Ampyra (Dalfampridine)

AMPYRA is indicated as a treatment to improve walking in adult patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed

[see

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.

].

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.

• Pregnancy: Based on animal data, may cause fetal harm (
  8.1 Pregnancy

  Risk Summary

  There are no adequate data on the developmental risk associated with use of AMPYRA in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses [see

  Data

  ]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

  Data

  Animal Data

  Oral administration of dalfampridine to pregnant rats and rabbits throughout organogenesis resulted in no evidence of developmental toxicity in either species. The highest doses tested (10 mg/kg/day in rats, 5 mg/kg/day in rabbits), which were associated with maternal toxicity, are approximately 5 times the MRHD on a body surface area (mg/m²) basis.

  Oral administration of dalfampridine (0, 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to female rats throughout pregnancy and lactation resulted in decreased offspring viability at the highest dose tested and decreased body weight in offspring at the mid and high doses. The no-effect dose for pre- and postnatal developmental toxicity in rats (1 mg/kg/day) is less than the MRHD on a mg/m²basis.
  )
• 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 CONTRAINDICATIONS

  The use of AMPYRA is contraindicated in the following conditions:

  • History of seizure [
    see Warnings and Precautions (5.1)]
  • Moderate or severe renal impairment (CrCl≤50 mL/min) [see
    Warnings and Precautions (5.2)
    ]
  • History of hypersensitivity to AMPYRA or 4-aminopyridine; reactions have included anaphylaxis [see
    Warnings and Precautions (5.4)
    ]

  • History of seizure
  • Moderate or severe renal impairment (CrCl≤50 mL/min)
  • History of hypersensitivity to AMPYRA or 4-aminopyridine
  ,
  5.2 Renal Impairment

  AMPYRA is eliminated through the kidneys primarily as unchanged drug

  [see Clinical Pharmacology (12.3)].

  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)]

  .
  ,
  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 (12.3)]

  . 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 (2.3)and Warnings and Precautions (5.2)]

  .
  )

• 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 Seizures

  AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily (2 times the maximum recommended dosage) 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. Permanently discontinue AMPYRA in patients who have a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures

  [see Contraindications (4)]

  .
  )
• Avoid concomitant use with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same (
  5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine

  Avoid concomitant use with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Instruct patients to 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.
  )
• AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs (
  5.4 Anaphylaxis

  AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. AMPYRA is contraindicated in patients with a history of hypersensitivity to AMPYRA or 4-aminopyridine. Inform patients of the signs and symptoms of anaphylaxis and instruct them to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur.
  )

The following serious adverse reactions are described in more detail elsewhere in the labeling:

• Seizures
  [see

  5.1 Seizures

  AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily (2 times the maximum recommended dosage) 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. Permanently discontinue AMPYRA in patients who have a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures

  [see Contraindications (4)]

  .

  ]
• Anaphylaxis
  [see

  5.4 Anaphylaxis

  AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. AMPYRA is contraindicated in patients with a history of hypersensitivity to AMPYRA or 4-aminopyridine. Inform patients of the signs and symptoms of anaphylaxis and instruct them to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur.

  ]