2010年1月22日，美国食品药品管理局批准Ampyra（dalfampridine）缓释片用于提高多发性硬化症（MS）患者的步行速度。该药品是首个获批用于这一用途的药物。 MS是一种能够影响人类中枢神经系统-大脑、脊髓和视神经，从而致残的慢性疾病。美国大约有40万MS患者，全球约有2500万MS患者。MS的病程进展、严重程度和症状是不可预知的，并且不同患者的情况也可能会互不相同。有些患者的症状可能是轻度的，如四肢麻木；有些患者的症状可能是严重的，如麻痹或失明。虽然这些症状常常较轻微且易被忽略，但大约一半的MS患者都曾有过认知缺损的经历，例如在注意力、记忆和判断方面存在困难。MS患者中也常会出现抑郁症状。 FDA药品审评与研究中心神经病学产品部主任、医学博士Russell Katz说，“MS患者面对的最重要的问题之一是行走困难。” 临床试验显示，接受Ampyra治疗的患者步行速度比接受安慰剂治疗的患者步行速度更快。最常见的不良反应包括泌尿道感染、失眠、头晕、头痛、恶心、虚弱、背痛、平衡障碍、鼻咽肿胀、便秘、腹泻、消化不良、咽喉痛、发烧、注射部位麻刺感或瘙痒。 当所用Ampyra剂量超过推荐剂量（10毫克，每天两次）时，可能会引起癫痫发作。患有中度或严重肾脏疾病的患者应禁止使用Ampyra。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AMPYRA safely and effectively. See full prescribing information for AMPYRA. AMPYRA®(dalfampridine) Extended Release Tablets, for oral use Initial U.S. Approval: 2010 INDICATIONS AND USAGE AMPYRA®(dalfampridine) is a potassium channel blocker indicated to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed (1, 14). DOSAGE AND ADMINISTRATION The maximum recommended dose is 10 mg twice daily (approximately 12 hours apart), with or without food. Tablets should only be taken whole; do not divide, crush, chew, or dissolve (2) Estimated creatinine clearance (CrCl) should be known before initiating treatment with AMPYRA. In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA may reach plasma levels associated with a greater risk of seizures, and the potential benefits of AMPYRA should be carefully considered against the risk of seizures in these patients (2, 5.2, 8.6) Patients should not take double or extra doses if a dose is missed. No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse events, including seizures, were more frequent at higher doses (2) DOSAGE FORMS AND STRENGTHS 10mg tablets (3) CONTRAINDICATIONS History of seizure (4) Moderate or severe renal impairment (CrCl≤50 mL/min) (4) History of hypersensitivity to AMPYRA or 4-aminopyridine (4) WARNINGS AND PRECAUTIONS AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; discontinue AMPYRA and do not restart if a seizure occurs (5.1) AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same (5.3) AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs (5.4) ADVERSE REACTIONS The most common adverse events (incidence ≥2% and at a rate greater than the placebo rate) for AMPYRA were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS None identified (7) USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3) Geriatric use: Because elderly patients are more likely to have decreased renal function, it is particularly important to know the estimated CrCl in these patients before initiating AMPYRA treatment (4, 5.2, 8.6) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 1/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE AMPYRA (dalfampridine) is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION The maximum recommended dose of AMPYRA is one 10 mg tablet twice daily, taken with or without food, and should not be exceeded. Doses should be taken approximately 12 hours apart. Tablets should only be taken whole; do not divide, crush, chew, or dissolve. Patients should not take double or extra doses if a dose is missed. Estimated creatinine clearance (CrCl) should be known before initiating treatment with AMPYRA, and monitored at least annually during treatment with AMPYRA. CrCl can be estimated using the following equation (multiply by 0.85 for women): CrCl = (140 - age) × weight(kg) SerumCr(mg/dl)× 72 In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures. As mild renal impairment is common after age 50, estimating CrCl is particularly important in these patients. The potential benefits of AMPYRA should be carefully considered against the risk of seizures in these patients [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.4)]. No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse reactions and discontinuations because of adverse reactions were more frequent at higher doses [see FDA-Approved Patient Information for complete "Instructions for Use"]. 3 DOSAGE FORMS AND STRENGTHS AMPYRA is available in a 10 mg strength and is a film-coated, white to off-white, biconvex, oval shaped, non-scored tablet with flat edge, debossed with "A10" on one side. 4 CONTRAINDICATIONS The use of AMPYRA is contraindicated in the following conditions: History of seizure Moderate or severe renal impairment (CrCl≤50 mL/min) History of hypersensitivity to AMPYRA or 4-aminopyridine 5 WARNINGS AND PRECAUTIONS 5.1 SeizuresAMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9–14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy. AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4)]. 5.2 Renal ImpairmentAMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4)]. Because patients with moderate to severe renal impairment (CrCl ≤50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4)]. In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1)]. 5.3 Concurrent Treatment with Other Forms of 4-AminopyridineAMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Patients should discontinue use of any product containing 4-aminopyridine prior to initiating treatment with AMPYRA in order to reduce the potential for dose-related adverse reactions. 5.4 AnaphylaxisAMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Patients should be informed of the signs and symptoms of anaphylaxis and instructed to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur (17.3). 5.5 Urinary Tract InfectionsUrinary tract infections (UTIs) were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg twice daily (12%) as compared to placebo (8%). UTIs in AMPYRA-treated patients should be evaluated and treated as clinically indicated. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Seizures, Anaphylaxis, and Urinary Tract Infections. 6.1 Controlled Clinical Trials Experience In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%). Table 1 lists adverse reactions that occurred in ≥2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials. Table 1: Adverse reactions with an incidence ≥2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials  Adverse Reaction Placebo (N=238) AMPYRA 10 mg twice daily (N=400) Urinary tract infection 8% 12% Insomnia 4% 9% Dizziness 4% 7% Headache 4% 7% Nausea 3% 7% Asthenia 4% 7% Back pain 2% 5% Balance disorder 1% 5% Multiple sclerosis relapse 3% 4% Paresthesia 3% 4% Nasopharyngitis 2% 4% Constipation 2% 3% Dyspepsia 1% 2% Pharyngolaryngeal pain 1% 2% 6.2 Other Adverse Reactions AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13–0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21–6.28). 7 DRUG INTERACTIONS In humans, dalfampridine is eliminated predominantly unchanged by the kidneys. No clinically significant drug interaction was identified. In particular, no interaction was identified between dalfampridine and baclofen [see Clinical Pharmacology, Pharmacokinetics (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of AMPYRA in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at doses similar to the maximum recommended human dose (MRHD) of 20 mg/day. AMPYRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In developmental toxicity studies in rats and rabbits, dalfampridine was administered orally at doses up to 10 and 5 mg/kg/day, respectively, during the period of organogenesis. These doses are approximately 5 times the MRHD on a body surface area (mg/m2) basis. No evidence of developmental toxicity was found in either species at the highest doses tested, which were maternally toxic. Oral administration of dalfampridine (at doses of 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to rats throughout the pregnancy and lactation periods resulted in decreased offspring survival and growth. The no-effect dose for pre- and postnatal developmental toxicity in rats (1 mg/kg) is approximately 0.5 times the MRHD on a mg/m2 basis. 8.2 Labor and delivery The effect of AMPYRA on labor and delivery in humans is unknown. 8.3 Nursing mothers It is not known whether dalfampridine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dalfampridine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of AMPYRA in patients younger than 18 years of age have not been established. 8.5 Geriatric use Clinical studies of AMPYRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. A population PK analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate a modification of dose with age. Other reported clinical experience has identified no differences in responses between the elderly and younger patients. AMPYRA is known to be substantially excreted by the kidneys and the risk of adverse reactions, including seizures, is greater with increasing exposure of dalfampridine. Because elderly patients are more likely to have decreased renal function, it is particularly important to know the estimated creatinine clearance (CrCl) in these patients [see Warnings and Precautions (5.2)]. 8.6 Impaired Renal Function Clearance of dalfampridine is decreased in patients with renal impairment and is significantly correlated with creatinine clearance (CrCl) [see Clinical Pharmacology, Special Populations (12.4)]. AMPYRA is contraindicated in patients with moderate or severe renal impairment (CrCl ≤50 mL/min) [see Contraindications (4)]. The risk of seizures in patients with mild renal impairment (CrCl 51–80 mL/min) is unknown, but dalfampridine plasma levels in these patients may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures. If unknown, estimated creatinine clearance should be calculated prior to initiating treatment with AMPYRA [see Dosage and Administration (2) and Warnings and Precautions (5.2)]. 10 OVERDOSAGE Three cases of overdose were reported in controlled clinical trials with AMPYRA, involving two MS patients. The first patient took six times the currently recommended dose (60 mg) and was taken to the emergency room with altered mental state. The second patient took 40 mg doses on two separate occasions. In the first instance, she experienced a complex partial seizure and, in the second instance, a period of confusion. Both patients recovered by the following day without sequelae. Several cases of overdose are found in the scientific literature in which various formulations of dalfampridine were used, resulting in numerous adverse events including seizure, confusion, tremulousness, diaphoresis, and amnesia. In some instances, patients developed status epilepticus, requiring intensive supportive care and were responsive to standard therapy for seizures. In one published case report, an MS patient who ingested 300 mg of 4-aminopyridine (dalfampridine) developed a condition that resembled limbic encephalitis. This patient developed weakness, reduced awareness, memory loss, hypophonic speech, and temporal lobe hyperintensities on MRI. The patient's speech and language and ambulation improved over time, and an MRI at 4 months after the overdose no longer showed signal abnormalities. At one year, the patient continued to have difficulty with short term memory and learning new tasks. 11 DESCRIPTION AMPYRA (dalfampridine) is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet contains 10 mg dalfampridine, formulated as an extended release tablet for twice-daily oral administration. Dalfampridine is also known by its chemical name, 4-aminopyridine, with the following structure: AMPYRA (dalfampridine) Extended Release tablets are available in a 10 mg strength and are white to off-white, biconvex, oval shaped, film-coated, non-scored tablets with flat edge, debossed with "A10" on one side, containing 10 mg of dalfampridine. Inactive ingredients consist of colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Dalfampridine is a fine white powder with a molecular weight of 94.1, CAS 504-24-5, and a molecular formula of C5H6N2. At ambient conditions, dalfampridine is soluble in water, methanol, acetone, tetrahydrofuran, isopropanol, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, and ethanol. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of action The mechanism by which dalfampridine exerts its therapeutic effect has not been fully elucidated. Dalfampridine is a broad spectrum potassium channel blocker. In animal studies, dalfampridine has been shown to increase conduction of action potentials in demyelinated axons through inhibition of potassium channels. 12.2 Pharmacodynamics AMPYRA does not prolong the QTc interval and does not have a clinically important effect on QRS duration. 12.3 Pharmacokinetics Absorption and Distribution: Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of extended release AMPYRA tablets has not been assessed, but relative bioavailability is 96% when compared to an aqueous oral solution. The extended release tablet delays absorption of dalfampridine relative to the solution formulation, giving a slower rise to a lower peak concentration (Cmax), with no effect on the extent of absorption (AUC). Single AMPYRA tablet 10 mg doses administered to healthy volunteers in a fasted state gave peak concentrations ranging from 17.3 ng/mL to 21.6 ng/mL occurring 3 to 4 hours post-administration (Tmax). In comparison, Cmax with the same 10 mg dose of dalfampridine in an oral solution was 42.7 ng/mL and occurred approximately 1.3 hours after dosing. Exposure increased proportionally with dose. Dalfampridine is largely unbound to plasma proteins (97–99%). The apparent volume of distribution is 2.6 L/kg. There is no apparent difference in pharmacokinetic parameter values following administration of AMPYRA tablets to either healthy volunteers or patients with MS. When dalfampridine is taken with food, there is a slight increase in Cmax (12–17%) and a slight decrease in AUC (4–7%). These changes in exposure are not clinically significant, and therefore the drug may be taken with or without food [see Dosage and Administration (2)]. Metabolism and Elimination: Dalfampridine and metabolites elimination is nearly complete after 24 hours, with 95.9% of the dose recovered in urine and 0.5% recovered in feces. Most of the excreted radioactivity in urine was parent drug (90.3%). Two metabolites were identified: 3-hydroxy-4-aminopyridine (4.3%) and 3-hydroxy-4-aminopyridine sulfate (2.6%). These metabolites have been shown to have no pharmacologic activity on potassium channels. The apparent elimination half-life of dalfampridine following administration of the extended release tablet formulation of AMPYRA is 5.2 to 6.5 hours. The plasma half-life of the sulfate conjugate is approximately 7.6 hours and the half-life of 3-hydroxy-4-aminopyridine could not be calculated because concentrations for most subjects were close to or below the limit of quantitation. In vitro studies with human liver microsomes indicate that CYP2E1 was the major enzyme responsible for the 3-hydroxylation of dalfampridine. The identity of the CYP enzymes suspected of playing a minor role in the 3-hydroxylation of dalfampridine could not be established unequivocally. 12.4 Special Populations Pediatric The safety and effectiveness of AMPYRA in patients younger than 18 years of age have not been established. Geriatric A population pharmacokinetic analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate a modification of dose. Gender A population pharmacokinetic analysis suggested that female patients would be expected to have higher maximum dalfampridine plasma concentration than male patients. The magnitude of these differences is small and does not necessitate any dose modification. Renal Impairment [see Contraindications (4) and Warnings and Precautions, Renal Impairment (5.2)]. The pharmacokinetics of dalfampridine was studied in 9 male and 11 female subjects with varying degrees of renal function. Elimination of the drug is significantly correlated with the creatinine clearance. Total body clearance of dalfampridine was reduced by about 45 % in patients with mild renal impairment (CrCl 51–80 mL/min), by about 50% in patients with moderate renal impairment (CrCl = 30–50 mL/min), and by about 75% in patients with severe renal impairment (CrCl <30 mL/min). The terminal half-life of dalfampridine is about 3.3 times longer in patients with severe renal impairment but is not prolonged in patients with mild or moderate renal impairment. Hepatic Impairment The pharmacokinetics of dalfampridine in hepatically impaired subjects has not been studied. Since dalfampridine is primarily excreted unchanged in the urine, hepatic impairment is not expected to significantly affect dalfampridine pharmacokinetics or recommended dosing. Race There were too few non-Caucasians in the patient population to evaluate the effect of race. Drug Interactions Effects of Co-administered Drugs on Dalfampridine Interferon Dalfampridine kinetics were not affected by co-administration of subcutaneous injections of 8 million units interferon beta-1b. Baclofen Based on a population analysis, dalfampridine kinetics were not affected by baclofen. Effects of Dalfampridine on Co-administered Drugs In vitro data with human liver microsomes showed that dalfampridine was not a direct or time-dependent inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of these enzymes. Other in vitro studies with cultured human hepatocytes with 0.025 μM, 0.25 μM, 2.5 μM, and 25 μM dalfampridine had little or no effect on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzyme activities. Consequently, the potential for dalfampridine to induce human hepatocytes at therapeutic concentrations is remote. In vitro, dalfampridine is not a substrate or an inhibitor for the p-glycoprotein transporter. The pharmacokinetics of AMPYRA are unlikely to be affected by drugs that inhibit the p-glycoprotein transporter, and dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of the p-glycoprotein transporter. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenesis: Two year dietary carcinogenicity studies of dalfampridine were conducted in mice and rats. In mice, the doses tested (approximately 2, 12.5, and 80 mg/kg/day) were associated with plasma exposures (AUC) up to 11 times the plasma AUC in humans at the maximum recommended human dose (MRHD) of 20 mg/day. There was no evidence of drug-related carcinogenicity. In rats, the doses tested (approximately 2, 6, and 18 mg/kg/day) were approximately 1, 3, and 9 times the MRHD on a body surface area (mg/m2) basis. There was a significant increase in uterine polyps at the highest dose tested Mutagenesis: Dalfampridine was negative in in vitro (bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration) and in vivo (mouse bone marrow, rat erythrocyte micronucleus) genetic toxicology assays. Impairment of Fertility: Oral administration of dalfampridine (doses of 1, 3, and 9 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females up to day 13 of gestation or day 21 of lactation resulted in no adverse effects on fertility. Reduced offspring viability and body weight were observed at 9 mg/kg/day. The mid dose (a no-effect dose) was similar to the MRHD on a mg/m2 basis. 14 CLINICAL STUDIES The effectiveness of AMPYRA in improving walking in patients with multiple sclerosis was evaluated in two adequate and well controlled trials involving 540 patients. Patients in these two clinical trials had a mean disease duration of 13 years and a mean Kurtzke Expanded Disability Status Scale (EDSS) score of 6. Trial 1 was a randomized, placebo-controlled, parallel group, 21-week study (one week post screening, two-week, single-blind placebo run-in, 14-week double-blind treatment, and 4-week no treatment follow-up) in 301 patients with multiple sclerosis at 33 centers in the U.S. and Canada: 229 patients assigned to AMPYRA 10 mg twice daily and 72 patients assigned to placebo. A total of 283 patients (212 AMPYRA and 71 placebo) completed all study visits. Patient inclusion criteria included the ability to walk 25 feet in 8–45 seconds. Patient exclusion criteria included a history of seizures or evidence of epileptiform activity on a screening EEG, and onset of an MS exacerbation within 60 days. Trial 2 was a randomized, placebo-controlled, parallel group, 14-week study (one week post-screening, two weeks of single-blind, placebo run-in, nine weeks of double-blind treatment, and two weeks of no-treatment follow-up) in 239 patients with multiple sclerosis at 39 centers in the U.S. and Canada: 120 patients assigned to 10 mg twice daily and 119 assigned to placebo. A total of 227 patients (113 AMPYRA and 114 placebo) completed all study visits. The patient inclusion and exclusion criteria used in Trial 1 were employed in Trial 2, and in addition patients with severe renal impairment were also excluded. The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25FW), using a responder analysis. A responder was defined as a patient who showed faster walking speed for at least three visits out of a possible four during the double-blind period than the maximum value achieved in the five non-double-blind no treatment visits (four before the double-blind period and one after). A significantly greater proportion of patients taking AMPYRA 10 mg twice daily were responders, compared to patients taking placebo, as measured by the T25FW (Trial 1: 34.8% vs. 8.3%; Trial 2: 42.9% vs. 9.3%). The increased response rate in the AMPYRA group was observed across all four major types of MS disease course. During the double-blind treatment period, a significantly greater proportion of patients taking AMPYRA 10 mg twice daily had increases in walking speed of at least 10%, 20%, or 30% from baseline, compared to placebo (Figure 1 and Figure 2). Figure 1: Average walking speed change (%) from baseline during the double-blind phase of Trial 1 Figure 2: Average walking speed change (%) from baseline during the double-blind phase of Trial 2 In Trial 1 and Trial 2, consistent improvements in walking speed were shown to be associated with improvements on a patient self-assessment of ambulatory disability, the 12-item Multiple Sclerosis Walking Scale (MSWS-12), for both drug and placebo treated patients. However, a drug-placebo difference was not established for that outcome measure. The majority of patients in these trials (63%) were using immunomodulatory drugs (interferons, glatiramer acetate, or natalizumab), but the magnitude of improvement in walking ability was independent of concomitant treatment with these drugs. No differences in effectiveness based on degree of impairment, age, gender, or body mass index were detected. There were too few non-Caucasians in the patient population to evaluate the effect of race. 16 HOW SUPPLIED/STORAGE AND HANDLING AMPYRA (dalfampridine) extended release tablets, 10 mg are film-coated, white to off-white, biconvex, oval shaped, non-scored tablets with flat edge. The tablets are identified by a debossed code "A10" on one side and are available in bottles of 60. NDC 10144-427-60 bottles of 60 tablets Store at 25°C (77°F). Excursions permitted 15–30°C (59–86°F). 达方吡啶缓释片（dalfampridine/Ampyra）的临床研究 2010年1月获得FDA批准，用于口服治疗多发性硬化病患者以改善他们的行走能力。这是FDA首次批准用于此用途的药物。达方吡啶可以单用，也能与现有多发性硬化病治疗药物包括免疫调节剂联合使用。 临床研究已经证实，达方吡啶能够提高多发性硬化病患者的行走速度，且其对所有4种主要多发性硬化病亚型（复发-缓解型、继发性进行性、进行性-复发型和原发性进行性）均有效。 达方吡啶缓释片采用Elan药物技术公司的基质药物吸附系统（MXDAS）专有口服控释技术制备，推荐剂量方案为每日2次、每次相隔约12小时各服用1片（10mg）。达方吡啶改善多发性硬化病患者行走能力的疗效和安全性已得到两项Ⅲ期双盲、随机、安慰剂对照试验的确认。这两项研究结果显示，相对于安慰剂，达方吡啶治疗可使更高比例患者的行走速度至少较基线提高10%、20%和30%。两项研究还发现，行走速度提高患者自我评价的《12项多发性硬化病行走量表（MSWS-12）》得分也获得相应改善。 达方吡啶可能会剂量依赖性地提高用药者的癫痫发作风险，故该药不应以高于推荐剂量方案使用。为保证安全，达方吡啶禁用于具有癫痫发作史的患者，同时也禁用于呈中至重度肾损害患者（达方吡啶亦会提高这类患者的癫痫发作风险）。达方吡啶治疗在临床试验中的最常报告不良反应包括泌尿道感染、失眠、头晕、头痛、恶心、虚弱、背痛、平衡障碍、多发性硬化病复发、感觉异常、鼻咽炎、便秘、消化不良和咽喉痛。 达方吡啶即4-氨基吡啶（4-aminopyridine），属钾通道阻滞剂。实验室研究发现，达方吡啶能够改善神经髓鞘中已遭损害的神经纤维的脉冲传导。而多发性硬化病作为一种慢性且通常呈进行性的中枢神经系统疾病，正是以免疫系统攻击并毁损脑和脊髓中神经纤维的功能为特征的。全球估计有250万（美国40万）人受到多发性硬化病的影响，其中64%~85%的患者行走困难，约70%的患者认为行走困难是该疾病最为恼人的症状。多发性硬化病诊出后15年内，50%患者行走常需辅助器械；在疾病晚期，高达1/3的患者将不能行走。