) 4 (1.0%) - Sinusitis 8 (3.4%) 6 (1.5%) - Upper respiratory tract infection 15 (6.3%) 20 (5.0%) - Urinary tract infection 20 (8.4%) 48 (12.0%) 3.6% Viral infection 1 (0.4%) 6 (1.5%) 1.1% * TEAEs – Treatment Emergent Adverse Events 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Concurrent treatment with other medicinal products containing fampridine (4-aminopyridine) is contraindicated (see section 4.3). Fampridine is eliminated mainly via kidneys with active renal secretion accounting for about 60% (see section 5.2). OCT2 is the transporter responsible for the active secretion of fampridine. Thus, the concomitant use of fampridine with medicinal products that are inhibitors of OCT2 for example, cimetidine are contraindicated (see section 4.3) and concomitant use of fampridine with medicinal products that are substrates of OCT2 for example, carvedilol, propanolol and metformin is cautioned (see section 4.4.) Interferon: fampridine has been administered concomitantly with interferon-beta and no pharmacokinetic medicinal product interactions were observed. Baclofen: fampridine has been administered concomitantly with baclofen and no pharmacokinetic medicinal product interactions were observed. 4.6 Fertility, pregnancy and lactation Pregnancy There are no data from the use of fampridine in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure it is preferable to avoid the use of Fampyra in pregnancy. Breast-feeding It is unknown whether fampridine is excreted in human or animal milk. Fampyra is not recommended during breast-feeding. Fertility In animal studies no effects on fertility were seen. 4.7 Effects on ability to drive and use machines Fampyra has moderate influence on the ability to drive and use machines because Fampyra can cause dizziness. 4.8 Undesirable effects The safety of Fampyra has been evaluated in randomised controlled clinical studies, in open label long term studies and in the post marketing setting. Adverse reactions identified are mostly neurological and include seizure, insomnia, anxiety, balance disorder, dizziness, paraesthesia, tremor, headache and asthenia. This is consistent with fampridine's pharmacological activity. The highest incidence of adverse reactions identified from placebo-controlled trials in multiple sclerosis patients with Fampyra given at the recommended dose, are reported as urinary tract infection (in approximately 12% of patients). Adverse reactions are presented below by system organ class and absolute frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness MedDRA SOC Adverse Reaction Frequency category Infections and infestations Urinary tract infection Very Common Immune system disorders Anaphylaxis Angioedema Hypersensitivity Uncommon Uncommon Uncommon Psychiatric disorders Insomnia Anxiety Common Common Nervous system disorders Dizziness Headache Balance disorder Paraesthesia Tremor Seizure Exacerbation of trigeminal neuralgia Common Common Common Common Common Uncommon Uncommon Vascular disorders Hypotension* Uncommon Respiratory, thoracic and mediastinal disorders Dyspnoea Pharyngolaryngeal pain Common Common Gastrointestinal disorders Nausea Vomiting Constipation Dyspepsia Common Common Common Common Skin and subcutaneous tissue disorders Rash Urticaria Uncommon Uncommon Musculoskeletal and connective tissue disorders Back pain Common General disorders and administration site conditions Asthenia Chest discomfort* Common Uncommon * These symptoms were observed in the context of hypersensitivity Description of selected adverse reactions Seizure In post-marketing experience, there have been reports of seizure, the frequency is not known (cannot be estimated from the available data). For further information on seizure risk, please refer to sections 4.3 and 4.4. Hypersensitivity In post-marketing experience, there have been reports of hypersensitivity reactions (including anaphylaxis) which have occurred with one or more of the following: dyspnoea, chest discomfort, hypotension, angioedema, rash and urticaria. For further information on hypersensitivity reactions, please refer to sections 4.3 and 4.4. 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: 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose Symptoms Acute symptoms of overdose with Fampyra were consistent with central nervous system excitation and included confusion, tremulousness, diaphoresis, seizure, and amnesia. Central nervous system side effects at high doses of 4-aminopyridine include confusion, seizures, status epilepticus, involuntary and choreoathetoid movements. Other side effects at high doses include cases of cardiac arrhythmias (for example, supraventricular tachycardia and bradycardia) and ventricular tachycardia as a consequence of potential QT prolongation. Reports of hypertension have also been received. Management Patients who overdose should be provided supportive care. Repeated seizure activity should be treated with benzodiazepine, phenytoin, or other appropriate acute anti-seizure therapy. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX07. Pharmacodynamic effects Fampyra is a potassium channel blocker. By blocking potassium channels, Fampyra reduces the leakage of ionic current through these channels, thereby prolonging repolarization and thus enhancing action potential formation in demyelinated axons and neurological function. Presumably, by enhancing action potential formation, more impulses might be conducted in the central nervous system. Clinical efficacy and safety Two phase III, randomized, double-blind, placebo controlled confirmatory studies, (MS-F203 and MS-F204) have been performed. The majority of patients in these studies were using immunomodulatory medicines. The Fampyra dose was 10mg BID. The primary endpoint was the responder rate in walking speed as measured by the Timed 25-foot Walk (T25FW). A responder was defined as a patient who consistently had a faster walking speed for at least three visits out of a possible four during the double blind period as compared to the maximum value among five non-double blind off-treatment visits. A significantly greater proportion of patients taking Fampyra 10 mg BID were responders as compared to placebo (MS-F203: 34.8% vs. 8.3%, p<0.001; MS-F204: 42.9% vs. 9.3%, p<0.001). Patients who responded to Fampyra increased their walking speed on average by 26.3% vs 5.3% on placebo (p<0.001) (MS-F203) and 25.3% vs 7.8% (p< 0.001) (MS-F204). The improvement appeared rapidly (within weeks) after starting Fampyra. Statistically and clinically meaningful improvements in walking were seen, as measured by the 12- item Multiple Sclerosis Walking Scale. Pivotal Studies MS-F203 and MS-F204 STUDY * MS-F203 MS-F204   Placebo Fampyra 10 mg BID Placebo Fampyra 10 mg BID n of subjects 72 224 118 119 Consistent improvement 8.3% 34.8% 9.3% 42.9% Difference   26.5%   33.5% CI95%   17.6%, 35.4%   23.2%, 43.9% P-value   < 0.001   < 0.001 ≥20% improvement 11.1% 31.7% 15.3% 34.5% Difference   20.6%   19.2% CI95%   11.1%,30.1%   8.5%,29.9% P-value   <0.001   <0.001 Walking speed Feet/sec Ft per sec Ft per sec Ft per sec Ft per sec Baseline 2.04 2.02 2.21 2.12 Endpoint 2.15 2.32 2.39 2.43 Change 0.11 0.30 0.18 0.31 Difference 0.19 0.12 p-value 0.010 0.038 Average % Change 5.24 13.88 7.74 14.36 Difference 8.65 6.62 p-value < 0.001 0.007 MSWS-12-score (mean, sem) (Multiple Sclerosis Walking Scale)         Baseline 69.27 (2.22) 71.06 (1.34) 67.03 (1.90) 73.81 (1.87) Average change -0.01 (1.46) -2.84 (0.878) 0.87 (1.22) -2.77 (1.20) Difference 2.83 3.65 p-value 0.084 0.021 LEMMT (mean, sem) (Lower Extremity Manual Muscle Test)         Baseline 3.92 (0.070) 4.01 (0.042) 4.01 (0.054) 3.95 (0.053) Average change 0.05 (0.024) 0.13 (0.014) 0.05 (0.024) 0.10 (0.024) Difference 0.08 0.05 p-value 0.003 0.106 Ashworth Score (A test for muscle spasticity)         Baseline 0.98 (0.078) 0.95 (0.047) 0.79 (0.058) 0.87 (0.057) Average change -0.09 (0.037) -0.18 (0.022) -0.07 (0.033) -0.17 (0.032) Difference 0.10 0.10 p-value 0.021 0.015 The European Medicines Agency has waived the obligation to submit the results of studies with Fampyra in all subsets of the paediatric population in treatment of multiple sclerosis with walking disability (see section 4.2 for information on paediatric use). The medicinal product has been authorised under a so-called "conditional approval" scheme. This means that further evidence on this medicinal product is awaited, in particular about Fampyra's benefits beyond its effects on walking speed and with respect to early identification of responders. A study will be conducted to investigate this. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Absorption: Orally administered fampridine is rapidly and completely absorbed from the gastrointestinal tract. Fampridine has a narrow therapeutic index. Absolute bioavailability of Fampyra prolonged-release tablets has not been assessed, but relative bioavailability (as compared to an aqueous oral solution) is 95%. The Fampyra prolonged-release tablet has a delay in the absorption of fampridine manifested by slower rise to a lower peak concentration, without any effect on the extent of absorption. When Fampyra tablets are taken with food, the reduction in the area under the plasma concentration-time curve (AUC0-∞) of fampridine is approximately 2-7% (10 mg dose). The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. However, Cmax increases by 15-23%. Since there is a clear relationship between Cmax and dose related adverse reactions, it is recommended to take Fampyra without food (see section 4.2). Distribution: Fampridine is a lipid-soluble medicinal product which readily crosses the blood-brain barrier. Fampridine is largely unbound to plasma proteins (bound fraction varied between 3-7% in human plasma). Fampridine has a volume of distribution of approximately 2.6 l/kg. Fampridine is not a substrate for P-glycoprotein. Biotransformation: Fampridine is metabolised in humans by oxidation to 3-hydroxy-4-aminopyridine and further conjugated to the 3-hydroxy-4-aminopyridine sulfate. No pharmacological activity was found for the fampridine metabolites against selected potassium channels in vitro. The 3-hydroxylation of fampridine to 3-hydroxy-4-aminopyridine by human liver microsomes appeared to be catalyzed by Cytochrome P450 2E1 (CYP2E1). There was evidence of direct inhibition of CYP2E1 by fampridine at 30 μM (approximately 12% inhibition) which is approximately 100 times the average plasma fampridine concentration measured for the 10 mg tablet. Treatment of cultured human hepatocytes with fampridine had little or no effect on induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5 enzyme activities. Elimination: The major route of elimination for fampridine is renal excretion, with approximately 90% of the dose recovered in urine as parent medicinal product within 24 hours. Renal clearance (CLR 370 ml/min) is substantially greater than glomerular filtration rate due to combined glomerular filtration and active excretion by the renal OCT2 transporter. Faecal excretion accounts for less than 1% of the administered dose. Fampyra is characterized by linear (dose-proportional) pharmacokinetics with a terminal elimination half-life of approximately 6 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase proportionately with dose. There is no evidence of clinically relevant accumulation of fampridine taken at the recommended dose in patients with full renal function. In patients with renal impairment accumulation occurs relative to the degree of impairment. Special Populations Older people: Clinical studies of Fampyra did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Fampyra is primarily excreted unchanged by the kidneys, and with creatinine clearance known to decrease with age, monitoring of renal function in older patients should be considered (see section 4.2). Paediatric Population: No data are available. Patients with renal impairment: Fampridine is eliminated primarily by the kidneys as unchanged medicinal product and therefore renal function should be checked in patients where renal function might be compromised. Patients with mild renal impairment can be expected to have approximately 1.7 to 1.9 times the fampridine concentrations achieved by patients with normal renal function. Fampyra must not be administered to patients with mild, moderate and severe renal impairment (see section 4.3). 5.3 Preclinical safety data Fampridine was studied in oral repeat dose toxicity studies in several animal species. Adverse responses to orally administered fampridine were rapid in onset, most often occurring within the first 2 hours post-dose. Clinical signs evident after large single doses or repeated lower doses were similar in all species studied and included tremors, convulsions, ataxia, dyspnoea, dilated pupils, prostration, abnormal vocalization, increased respiration, and excess salivation. Gait abnormalities and hyper-excitability were also observed. These clinical signs were not unexpected and represent exaggerated pharmacology of fampridine. In addition, single cases of fatal urinary tract obstructions were observed in rats. The clinical relevance of these findings remains to be elucidated, but a causal relationship with fampridine treatment cannot be excluded. In reproduction toxicity studies in rats and rabbits, decreased weight and viability of foetuses and offspring were observed at maternally toxic doses. However, no increased risk for malformations or adverse effects on fertility were noted. In a battery of in vitro and in vivo studies fampridine did not show any potential to be mutagenic, clastogenic or carcinogenic. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: Hypromellose Microcrystalline cellulose Silica, colloidal anhydrous Magnesium stearate Film-coat: Hypromellose Titanium dioxide (E-171) Polyethylene glycol 400 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. After first opening a bottle, use within 7 days. 6.4 Special precautions for storage Store below 25°C. Store the tablets in the original packaging in order to protect from light and moisture. 6.5 Nature and contents of container Fampyra is supplied in either bottles or blister packs. Bottles HDPE (high-density polyethylene) bottle with polypropylene caps, each bottle contains 14 tablets and a silica gel desiccant. Pack size of 28 (2 bottles of 14) tablets. Pack size of 56 (4 bottles of 14) tablets. Blister packs Foil blisters (aluminium / aluminium), each blister tray contains 14 tablets. Pack size of 28 (2 blisters of 14) tablets. Pack size of 56 (4 blisters of 14) tablets. 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 Limited Innovation House 70 Norden Road Maidenhead Berkshire SL6 4AY United Kingdom 8. Marketing authorisation number(s) EU/1/11/699/001 EU/1/11/699/002 EU/1/11/699/003 EU/1/11/699/004 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 20 July 2011 Date of latest renewal: 3 July 2015 10. Date of revision of the text July 2015 Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu