Dalfampridine Extended Release Tablets—Clinical Need and Use
dalfampridine-treated than placebo patients had increases in walking speed of ≥20, ≥30 and, ≥40%, moving from restricted (household) mobility (walking speed <1.3ft/s) to full community mobility (walking speed >2.6ft/s).34
originally developed for assessing stroke patients.36 responders showed a decline in this ability (see Table 2).34
These community ambulation categories were No dalfampridine Efficacy was
independent of MS disease type, duration of disease, and baseline EDSS score. Efficacy was also similar irrespective of concomitant immunomodulator use: interferon betas (IFNβ) (36.8%), glatiramer acetate (37.1%), or natalizumab (27.3%) compared with efficacy in 39.8% of patients not on immunomodulatory therapy.33
However, not all patients receiving dalfampridine showed improvements in walking ability. The mean effect was small, since 35–43% of people had a consistent response to treatment, but that group experienced meaningful change. In general, the greater the increase in walking speed, the smaller the proportion of patients achieving it. For example, 54.1% of patients showed an improvement in walking speed of ≥10% but only 31.5% showed an improvement of ≥20%.37
An interim analysis of two open-label extension studies (MS-F203EXT and MS-F204EXT) has recently been presented. Patients were assessed at two, 14, and 26 weeks, and every six months up to 2.5 years. The walking speed of patients who continued on dalfampridine from the double-blind trial remained above baseline whereas those not on dalfampridine fell below that level. The response tended to drop back to baseline for patients continuing on dalfampridine at 2.5 years in MS-F203EXT and at 1.2 years in MS-F204EXT.38
Safety Data
In the treatment group, 2.8% of patients withdrew from the study because of adverse effects compared with 2.1% in the placebo group. Falls were seen at similar levels across treatment and placebo group patients, but UTIs were slightly more frequent with dalfampridine. These findings are consistent with previous safety results shown in clinical studies using dalfampridine.2,28,30
The incidence of seizures was the biggest safety concern in these trials, since earlier studies indicated that dalfampridine had a narrow toxic–therapeutic ratio.39
However, those studies did not use extended
release formulations. The frequency of seizures in these trials was low and similar to the background rate of first seizure of approximately 0.35/100 patient-years. Five additional seizures were reported in patients in the open-label extension studies but the onset of seizure is unrelated to the time on the drug. No new adverse effects have been noted.40
The
incidence of MS relapse was low in the pooled treatment (5.3%) and placebo groups (3.8%). Post-treatment, the incidence of relapse was higher in the treatment group than the placebo group (1.8 versus 0.4%).41
Cases of unintentional overdose of compounded 4-AP in MS have been reported42
US NEUROLOGY and seizures can occur with overdose of both the immediate
Managing Expectations of Dalfampridine in Multiple Sclerosis Patients
Any medication that offers improvements in walking in MS will be of great interest to patients and may raise hopes of restoring lost mobility. However, patient expectations of dalfampridine could be too high and it is critical that patients have a realistic view. Dalfampridine provides
79
The safety analysis population for the combined studies included 638 patients. The profile of adverse effects was consistent over all three studies. The most common adverse effects were falls, urinary tract infections (UTI), insomnia, asthenia, dizziness, headaches, nausea, and back pain, which were mostly mild to moderate and transient in nature (see Table 3).37
Table 2: Combined Changes in Walking Ability in Dalfampridine Responders, Dalfampridine Non-responders, and Patients Receiving Placebo in the MS-F202, MS-F203, and MS-F204 Studies
Change in Walking Ability Limited → full
Responders Non-responders +22.4%
+9.7%
community mobility (improvement) Household → limited +10.2%
community mobility (improvement) Full community →
limited community (worsening)
Limited community → 0% household
Net shift in mobility Source: Edwards et al., 2010.34
Table 3: Combined Numbers (and Percentage) of Treatment-emergent Adverse Events Reported by ≥5% of Patients Receiving Either Dalfampridine or Placebo in the MS-F202, MS-F203, and MS-F204 Studies
Treatment-emergent Adverse Events (TEAEs)
Total patients reporting any TEAE TEAEs leading to discontinuation Fall
UTIs
Insomnia Asthenia Dizziness Headache Nausea Fatigue
Balance disorder
Upper respiratory tract infection MS relapse Back pain
Incidence Number of Patients (%)
Dalfampridine 10mg Placebo (n=400)
(n=238)
339 (84.8) 11 (2.8) 64 (16.0) 58 (14.5) 37 (9.3) 33 (8.3) 31 (7.8) 30 (7.5) 28 (7.0) 26 (6.5) 23 (5.8) 23 (5.8) 21 (5.3) 22 (5.5)
175 (73.5) 5 (2.1)
39 (16.4) 22 (9.2) 9 (3.8)
10 (4.2) 10 (4.2) 10 (4.2) 6 (2.5)
11 (4.6) 3 (1.3)
17 (7.1) 9 (3.8) 5 (2.1)
MS = multiple sclerosis; UTI = urinary tract infection. Source: Schapiro et al. 2010.37 and extended-release formulations.28,43 Overall, dalfampridine is well
tolerated. However, it is contraindicated in patients with a history of seizures and in those with moderate or severe renal impairment. A risk evaluation and mitigation strategy (REMS) program, involving a detailed medication guide that stresses the necessity for adherence to the 10mg twice-daily dosage, is now available.44
+32.6% –1.6% +7.7% –1.7% +8.4% 0% +1.2% –1.6% +10.5% +1.7% –2.1% Dalfampridine-treated Placebo-treated
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