Countdown

22 ... 21 ... 20 ... 19 ... 18 .......

It's the final countdown, but not just for New Year's 2010; we have 22 days to go until the PDUFA (Prescription Drug User Fee Act) for Acorda's (ACOR) Fampridine-SR (01/22/10).

2010 will be an exciting year for MS patients, families, loved ones and neurologists. In January, we should see the FDA approve the NDA (New Drug Application) for Fampridine-SR. Sometime in January, we expect Novartis (NVS) to file Fingolimod (FTY720) with the EMEA (European Medicines Agency) and the U.S. FDA (Food and Drug Administration). Although many of us expected the filing of Fingolimod's NDA to be in December 2009, it may still precede Merck KGaA and EMD Serono's oral Cladribine (Mylinax or Movectro) refiling after the disappointing Refusal to File (RTF) in November 2009.

In the spirit of advancement, and especially advancement of knowledge and education, I would like to take this opportunity to discuss various scenarios ('cases') that will face neurologists and patients with MS regarding the imminent approval of Fampridine-SR.

Although Compounded 4-Aminopyridine has some similarities to Sustained (Extended) Release Fampridine, it should be clear by now that these are, in many ways, different drugs and there is little justification to starting someone de novo on Compounded 4-Aminopyridine once Fampridine-SR is approved.

SCENARIOS:

Scenario #1

Mr. A is an MS patient with walking difficulties who has never been on Compounded 4-Aminopyridine or Fampridine-SR to improve their walking (or other symptoms helped by blocking the potassium channels and extending the electrical signals in the nerves; these other symptoms -- not endorsed by Acorda -- include, spasticity, pain, 'MS hug,' trigeminal neuralgia, Lhermitte's phenomenon, sensory symptoms, cognition, arm mobility, fatigue etc.).

Since Mr. A has never been on Compounded 4-Aminopyridine, it would make no sense to initiate it once Fampridine-SR is approved. The reasons for this include: safety, efficacy and tolerability.

Thus far it seems that Fampridine-SR 10 mg -- one pill twice a day, does not increase the risk for seizures. We know, however, that the mechanism of action whereby potassium channels are blocked, could theoretically lead to a lower threshold (as seen in higher doses). Since Compounded 4-Aminopyridine is made in a non-standardized fashion with variations from batch to batch in the same pharmacy and from pharmacy to pharmacy, patients may be receiving variable quantities of the actual medicine.

[The epilepsy community faces similar threats with generic anti-seizure medications, even though they are made in internally standardized factories; the whole issue is that there is variability among the different versions of the medication. Advocacy efforts have led to insurance companies recognizing the dangers to patients, as noted in a letter -- http://sparklightadvocacy.files.wordpress.com/2009/12/wellmarkongenerics.pdf ]

Compounded 4-Aminopyridine is not sustained release at here is wearing off of its effects.

The largest tolerability issue with Compounded 4-Aminopyridine (besides the risk of seizures) is gastrointestinal upset. Since Fampridine-SR is coated (allowing the sustained release), there is less tolerability issues.

Scenario #2

Mrs. B was on Compounded 4-Aminopyridine 2 years ago for 3 months, but had no noticeable change in her functioning or symptoms and therefore stopped the medication. Once Fampridine-SR is on the market, it would make sense to try it in this patient with walking difficulties.

Mrs. B may now respond to the Fampridine-SR because it is a better drug than the compounded version, in addition to her having accumulated more difficulty walking, and the effects of the potassium channel blockade are now more apparent.

Scenario #3

Ms. C tried Compounded 4-Aminopyridine 3 years ago, but had stomach pains or other tolerability issues with the medication. As noted above, Fampridine-SR has a better tolerability profile than Compounded 4-Aminopyridine and so Ms. C may have the beneficial effects of the potassium channel blockade without the unpredictable tolerability issues of the compounded medication.

Scenario #4

Mr. D tried Compounded 4-Aminopyridine 10 mg twice a day, 3 months ago and had a seizure, but on further clarification, there was a compounding error and the pharmacy prepared 40 mg twice a day. Mr. D wants to go back on the medication because he felt better while on it, until the seizure occurred.

This is a difficult scenario, since the seizure was because of an overdose of the compounded medication, and we know that even Fampridine-SR reduces the threshold seizure at higher doses; one could argue that Fampridine-SR should not be withheld from him because of a past compounding error. On the other hand, he may be at risk for future seizures. Like in all situations, a long discussion between the patient and neurologist is important. In addition, the family becomes crucial here because having another seizure has many implications for driving and working.

A middle of the road approach may be to wait until Mr. D is seizure free for a longer period (6 months? 12 months? 24 months?) prior to initiating Fampridine-SR. Other seizure risk fators need to be assessed (including the location of the MS plaques) and individual states have variable driving laws.

Scenario #5

Ms. E was on Compounded 4-Aminopyridine 10 mg (1 pill twice a day) for 2 years, but 3 years ago she had a seizure and stopped the medication (despite it helping her walking). On careful examination of the pharmacy records, it looks like there was no compounding error. This is an even more difficult scenario since it is possible that Ms. E may have a lower seizure threshold with Fampridine-SR, as well. Granted, 10 mg of Compounded 4-Aminopyridine is not equivalent to 10 mg of Fampridine-SR, but most patients do not have seizures at that dose of Compounded 4-Aminopyridine.

Since this scenario is so controversial, and there may be extenuating circumstances pushing us in one direction or another, I will not comment on it here (although some of my patients face this difficult situation and each one is going through individualized counseling). This scenario highlights the importance of a strong, reciprocal relationship between the neurologist and patient so that the nuances of care can be explored, discussed and agreed upon.

Scenario #6

Mrs. F has been on Compounded 4-minopyridine for the past 4 years, with what she calls an excellent response. Granted, she still has some difficulties with walking, but she is much better than she was prior to initiating the medication and she "wouldn't give it up for the world." This is a common question I receive; switching to Fampridine-SR makes sense for several reasons:

1. Mrs. F may have an even better response to Fampridine-SR, both in terms of magnitude and duration throughout the day.

2. Mrs. F may not be as functional as she could be. She knows that when she skips a few doses of Compounded 4-Aminopyridine she feels worse (and this tells her it is helping), she doesn't know if she respond even better to Fampridine-SR.

3. Although Mrs. F knows that her walking improves with Compounded 4-Aminopyridine, other symptoms may not be helped. Theoretically Fampridine-SR may help with these other symptoms, as well (longer acting, less variability etc.).

4. As we understand it, there is less of a risk for seizures with Fampridine-SR than Compounded 4-Aminopyridine.

5. Mrs. F may not realize that she is having tolerability issues from the compounded medication.

We all recognize that 2009 has been a confusing year (including the question of CCSVI) and I wanted to clarify some things as we look towards 2010.

Happy New Year and let's keep the ball rolling!

- Dr. Daniel Kantor, MD BSE

Medical Director
Neurologique

info@neurologique.org
www.neurologique.org