National PBM Monograph Template Rev20091005 s2

PBM-MAP-VPE Drug Monograph: Dalfampridine (Ampyrat®)

National Drug Monograph Dalfampridine (Ampyra®) September 2010 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary:  Dalfampridine is the first oral agent approved by the FDA for the treatment of Multiple Sclerosis (MS) symptoms.  Dalfampridine blocks voltage sensitive potassium channels, a large family of membrane spanning proteins which are present on electrically active cells.  It has been shown to bind reversibly to the cytoplasmic side of these channels, blocking the ion conductance pathway. This blockade leads to prolongation of action potentials in unmyelinated nerve fibers, increased transmitter release at synaptic endings and improved conduction in demyelinated nerve fibers.  These effects are thought to be involved in the symptomatic improvements seen in MS patients.  The trials of dalfampridine employed a responder analysis to evaluate therapy. In using this outcome only 40% of patients from selected groups responded.  Results from clinical trials demonstrated that dalfampridine significantly increased average change in walking speed over a distance of 25 feet compared to placebo during 14 weeks of treatment. While receiving dalfampridine, patients walking speed increased an average of 0.28-0.29 feet/second compared to 0.1-0.17 feet/second while taking placebo.  Due to the high rate of nonresponding patients, a 2to 4 weeks trial of therapy should be carried out before treatment is instituted on a continuing basis.  Commonly occurring events include dizziness, fatigue, insomnia, nausea, back pain, balance disorder and headache.  Dalfampridine is contraindicated in patients with moderate or severe renal impairment or a history of seizures.  Dalfampridine is not indicated to decrease relapse rate or prevent the accumulation of disability.  The FDA has required a REMS program (Risk Evaluation and Mitigation Strategy) for dalfampridine. It involves a detailed medication guide dispensed with each prescription fill. Additionally, provider education involving the potential increased risk of seizure, especially in renal compromise must be given.. Introduction

Dalfampridine is the first oral agent approved by the FDA for the treatment of Multiple Sclerosis (MS) symptoms. Currently available agents work as disease modifying therapies (DMARD) thereby preventing relapses of the disease and/or delaying the progression of MS and are not target at the development of functional motor impairment.

The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to considering dalfampridine for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology 1 Dalfampridine is broadly classified as a potassium-channel blocker, with a primary mechanism of action described as dose- dependent blockade of slowly inactivating or noninactivating voltage-gated potassium channels. These changes can occur in both the peripheral as well as central nervous systems. When the myelin sheath is damaged, potassium may become too active, causing a decrease in nerve function. Dalfampridine blocks potassium from entering the channel, thereby decreasing the disruptions in conduction along the nerves, decreasing the development of functional motor impairment. Evidence suggests that a secondary effect of dalfampridine is to increase neurotransmitter release by allowing larger than normal calcium influx at presynaptic terminals, which enhances neuronal communication.

September 2010 1 Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

1 PBM-MAP-VPE Drug Monograph: Dalfampridine (Ampyrat®)

Pharmacokinetics/Pharmacodynamics 1-4

Pharmacokinetic studies with both immediate-release and sustained-release formulations of fampridine have been performed in healthy subjects and in patients with MS and spinal cord injuries as well as animal models. The sustained release form, dalfampridine, was developed to lessen the toxicity associated with high serum drug concentrations and improve compliance thru twice daily dosing. Fampridine is a lipid-soluble drug that readily crosses the blood–brain barrier.

When given orally, dalfampridine is rapidly absorbed with demonstrating an oral bioavailability of 95% and a time to peak serum concentration of 5 hrs in MS patients. Steady state is reached in 4 days when dalfampridine is dosed twice daily. More than 90% of the drug is excreted unchanged in the urine. There is no evidence that dalfampridine undergoes hepatic transformation via glucuronidation, sulfonation or N-acetylation.

FDA Approved Indication(s) and Off-label Uses 1 Dalfampridine is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). This drug is not indicated to decrease relapse rate or prevent the accumulation of disability.

This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the VA PBM Intranet site only). Some of these uses may include use in treating fatigue in MS patients and in spinal cord injury patients to enhance nerve transmission to affected muscles.

Current VA National Formulary Alternatives Currently, the only agents available on the VA National Formulary are the disease modifying agents used to slow the progression of MS. These include beta-interferon, glatiramer acetate, natalizumab and mitoxantrone. Dosage and Administration 1 The maximum recommended dose of dalfampridine is one 10 mg tablet twice daily, taken with or without food. Doses should be taken approximately 12 hours apart. 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 reactions and discontinuations because of adverse reactions were more frequent at higher doses. Tablets should only be taken whole; do not divide, crush, chew, or dissolve.

Renal Impairment: Dalfampridine is contraindicated in patients with moderate or severe renal impairment ( CrCl <50 ml/min); the risk of seizures in patients with mild renal impairment ( CrCl 51-80 ml/min) is unknown, but 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

Efficacy Multiple Sclerosis The Expanded Disability Status Scale (EDSS)5 is commonly used in MS trials to assess outcome. In the clinical trials of dalfampridine, three key measures were used in addition to the EDSS. The Timed 25-Foot Walk test (T25FW), the 9 hole Peg test and the Paced Auditory Serial Addition test6. These measures evaluated lower extremity, upper extremity and cognitive function, respectfully. Patients were allowed to use an assistive device as long as it was consistently used across visits.

Secondary outcome measures of efficacy have included the Ashworth score for spasticity and a lower extremity manual muscle test (LEMMT) done at each visit. The LEMMT measured strength in four muscle groups bilaterally (hip flexors, knee flexors and extensors, and ankle dorsi-flexors). The 12-item multiple sclerosis walking scale (MSWS-12), a rating scale that captures patients’ perspectives on their ambulatory disability, was employed to validate the clinical significance of the

2 PBM-MAP-VPE Drug Monograph: Dalfampridine (Ampyrat®) timed walk test.7 Other secondary validation variables include the subject global impression (SGI) using a seven point scale to describe their impression of the study drug effects over the past week (1=terrible and 7=delighted) and a clinician global impression (CGI)using a seven point scale(1=very much improved to 7=very much worse).

Early studies of that support the use of dalfampridine were performed using the agent 4-aminopyridrine.8-17 This is an immediate release product that was prepared by compounding pharmacies. These studies investigated potential benefits in the areas of visual acuity, cognition, fatigue and ambulation,. It is difficult to compare trial results as these studies were conducted in small populations for variable durations up to 6 months. The most improved efficacy measures used in these early trials were those that measured effects on ambulation. Subsequent trials have evaluated escalating doses of dalfampridine for safety and efficacy. Goodman and colleagues evaluated the safety and efficacy of sustained release fampridine (F-SR) in 206 patients with clinically definite MS of any type who had shown a T25FW test of 8-60 seconds on two separate occasions.19 This was a randomized, double blind trial of 206 patients who were randomized to placebo, 10 mg, 15mg or 20 mg of dalfampridine twice daily for 14 weeks. Response to treatment was defined as a T25FW on at least 3 visits that were faster than the maximum speed demonstrated on five “non-treatment” visits. This trial demonstrated no significant difference in walking speed in comparison to baseline and treatment for any of the dalfampridine treatment groups. All three treatment doses demonstrated a >20% increase in walking speed. The FDA allowed the use of a responder analysis for this trial. The use of this outcome measure recognizes that in some situations, response for an individual may be more important than the response of the group as a whole. For this trial the responder was defined as greater than 20% improvement from baseline in walking speed, averaged over the treatment period. In this trial the proportion of responder for 10 mg, 15 mg and placebo were 23.5%, 26% and 12.8% respectively with no group reaching significance. For secondary outcomes, there was a statistically significant increase in LEMMT for the 10 and 15 mg twice daily dose versus placebo. There was no significant difference in the frequency of adverse events in the placebo (81%) versus dalfampridine groups (87%).

A Phase III study (MS-F203)20 was a double-blind, placebo-controlled, 21 week (14 weeks on active treatment), parallel group study. Inclusion criteria was a diagnosis of clinically definite MS for at least 2 months, aged 18 to 70 years, and able to perform two trials of Timed 25 foot walk within 8 to 45 seconds at the screening visit.6 Following a 2 week placebo run in period, 300 patients were randomized to dalfampridine 10 mg (n=228) or placebo (n=72) twice daily for 14 weeks. Patients were then followed for an additional 4 weeks.

The primary efficacy endpoint was response to treatment, which was defined as a faster walking speed on two T25WT on at least 3 of 4 visits on active treatment compared to the maximum speed for any of the 5 “off-treatment” visits. A secondary outcome, (the MSWS-12) is based on 12 questions asking patients to rate their limitations in mobility during the preceding two weeks on a 5-point scale (from 1= not at all to 5 = extremely). This trial employed the same responder definitions from the Goldman trial previously discussed. For the primary endpoint, the dalfampridine group had a response rate of 35% with only 8% responders in the placebo treated group ( OR 4.75, 95% CI 2.08-10.86, p<0.001). However, when the outcome of walking speed alone is used, it does not reach statistical significance. Of the 35% of the treated population who responded, the average change from baseline in walking speed in the dalfampridine responders was 0.51 ft/sec and 0.1 ft/sec in the placebo group. The average change from baseline in walking speed for non-responders was 0.16 ft/sec. During the treatment period, improvement in LEMMT score was 0.18 versus 0.04 in the dalfampridine and placebo groups, respectively (p=0.0002). Other pertinent outcome measures reviewed by the FDA can be found in Table 1.

Table 1- Outcomes of MS-F203

Study MS-F203 Placebo Fampridine p value (n=72) (n=224) Baseline walking speed (ft/sec) 2.12 2.14 0.88 Visit 6 Walking speed (ft/sec) 2.16 2.35 0.19 Walking speed change Visit 6 vs. baseline (ft/sec) 0.05 0.21 0.03 Walking speed change Visit 6 vs. baseline (%) 5.58 10.90 0.24 Walking speed on drug (average) 2.16 2.34 0.17 Walking speed change (ft/sec) on drug (average) vs. 0.10 0.28 0.0004 baseline Walking speed change (%) on drug (average) vs. baseline 4.71 13.63 0.0003 MSW12 change on drug (average) vs. baseline 0.62 -2.72 0.084 MSW12 change Visit 6 vs. baseline 3.59 -1.56 0.063

The second Phase 3 trial included 240 patients between the ages of 18 and 70 years from 39 centers across the US and Canada.1 As with earlier trials, patients with any of the 4 major types of MS were allowed to participate and could remain on stable doses of their current medications. The primary outcome of the trial, as measured in the first Phase 3 study, was response in theT25FW. An increase in leg strength as measured by the LEMMT score was the only secondary outcome identified prospectively. Patients were randomized to receive either 10 mg of fampridine-SR twice daily or placebo for 8 weeks. Results showed that 42.9% of fampridine-SR–treated patients had consistent improvements in their walking speed as compared with 9.3% of those receiving placebo (p < 0.001). An increase in leg strength was observed in fampridine-SR responders compared with subjects on placebo (p = 0.028). In their review the FDA noted that there was no significant difference between the dalfampridine group (2.41 ft/sec; CI, 2.25-2.56) and the placebo group (2.37 ft/sec; CI, 2.22-2.53) for the average walking speed during the double blind period. This effect remained when the average walking speed was compared at the end of the double blind period. When compared to baseline walking speed, there was a difference (p=0.0089) in the dalfampridine group (0.29; CI, 0.23-0.35) compared to the placebo group (0.17; CI, 0.11-0.23). Additionally, the average percentage change from baseline in the timed 25 feet walk test for dalfampridine responders was 24.7%, non- responders was 15.5% and 18.2% for the placebo group. A comparison of outcomes for this trial can be seen in Table 2.

Table 2: Outcomes of Study MS-F204 FDA review document

Study MS-F204 Placebo Fampridine p value Baseline walking speed (ft/sec) 2.28 2.21 0.5463 Visit 6 Walking speed (ft/sec) 2.39 2.42 0.7284 Walking speed change Visit 6 vs. baseline (ft/sec) 0.11 0.22 0.0425 Walking speed change Visit 6 vs. baseline (%) 4.87% 10.64% 0.0392 Walking speed on drug (average) 2.37 2.41 0.7135 Walking speed change (ft/sec) on drug (average) vs. 0.17 0.29 0.0089 baseline Walking speed change (%) on drug (average) vs. baseline 7.67% 13.99% 0.0072

The long term safety of dalfampridine has been evaluated in open extension arms of the pivotal approval trials.1 Patients received dalfampridine 10 mg twice daily. In the MS-F203 trial, 265 patients elected to remain in the open extension phase. Patients who were termed responders maintained a response rate of 42.9% and 36.1% at 1 and 2 years respectively. Patients who were non-responders had response rates of 19.7% and 17.5% at 1 and 2 years respectively with placebo treated patients having a response rate of 16.2% and 20.8% at 1 and 2 years, respectively. In the other pivotal trial, the open extension phase demonstrated 71.4% of responders maintain response, 30% of non-responders did respond and 50% of placebo treated patients became responders.1

Spinal Cord Injury

Advances are being made in the area of sensorimotor function restoration after a spinal cord injury. Many types of spinal cord injury have been studied in trials; traumatic, motor-incomplete, involving paraplegia, tetraplegia and or quadriplegia. Additionally, duration post injury remains a variable which is different between trials. Many of the investigations have been open label, case series and/or small enrollment. These characteristics complicate the evaluation and extrapolation of medical literature evidence to the treatment of all spinal cord injury patients. The primary and secondary variables studied have included pulmonary function, spasticity, sensationelectromyographic activation, CGI, SGI and bowel/bladder management.

An early investigation evaluated open label, immediate release 4-aminopyridine in 25 patients with traumatic SCI involving both tetraplegics and paraplegics over a two year and longer period.23 After receiving 30 mg or 60 mg per day doses of 4- aminopyridine for 3 months, patients decreased spasticity, enhanced pulmonary function and partial recovery of sensory and motor function. These same doses of 4-aminopyridine were used in an evaluation of traumatic SCI patients who had been tetraplegic or paraplegic for at least 1.5 years.24 Efficacy after a 12 week treatment period was evaluated by sensation and independence measures. The response to pin prick and light touch showed statistically significant improvement as well as measures of independence evaluated by self care, respiratory and sphincter management and mobility. A more recent evaluation failed to confirm the benefit of 4-aminopyridine in ambulatory spinal cord injury patients.25 The doses of 4- aminopyridine used in this trial were up to 40 mg/day in one patient group. Patients in the higher dose group displayed more adverse events than the lower dose groups. There was no benefit on gait measures for any of the treatment groups in

4 PBM-MAP-VPE Drug Monograph: Dalfampridine (Ampyrat®) comparison to placebo. These same doses of 4-aminopyridine were investigated in a Phase II trial of motor incomplete SCI patients.26 There was improvement in SGI measures and some reduction of spasticity. Again, the patients receiving higher doses developed more adverse events and discontinuations.

Adverse Events (Safety Data)

Deaths and Other Serious Adverse Events (Sentinel Events)

There were no reports of death during the Phase III trials for dalfampridine. In the FDA analysis, it was observed that in MS controlled trials, serious adverse events were 3 times more frequent among dalfampridine-treated subjects (6.5%) than in placebo-treated subjects (2.1%) and the risk for all serious adverse events appeared dose related. In the MS-F203 trial, one patient did experience a seizure although the patient was septic at the time of the event, an potential link to dalfampridine could be made.

Common Adverse Events . In the Phase III trials common adverse events are listed in Table 3. Commonly occurring events include dizziness, fatigue, insomnia, nausea, back pain, balance disorder and headache. Tolerability In the Phase III trials the discontinuation rate ranged from 4.8%-10% in the dalfampridine treated groups. Contraindications Dalfampridine is contraindicated in patients with moderate or severe renal impairment ( CrCl <50 ml/min); the risk of seizures in patients with mild renal impairment ( CrCl 51-80 ml/min) is unknown, but 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.

Table 3: Common AEs in MS controlled trials (FDA Summary)

AE Preferred term Placebo Fampridine Fampridine Fampridine Fampridine (n=238) Total (n=507) 10mg bid 15mg bid (n=50) 20mg bid (n=57) (n=400) Subjects with ≥1 AEs 73.5% 86.4% (438) 84.8% (339) 94% (47) 91.2% (52) (175) Urinary tract infection 9.2% (22) 14.3% (72) 14.5% (58) 10% (5) 15.8% (9) Insomnia 3.8% (9) 10.5% (53) 9.3% (37) 18% (9) 12.3% (7) Dizziness 4.2% (10) 9.5% (48) 7.8% (31) 20% (10) 12.3% (7) Headache 4.2% (10) 8.9% (45) 7.5% (30) 14% (7) 14% (8) Asthenia 4.2% (10) 8.7% (44) 8.3% (33) 18% (9) 3.5% (2) Nausea 2.5% (6) 7.7% (39) 7% (28) 10% (5) 10.5% (6) Fatigue 4.6% (11) 7.5% (38) 6.5% (26) 14% (7) 8.8% (5) MS relapse 3.8% (9) 6.5% (33) 5.3% (21) 8% (4) 14% (8) Balance disorder 1.3% (3) 6.3% (32) 5.8% (23) 8% (4) 8.8% (5) Paresthesia 3.4% (8) 5.7% (29) 4.8% (19) 6% (3) 12.3% (7) Back pain 2.1% (5) 5.3% (27) 5.5% (22) 4% (2) 5.3% (3) Muscle spasms 3.4% (8) 4.1% (21) 3.8% (15) 6% (3) 5.3% (3) Constipation 2.1% (5) 3.7% (19) 3.5% (14) 4% (2) 5.3% (3) Diarrhea 2.5% (6) 2.8% (14) 2.5% (10) 6% (3) 1.8% (1) 7% (4) Difficulty walking 1.3% (3) 2.8% (14) 2.5% (10) 0 Vomiting 0.4% (1) 2.4% (12) 2% (8) 6% (3) 1.8% (1) Pyrexia 0.8% (2) 2.2% (11) 1.8% (7) 4% (2) 3.5% (2) Rash 0.8% (2) 2.2% (11) 1.8% (7) 2% (1) 5.3% (3) Muscle spasticity 1.7% (4) 1.8% (9) 2% (8) 0 1.8% (1) Depression 0.8% (2) 1.6% (8) 1.3% (5) 2% (1) 3.5% (2) Urinary incontinence 0 1.6% (8) 1.3% (5) 0 5.3% (3) Dyspnea 0 1.4% (7) 1% (4) 4% (2) 1.8% (1) Muscular weakness 0 1% (5) 0.3% (1) 2% (1) 5.3% (3) Neck pain 0.8% (2) 1% (5) 1% (4) 0 1.8% (1) Sensory disturbance 0.4% (1) 1% (5) 1% (4) 0 1.8% (1) Stomach discomfort 0.8% (2) 1% (5) 0.8% (3) 2% (1) 1.8% (1) Vertigo 0.4% (1) 1% (5) 1% (4) 0 1.8% (1)

Pregnancy and Lactation

There are no adequate and well-controlled studies of dalfampridine 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. Dalfampridine 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 9/6 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. 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.

REMS program Risk Evaluation and Mitigation Strategy The FDA approved dalfampridine with a risk evaluation and mitigation strategy (REMS) program comprising a medication guide and communication plan. The goals of the communication plan are to inform patients about the serious risks, including seizures, associated with use of higher than recommended doses, and the change of the generic name from fampridine to dalfampridine. The manufacturer, Accorda, is utilizing a specialty distributor in the drug procurement process though this was not mandated by the FDA. Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion:

LA/SA for generic name dalfampridine: desipramine, delavirdine LA/SA for trade name Ampyra: Anakinra Drug Interactions To date, no formal drug interaction studies with dalfampridine have been completed. Patients in the registration trials were allowed to remain on concurrent therapy with DMARDs as long as there had been no dose changes in the previous 6 months. As dalfampridine has been shown to induce seizures, caution should be exercised when considering The concurrent use of fampridine with medications known to lower the seizure threshold. Acquisition Cost* Drug/Dose Cost* per day Cost* per year Dalfampridine 10 mg BID $26.62 $9716.30 *VA Prices as of 5/24/10; check VA pricing sources for update information

Pharmacoeconomic Analysis There have been no pharmacoeconomic evaluations of dalfampridine at this time. Conclusions Dalfampridine represents a potential therapy not available before for MS patients. As an oral therapy, compliance may be better for patients as well as the ability to improve a functional deficit seen in MS patients. The results of the two Phase II trials have shown that there may be benefit for select patient groups on ambulation measures. However, interpreting the clinical benefit is somewhat difficult. It appears that dalfampridine works to improve walking speed in some people who have MS. The use of a responder rate may acknowledge the fact that some patients may respond better than others. There are caveats to this method of analysis that need to be considered. In the Phase III trials, the trials may not have been powered to detect a difference in responder rates since the use of responder analysis reduces the power based on group averages. In study F203, 35% of the population walked “faster” while on therapy, compared to 8% of the placebo population. However, of the 35% of the study population who demonstrated this outcome, in looking at the actual outcome measurement, time to walk 25 feet, the walking speed change favored the dalfampridine group by just 0.88 seconds in study F203. The difference in walking speed was 0.5 seconds in the second pivotal trial (F204). In addition, at F203 trial endpoint, the walking speed was not clinically significant between the dalfampridine and placebo groups. The visit 6 walking speed (ft/sec) was 2.16 for placebo-treated patients and 2.35 for dalfampridine-treated patients (p=0.19).

Dalfampridine is associated with serious adverse events. It appears to have dose related adverse events, perhaps the most serious is an increase in MS relapse and of seizures. Consider also that the length of the trials, 14 and 9 weeks of active treatment, were of short duration for this expected long term therapy.

Potential off label uses of dalfampridine may occur as a result of trials conducted with the immediate-release formulation. These trials suggest that dalfampridine may be useful for symptoms of MS other than impaired ambulation. In particular,

7 PBM-MAP-VPE Drug Monograph: Dalfampridine (Ampyrat®) many patients report improved stamina. Less commonly, patients have reported improvements in vision, sensation, coordination or sexual function. These outcomes will need further investigation with randomized, controlled, blinded trials.

In the treatment of spinal cord injury, dalfampridine may have benefit on functional measures related to bladder and bowel management as well as decreasing spasticity. The currently available evidence has been conducted for variable time periods and used doses of up to 40 mg/day. The evidence is not robust but may support the use of dalfampridine in certain types of SCI patients.

Dalfampridine is not a DMARD therapy for MS. However, it has the potential to improve walking ability and lower leg strength of MS patients. This may provide patients with the ability to stay independent for longer periods of time and improves quality of life as measured by the MSWS-12.

Prepared August 2010. Contact person: Kathy Tortorice, Pharm.D., BCPS, Pharmacy Benefits Management Services

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19. Goodman AD, Brown TR, Cohen JA, Krupp LB, Schapiro R, Schwid SR, Cohen R, Marinucci LN, Blight AR; Fampridine MS-F202 Study Group. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology. 2008 Oct 7;71(15):1134-41. 20. Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight AR; Fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009 Feb 28;373(9665):732-8. 21. Bever CT Jr. 10 questions about 4-aminopyridine and the treatment of multiple sclerosis. Neurologist. 2009 May;15(3):161-2. 22. Korenke AR, Rivey MP, Allington DR. Sustained-release fampridine for symptomatic treatment of multiple sclerosis. Ann Pharmacother. 2008 Oct;42(10):1458-65. 23. Segal JL, Pathak MS, Hernandez JP, Himber PL, Brunnemann SR, Charter RS. Safety and efficacy of 4- aminopyridine in humans with spinal cord injury: a long-term, controlled trial. Pharmacotherapy. 1999 Jun;19(6):713-23. 24. Grijalva I, Guízar-Sahagún G, Castañeda-Hernández G, Mino D, Maldonado-Julián H, Vidal-Cantú G, Ibarra A, Serra O, Salgado-Ceballos H, Arenas-Hernández R. Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial. Pharmacotherapy.2003 Jul;23(7):823-34. 25. DeForge D, Nymark J, Lemaire E, Gardner S, Hunt M, Martel L, Curran D, Barbeau H. Effect of 4- aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial. Spinal Cord. 2004 Dec;42(12):674-85. 26. Cardenas DD, Ditunno J, Graziani V, Jackson AB, Lammertse D, Potter P, Sipski M, Cohen R, Blight AR. Phase 2 trial of sustained-release fampridine in chronic spinal cord injury. Spinal Cord. 2007 Feb;45(2):158-68. Epub 2006 Jun 13. PubMed PMID: 16773037. 27. Romani A, Bergamaschi R, Candeloro E, Alfonsi E, Callieco R, Cosi V. Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment. Mult Scler. 2004 Aug;10(4):462-8. 28. Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, Carlesimo GA, Zibellini G, Caltagirone C. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo- controlled, crossover trial of oral 4-aminopyridine. Mult Scler. 2001 Dec;7(6):354-8. 29. Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R. Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Arch Phys Med Rehabil. 2004 Jan;85(1):29-34.. 30. Hayes KC, Potter PJ, Hansebout RR, Bugaresti JM, Hsieh JT, Nicosia S, Katz MA, Blight AR, Cohen R. Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4- aminopyridine) in patients with chronic spinal cord injury. Clin Neuropharmacol. 2003 Jul- Aug;26(4):185-92. 31. Hayes KC, Katz MA, Devane JG, Hsieh JT, Wolfe DL, Potter PJ, Blight AR. Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury. J Clin Pharmacol. 2003 Apr;43(4):379-85. PubMed PMID: 12723458.

10 Prasugrel Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov 11