Effective Date

Date of Origin   

10-01-2024           

07-01-2019

Firdapse®

(amifampridine)

Tablet

Treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients 6 years of age and older

1

Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by the gradual onset of muscle weakness, especially of the pelvic and thigh muscles. Approximately 60 percent of LEMS cases are associated with a small cell lung cancer (SCLC), and the onset of LEMS symptoms often precedes the detection of the cancer. The LEMS patients with cancer tend to be older and nearly always have a long history of smoking. In cases in which there is no associated cancer, disease onset can be at any age.(3)

LEMS may affect the patient’s ability to engage in strenuous exercise and may make such activities as climbing stairs or walking up a steep walkway difficult. Onset is gradual, typically taking place over several weeks to many months. There is often a progression of symptoms whereby the shoulder muscles, muscles of the feet and hands, speech and swallowing muscles and eye muscles are affected in a stepwise fashion. The symptoms progress more quickly when LEMS is associated with cancer. Most LEMS patients also exhibit the following autonomic symptoms: dry mouth, constipation, impotence, and decreased sweating. LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. In summary, LEMS is often described as a clinical “triad” of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes.(3)

LEMS occurs because autoantibodies damage the “voltage-gated calcium channels (VGCC)” on the motor nerve membrane at the neuromuscular junction. These channels normally conduct calcium into the nerve resulting in release of acetylcholine. Acetylcholine helps in the communication between nerve cells and muscles and is one of a group of chemicals known as neurotransmitters, which help to transmit nerve impulses. The autoantibodies attack the VGCC resulting in less acetylcholine release. In LEMS cases associated with cancer, it is believed that autoantibodies created against the VGCC on the small-cell lung tumor damage the VGCC on the nerve. It is unknown what causes autoantibody production in cases not associated with cancer.(3)

A differential diagnosis of LEMS must be determined due to its similarities in presentation to myasthenia gravis. Diagnosis of LEMS is based on clinical signs and symptoms, electrophysiological studies, and antibody testing. LEMS can be diagnosed when the patient is positive for antibodies against voltage-gated calcium channels (VGCC) unlike myasthenia gravis which as anti-acetylcholine receptor (AChR) and anti-muscle-specific tyrosine kinase (MuSK) antibodies.(4) The triad of electrophysiologic abnormalities in LEMS consists of the following:

• Diffusely reduced motor amplitudes on motor nerve conduction studies, often less than 50% of the laboratory’s lower limits of normal
• Decrement with low-frequency stimulation; as opposed to myasthenia gravis, where the decrement is usually maximal at the fourth or fifth stimulation in the train, in LEMS the maximal decrement may occur later in the train
•  Increment with high-frequency stimulation or facilitation after 10 seconds of maximal voluntary contraction. Increments of more than 100% are very suggestive for LEMS but not specific for LEMS and occur in some cases of botulism and myasthenia gravis

The most effective symptomatic treatment in LEMS is 3,4-diaminopyridine (3,4-DAP), also known as amifampridine. Through blocking voltage-gated potassium channels,3,4-DAP prolongs nerve terminal depolarization and increases acetylcholine release. In theory, pyridostigmine should be synergistic with 3,4-DAP but many patients with LEMS have no benefit from pyridostigmine either on its own or in combination with 3,4-DAP.(4)

Efficacy

The mechanism by which Firdapse (amifampridine) exerts its therapeutic effect in LEMS patients has not been fully elucidated. Amifampridine is a broad-spectrum potassium channel blocker.

The efficacy of Firdapse for the treatment of LEMS was demonstrated in two randomized, double-blind, placebo-controlled discontinuation studies. A total of 64 adults with LEMS (confirmed by either neurophysiology studies or a positive anti-P/Q type voltage-gated calcium channel antibody test. Patients were required to be on an adequate and stable dosage (30 to 80 mg daily) of amifampridine prior to entering the randomized discontinuation phases of both studies.(1)

The two co-primary measures of efficacy in both studies were the change from baseline to the end of the discontinuation period in the Quantitative Myasthenia Gravis (QMG) score and in the Subject Global Impression (SGI) score. The QMG is a 13-item physician-rated categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale, where a score of 0 represents no weakness, and a score of 3 represents severe weakness. Higher scores represent greater impairment. The SGI is a 7-point scale on which patients rated their global impression of the effects of the study treatment on their physical well-being. Lower scores on the SGI represent lower perceived benefit with the study treatment.(1)

A key secondary efficacy endpoint was the clinical global impression improvement (CGI-I) score, a 7-point scale on which the treating physician rated the global impression of change in clinical symptoms. A higher CGI-I score indicates a perceived worsening of clinical symptoms.(1)

Safety

• Firdapse is contraindicated in patients with:
  • A history of seizures
  • A hypersensitivity to amifampridine or another aminopyridine(1) 

1

Firdapse Prescribing Information. Catalyst Pharmaceuticals. May 2023.

2

Reference no longer used.

3

National Organization for Rare Disorders (NORD). Rare Disease Database. Lambert-Eaton Myasthenic Syndrome.

4

Nicolle MW. Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome. Continuum (Minneap Minn) 2016;22(6): 1978-2005.

Firdapse

amifampridine phosphate tab

10 MG

M ; N ; O ; Y

N

Firdapse

Amifampridine Phosphate Tab 10 MG (Base Equivalent)

10 MG

300

Tablets

30

DAYS

Firdapse

amifampridine phosphate tab

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Firdapse

Amifampridine Phosphate Tab 10 MG (Base Equivalent)

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The prescriber has provided information supporting that the patient has a diagnosis of Lambert Eaton myasthenic syndrome (LEMS) confirmed by at least ONE of the following: (medical records required)
   1. Decreased amplitude of compound muscle action potential (CMAP) to a single supramaximal stimulus OR
   2. Positive antibody test against voltage-gated calcium channels (VGCC)  AND
2. If the patient has an FDA approved indication, ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
3. The patient has weakness that interferes with normal function AND
4. The patient does NOT have a history of seizures AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  6 months

Note: If Quantity Limit applies, please see Quantity Limit criteria

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for an amifampridine containing agent through the plan’s Prior Authorization process AND
2. The patient has had clinical benefit with an amifampridine containing agent [e.g., improved weakness, improved fatigue, improvement in activities of daily living (ADLs)] AND
3. The patient has not developed a history of seizures while using the requested medication AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

Note: If Quantity Limit applies, please see Quantity Limit criteria

QL with PA

Quantity Limits for the Target Agent(s) will be approved when the requested quantity (dose) does NOT exceed the program quantity limit

Length of Approval: 6 months for initial 12 months for renewal