4-AMINOPYRIDINE TREATMENT FOR CHRONIC SPINAL CORD INJURY
Wise Young, Ph.D, M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey 08854-8082
Let me start from the beginning. Until recently, I have been reluctant to post much about 4-aminopyridine (4-AP) or fampridine for three reasons. First, although the drug can be dispensed by compounding pharmacies, there is limited data concerning the quality and shelf-life of the drug. I had heard that some formulations of the drug may lose as much as 10% of its potency per week. Second, Acorda Therapeutics was running two phase 3 clinical trials to assess a new sustained release formulation of the drug (Fampridine SR). Since I am on the Board of Directors of Acorda Therapeutics, I did not want my comments interpreted by the FDA or others as being for or against compounded formulations. Third, the drug is not innocuous and should not be taken without close supervision by a physician. I was forced to comment when I found out that many are taking the drug with minimal physician supervision.
Last year, unfortunately, the two Acorda-run phase 3 clinical trials assessing Fampridine SR in people with chronic spinal cord injury did not meet the efficacy criteria of significantly reducing spasticity in people with chronic spinal cord injury. This failure may have been due to several reasons. First, in theory, only people with demyelinated axons should show improvements in motor and sensory function. The reason why spasticity was chosen as the primary outcome measures of these trials was because phase 2 trials suggested that more people show reduced spasticity. Second, the effective dose of the drug is close to doses that cause unacceptable side effects such as seizures. Therefore, the dose of the drug was kept at a level where no seizures were seen. Third, people recruited into the trials had to have severe spasticity but were allowed to continue taking other anti-spasticity drugs such as baclofen. It is possible that some people reduced their other anti-spasticity drugs to qualify for the trial. The trials suggested that both the control and the treated groups had reduced spasticity.
Due to lack of funding for more clinical trials of Fampridine SR in spinal cord injury, Acorda Therapeutics has decided to focus on developing Fampridine SR for multiple sclerosis where a large percentage of patients show improved motor and sensory function on the drug. Once the drug is approved for MS, the company can go back and redo clinical trials for spinal cord injury. The company therefore stopped fampridine trials for spinal cord injury. It may be several years before the drug is approved for spinal cord injury. Therefore, I feel that it is appropriate for me to discuss the compounding formulations of 4-AP and its use in spinal cord injury. Several polls on CareCure suggested that as many as 15% of people with chronic spinal cord injury have tried or are taking 4-AP. Many questions are asked over and over again. Therefore, I will try to answer the most frequently asked questions:
What is the difference between immediate-release and time-release formulations of 4-AP? At the present, 4-AP comes from compounding pharmacies in two formulations. One is called immediate release or is just the drug mixed with filler and placed in a capsule. This is the most common form of the drug. The other is a time-release formulation where the drug dissolves slower. The immediate release formulation causes a rapid rise of the blood drug levels within about half an hour and then falls gradually to about half of its level within 6 hours. To maintain the level, one has to take a capsule every 5-6 hours. Little is known about the time-release capsule from compounding pharmacies. Acorda Therapeutics has developed and is testing a sustained release (SR) formulation with a half-time of about 12 hours, allowing higher doses of the drug to be taken every 12 hours.
How does 4-AP work? 4-AP blocks the fast voltage-sensitive potassium channel on neurons and other excitable tissues such as the heart and muscle. This has two effects on the nervous system. First, the potassium channel is responsible for shortening the duration of action potentials (the signals that axons conduct). Blocking the potassium channel increases duration of the action potentials and allows the signals to conduct through demyelinated areas. Second, the duration of the action potential determines the amount of neurotransmitters released by the axons. Thus, 4-AP not only increases the reliability of action potentials but strengthens their effects when they get through. In recommended doses, it primarily affects demyelinated axons and has relatively little effect on normally myelinated axons. At higher doses, however, it begins to affect normal axons and neurons, as well as heart, muscle, and other excitable tissues of the body. The effect of 4-AP goes away when the drug level drop below certain levels.
Will 4-AP help me? It is difficult to predict whether 4-AP will have an effect on a given person. If the person does not have demyelinated axons crossing the injury site, 4-AP should not improve motor or sensory function. Only about a third of people with spinal cord injury have demyelinated axons as a cause of their neurological loss. In people who do have demyelinated axons crossing the injury site, it should strengthen motor and sensory function. In addition, 4-AP reduces spasticity without weakening muscles. Other anti-spasticity drugs such as baclofen reduce spasticity but at the same time will weaken voluntarily muscle activation. 4-AP may also reduce neuropathic pain but this effect is mixed because 4-AP increases pain sensations. Some people who have taken 4-AP have discovered that they have pain that is masked by their spinal cord injury. Because different people have different populations of demyelinated axons, the degree of improvement and type function vary considerably from person to person.
What bad effects do 4-AP have? In general, 4-AP increases excitability of the nervous system. Side-effects of the drug include insomnia, nervousness, tingling, increased blood pressure and heart rate, and trembling. Also, at doses of greater than 10 mg, 4-AP may cause seizures in susceptible people. The side effects depend on peak blood drug levels. The immediate release formulation results in peak blood levels within 30 minutes and gradually decline to half that level in about 6 hours. The drug is cleared by the kidney and blood levels of the drug can be abnormally elevated if a person has renal problems (such as kidney damage or infection). The side effects are most prominent when a person starts taking the drug but they diminish after several days while the improvement in conduction remains. In very high overdoses, 4-AP can provoke overwhelming excitation of the nervous system, including status epilepticus (continuous seizures), life-threatening hypertension, cardiac arrythmias, and hyperthermia.
What is the treatment for 4-AP overdoses?. If a person is suspected of having taken an overdose of 4-AP, the treatment is to reduce excitability of nervous system. This include anti-seizure medications, major tranquilizers, and other treatments that are normally given to people who have severe seizures. Because the drug is cleared relatively quickly from the body, i.e. within 6-12 hours, the goal of the treatment is reduce excitability of the nervous system and prevent autonomic dysreflexia. The person needs to be monitored carefully and treated as necessary for hypertension, cardiac arrythmias, and hyperthermia. Intensive care in the hospital is necessary. Once the drug levels are down, these effects should subside. Thousands of people are taking 4-AP without adequate physician supervision. Despite this situation, reports of toxic reactions to the drug have been relatively infrequent. In clinical trials of 10 mg of 4-AP given four times a day, less than 1% of the people with spinal cord injury have had seizure activity. However, people with multiple sclerosis have a lower threshold for seizure activity, perhaps because the drug crosses the blood brain barrier more in people with multiple sclerosis and they have a higher risk of seizure activity.
What is the recommended dose of 4-AP for people with chronic spinal cord injury? The recommended dose of the immediate release 4-AP formulation is 10 mg four times a day for people with spinal cord injury. The risk of seizures and side effects depend on the peak blood levels of the drug in blood. At doses of greater than 10 mg every 6 hours, the risk of seizures becomes significant, particularly in people with multiple sclerosis, prior head injury, or a history of seizures. I do not know the dose of time-release or sustained release forumulations of 4-AP provided by compounding pharmacies. It is not clear what the pharmacies used to slow down the absorption of 4-AP. Because the absorption of the drug is slower, you should expect effects of a time-release or sustained release formulation to start slower and go for longer periods than an immediate release formulation. Also, because the peak blood levels of the drug is lower, you can take higher doses. Most sustained release formulations are designed to be taken twice a day.
How should I ramp up on the dose of 4-AP to avoid side-effects when I start taking the drug? Experience in clinical trials of 4-AP suggest that side-effects are less if people start with lower doses and increase the dose over a period of 1-2 weeks. The amount of 4-AP that you take at any given time determines the peak dose and the side-effects that you will experience. Since the drug comes in capsules, you can't easily divide the dose. One approach is for your pharmacies to make 5-mg and 10-mg capsules of immediate release formualtion of 4-AP. When you are starting 4-AP (for example, if you haven't taken it for at least a week or longer), start by taking
¥ Day 1. Take a 5-mg capsule in the morning.
¥ Day 2. Take a 5-mg capsule in the morning and 6 hours later in the afternoon.
¥ Day 3. Take a 5-mg capsule in the morning, 6 hours later in the afternoon, and 6 hours later in the early evening.
¥ Day 4. Take a 5-mg capsule in the morning, afternoon, early evening, and night, all separated by 6 hours.
¥ Day 5. Substitute a 10-mg capsule for the morning dose and take a 5-mg capsule in the afternoon, early evening, and night.
¥ Day 6. If you have no side effects from taking the 10-mg capsule from the previous day, substitute a 10-mg capsule in the morning dose and the afternoon dose, then 5-mg in the early evening and at night.
¥ Day 7. If you have no side effects from taking the 10-mg capsules in the morning and afternoon, substitute a 10-mg capsule in the morning, afternoon, and evening doses.
¥ Day 8. If you have no side-effects from taking the 10-mg capsules from the previous day, take 10-mg capsules in the morning, afternoon, evening, and night doses.
¥ Day 9. You may then want to adjust the timing of the doses, depending on the effects. For example, some people get insomnia at night if they take the drug just before sleep. If so you may want to skip the night dose or take the capsules during the day 5 hours apart (rather than 6 hours apart).
What should I do if I have side-effects from the drug. Fortunately, the drug has a short half-life in the body. In most people, the drug levels fall by about half in 6 hours. The drug is cleared by urine and the half-time may be less in people who are drinking a lot of fluids. It may be longer in people with urinary tract infections. If you have side-effects from the drug during the ramp-up, don't take the next dose until the side-effects are minimal. You should not go to higher doses of 15 mg or even 20 mg of the immediate release formulation without close supervision by a knowledgeable physician who knows how to handle a seizure.
What is the recommended dose of time-release or sustained release formulations of 4-AP for people with chronic spinal cord injury? Most time-release formulations simply add some binding agent to the 4-AP that result in slower release of the drug over 6-12 hours. Much of the drug may not be absorbed by the body. Although compounding pharmacies provide formulations that they call timed release or sustained release, most have not been assessed rigorously for the time course of drug release or absorption. Acorda Therapeutics has a sustained release formulation that has been carefully tested and calibrated so that the drug can be taken every 12 hours. Well-designed sustained release formulations allow higher doses of the drug to be taken and maintains optimal blood levels over 12 or more hours. For example, the Acorda sustained release formulation can be given in doses as high as 40 mg twice a day and appears to have less side effects than the immediate release formulation.
How long should I take 4-AP before I know that it is effective or not? The effects of 4-AP should be apparent within an hour after the drug is taken. The effects of course depend on dose. The effective dose of the drug vary considerably from person to person. Most people with chronic spinal cord injury will not see much effect from a 5 mg capsule and about a third should see some effect from a 10 mg capsule. The sensory improvement should be apparent within hours. However, improved motor response (i.e. greater strength) may not show because muscles that have not been used for a long time are weak. Motor improvement may take weeks or months to build up. Because the effects of 4-AP depend on the presence of demyelinated axons, the effects of 4-AP may vary considerably. A majority of people should see a reduction in spasticity. For example, some people report that they are able to extend their hands or move their fingers more rapidly. Some may have improved sensation in areas that previously had only abnormal sensations. Some may be able to feel their bladder or be able to achieve orgasms. In people with MS, 4-AP has been shown to improve their ability and time to get up and walk short distances, reduced fatigue, and better postural control. In general, if some beneficial effects are not evident once a person has taken up to 10 mg every 6 hours, it is likely that the standard dose of 4-AP is not effective. While some people have pushed the dose to higher levels, i.e. 15-20 mg four times a day, this should not be undertaken without close supervision by an experienced physician who can take care of side effects.
How should I stop taking 4-AP? Some people have reported increased spasticity when they suddenly stop taking the drug. These side-effects go away after several days. However, these side-effects of going off 4-AP can be minimized if a person reduces the dose of 4-AP gradually over several days. For example, if a person is taking 10-mg capsule every 6 hours, the taper can be accomplished substituting a 5-mg capsule for one of the 10-mg capsule on the first day, substituting 5-mg capsule for two the 10-mg on the second day, and so on. After the dose is down to 5-mg capsule every 6 hours, start increasing the time between capsules to 8 hours, then every 12 hours, and then 24 hours. In short, people should ramp down on 4-AP in a similar pattern as when they were ramping up.
How soon can I start taking 4-AP after spinal cord injury? There is not much experience giving 4-AP during the first year after spinal cord injury. While there is no theoretical reason why the drug would not be effective during the first year, we know that injury to the spinal cord causes demyelination and that the spinal cord is remyelinating during the first year. So, it is possible that the drug will have more effect on people during the first year after injury and, as the spinal cord remyelinates, they should get better and the drug effect should decrease. This is one of the reasons why clinical trials of 4-AP have generally excluded people who are within a year after injury. This is so that the effects of 4-AP can be distinguished from remyelination. There is no evidence that 4-AP changes the rate or extent of remyelination. This is uncharted territory.
What is the safest way for me to increase the dose of 4-AP beyond 10 mg every six hours. If you are getting benefits from an immediate release version of 4-AP but it is not lasting 6 hours till you take your next dose, one approach is reduce the time between doses. For example, you may want to take the drug every 5 hours or even every 4 hours. For example, I know a person with multiple sclerosis who titrates the dose and timing to his activity level. In the morning, when he gets up, he takes a 10-mg capsule at 8 am and then takes another one just before lunch at 12 noon or 1 pm. In the afternoon, if he is planning to do a lot, he may take another one at 4 pm. He may take another one at 8 pm and skips the night dose. A second possibilty is to add 5-mg capsule to the dose in the morning. In any case, all of these should be done under the supervision of an experienced clinician. For example, some people have worked with their doctors to go up to 20 mg capsules and combine this high dose with an anti-seizure drug.
In summary, 4-aminopyridine or fampridine is not an innocuous drug. Nor is it a cure for spinal cord injury. In theory, it improves the conduction of demyelinated axons. In people who have demyelinated axons, such as in multiple sclerosis, Gullain-Barre, or spinal cord injury, the drug should improve conduction and therefore motor, sensory, and autonomic function. The improved conduction should occur only while the drug is being taken and for several hours afterwards. When the drug is stopped, the benefits should go away. Because people have different populations of spinal axons remaining and only some may be demyelinated, the effects of 4-AP are not easily predictable. The effective dose of the drug varies a great deal from person to person. In some people, the effective dose is close to the dose that causes side effects. The recommended dose of immediate release fampridine for people with chronic spinal cord injury is 10 mg every 6 hours. Under the supervision of a doctor, it may be possible to adjust the timing and the dose.
I hope that this is helpful.