Introduction
Multiple sclerosis (MS) is a chronic, autoimmune disease that affects the central nervous system, disrupting the flow of information between the brain and the body. One of the most challenging aspects of MS is impaired walking ability, which affects approximately three-fourths of individuals with the condition. Dalfampridine, known by the brand name Ampyra, is an oral medication specifically designed to improve walking in adults with MS. Unlike disease-modifying therapies, Ampyra is a symptomatic treatment that does not alter the course of MS but rather enhances nerve signal transmission to improve ambulation.
What is Ampyra?
Ampyra (dalfampridine) is an extended-release tablet formulation of 4-aminopyridine (4-AP). It functions as a broad-spectrum potassium channel blocker. In the United States, dalfampridine extended release (ER) (Ampyra extended-release tablets; Acorda Therapeutics Inc, Ardsley, NY), in Europe, prolonged-release fampridine, and elsewhere, fampridine modified or sustained release, 10 mg twice daily, have been approved to improve walking in people with MS, as demonstrated by an increase in walking speed in two phase 3 clinical trials.
Mechanism of Action
Ampyra works by helping electrical signals move more efficiently along the nerves in the brain and spinal cord. In MS, the protective coating around nerves (myelin) is damaged, which disrupts the transmission of nerve signals. Dalfampridine promotes the restoration of action potential conduction in demyelinated axons in animal studies through the inhibition of potassium channels, thereby improving nerve signal transmission. By restoring the flow of these signals, Ampyra helps nerves send messages more effectively, improving muscle function and walking ability.
Regulatory Approval
On January 22, 2010, the FDA approved dalfampridine (Ampyra) as an oral medication to improve walking in patients with MS. It is the first and only brand prescription medicine indicated to help improve walking in adults with multiple sclerosis (MS).
Clinical Evidence of Ampyra's Efficacy
The effectiveness of dalfampridine has been demonstrated in several clinical trials.
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Phase 3 Clinical Trials
Two phase 3 clinical trials showed that approximately one-third of patients with MS responded to dalfampridine, exhibiting consistently faster walking speeds on the Timed 25 Foot Walk (T25FW) while on therapy compared to when they were not. In a phase IIIb clinical trial, a 10 mg twice daily dose was found effective, while a 5 mg twice daily dose did not demonstrate efficacy.
STEADY Study: Effects on Gait and Balance
The STEADY study-the Effects of Dalfampridine-ER on Speed, Gait, Balance, and Distance Walked in Patients with MS Study-was a single-center, single-arm, open-label proof-of-concept trial of dalfampridine-ER 10 mg twice daily. The study consisted of three consecutive periods: period 1 was a 7-day on-drug screening phase, with evaluations performed on the initial day (visit 1) and 1 week later, on study day 1 (visit 2), at which time dalfampridine-ER treatment was withdrawn; period 2 was a 10-day off-drug phase, with evaluations performed on day 5 (±2 days) (visit 3) and day 11 (±2 days) (visit 4), after which dalfampridine-ER treatment was reinitiated; and period 3 was a 4-day on-drug phase, with a final evaluation performed on day 15 (±2 days) (visit 5).
The study aimed to evaluate changes in gait and balance in dalfampridine-ER responders. Dalfampridine-ER responders, based on Timed 25-Foot Walk (T25FW) assessment before study entry, were included in this open-label, three-period, single-center study. Twenty patients aged 20 to 65 years with a definite MS diagnosis by the revised McDonald criteria participated in this study between January 19 and May 3, 2012. For study inclusion, patients were required to have been using dalfampridine-ER 10 mg twice daily for at least 2 weeks before screening and to have been Timed 25-Foot Walk test (T25FW) responders, defined as showing improvement of at least 20% in walking speed between an off-drug and on-drug evaluation before study entry, as determined by a study investigator (GP, a board-certified neurologist specializing in MS care).
The study found that patients demonstrated improvement in overall gait, walking speed, and distance after periods of dalfampridine-ER withdrawal and reinitiation. On 4 days of dalfampridine-ER reinitiation, after a withdrawal period of 10 days, patients exhibited a rapid, statistically significant mean improvement in overall gait, as quantified by an objective, computerized assessment using the NeuroCom SMART Balance Master and long force plate. NeuroCom gait composite scores worsened during period 2 relative to period 1 and improved during period 3; the mean ± SD difference in gait composite scores on drug was 4.03 ± 1.51 points (P = .015). Balance composite scores did not change significantly. Improvements were observed for off-drug versus on-drug for T25FW (0.36 ft/sec, P < .001), 2MWT (25.4 ft, P = .006), and BBS (1.7 points, P = .003).
Gait Parameters
The STEADY study also assessed various gait parameters using the NeuroCom system, which enabled the measurement of step width, step length, speed, endpoint sway velocity, turn time, and turn sway. The overall composite gait score showed high correlations with walking speed (T25FW) and distance (2MWT), as well as with balance assessed using the BBS. Statistically significant on-drug improvement was observed in several gait parameters, contributing to the overall score.
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Dosage and Administration
The recommended dosage of dalfampridine is one 10 mg extended-release tablet taken orally twice daily, approximately 12 hours apart. It can be taken with or without food. Patients should not double up doses if they miss a dose to reduce the risk of side-effects, including seizures. The tablets should be swallowed whole and not be broken, crushed, chewed, or dissolved, as this could lead to a rapid release of the medication and increase the risk of adverse effects.
Missed Dose
If a dose is missed, patients should not take an extra dose to make up for the missed one. Sticking to the prescribed schedule is crucial for maintaining consistent blood levels of the medication and reducing the risk of side effects.
Onset of Action
A response to dalfampridine is typically observed within 2-4 weeks. If no improvement is noted within this timeframe, prolonged trials beyond a month are generally not helpful, unless a medical event prevents the patient and the clinician from assessing the true effect of the medication.
Patient Selection
Reasonable candidates to try dalfampridine are patients with any type of MS who have walking problems from MS and for whom improvement in walking would be of clinical benefit. We note that the magnitude of effect of dalfampridine is usually modest, although significant to the patient. It is essential to remember that dalfampridine does not address all gait problems. Dalfampridine is more beneficial in patients with spastic paresis over those with mostly cerebellar or sensory ataxia.
Contraindications and Precautions
Dalfampridine is contraindicated in certain patient populations due to potential risks.
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Seizures
Ampyra can cause seizures. The risk of seizures increases with increasing doses. Permanently discontinue AMPYRA if seizure occurs. In the post-marketing period seizures have been reported. Ampyra has not been evaluated in patients with history of seizures or with epileptiform activity on an EEG, as these patients were excluded from clinical trials. Patients with a history of prior seizures or epileptiform activity on an EEG should not take dalfampridine.
Renal Impairment
Ampyra is cleared predominantly by the kidneys. It is contraindicated in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min). Caution should be exercised when prescribing dalfampridine to patients over 50 years of age, as they are at a higher risk of having mild renal impairment. The estimated creatinine clearance should be calculated in all patients prior to starting treatment and should be monitored at least yearly.
Concomitant Medications
Avoid concomitant use of AMPYRA with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same. Dalfampridine should not be used along with other forms of 4-aminopyridine.
Pregnancy and Breastfeeding
There are no adequate data on AMPYRA in pregnant women. Dalfampridine should not be used by women who are pregnant or nursing. It is not known if AMPYRA passes into your breast milk.
Adverse Reactions
The most common side effects associated with Ampyra include:
- Urinary tract infection
- Insomnia
- Dizziness
- Headache
- Nausea
- Asthenia (weakness)
- Back pain
- Balance disorder
- Paresthesia (burning, tingling, or itching on the skin)
- Nasopharyngitis (irritation of the nose and throat, or a sore throat)
- Constipation
- Dyspepsia (indigestion)
- Pharyngolaryngeal pain
Less common but more serious side effects include seizures and severe allergic reactions, such as anaphylaxis. Signs and symptoms of a severe allergic reaction may include respiratory compromise, urticaria, and angioedema of the throat or tongue.
Risk Evaluation and Mitigation Strategy (REMS)
The FDA approved dalfampridine with a risk evaluation and mitigation strategy (REMS) program comprising a medication guide and communication plan. Dalfampridine is presently available only through a specialty pharmacy.
Comprehensive Approach to Walking Limitations
Walking is a complex neurobiological function, and various strategies can improve walking skills beyond the use of dalfampridine. It is recommended that patients be assessed by a physical therapist skilled at gait assessment. When prescribing dalfampridine, a comprehensive approach to managing walking limitations is advised.