Wednesday, 12 March 2014

Accidental fampridine toxicity from a compounding pharmacy

Compounding pharmacies; a disruptive force or a danger to our safety? #MSBlog #MSResearch

When you buy slow-release fampridine you are paying for innovation; innovation costs money.  #MSBlog #MSResearch

"In response to a question yesterday about cheaper versions of Fampridine. The case below illustrates the dangers of using a compounding pharmacy to cut costs. The pharmacy made a mistake and gave the patient 10X the prescribed dose. As you can see the side effects of too much fampridine or 4-aminopyridine can be life threatening. Although this patient had a spinal cord injury the lessons are the same for MSers. In fact I have been told by a Canadian colleagues of a similar overdose in a patient of his with MS. Please be careful."

"The other thing about Fampridine is that it is slow release formulation. Being slow release is critical to its mode of action and safety. The slow-release formulation prevents peak blood levels that you see when you take the standard formulation. The peak drug levels are what causes the side effects; in particular seizures. The following figure below demonstrates to you the so called pharmacokinetic* profile of immediate- and prolonged-release fampridine formulations. You can see the levels on immediate release (red) peak at over 50ng/mL and fall very quickly. The slow-release (black) have a delayed peak, which is around 20ng/mL and fall slower. What you are paying for when you buy Fampridine is the R&D that has gone into developing this slow-release preparation and the costs of doing the clinical trials and showing that the drug is relatively safe and effective. Based on this I would not recommend using other formulations of fampridine. This is why it is illegal to prescribe alternative formulations in Europe if there is licensed formulation available. I am aware that this financial implications of this policy, but we have to trust our politicians when they make these sorts of rules."

* pharmacokinetic = may be simply defined as what the body does to a drug. Pharmacokinetic properties of drugs may be affected by elements such as the site of administration and the dose of administered drug. These may affect the absorption rate. Pharmacokinetics is often studied in conjunction with pharmacodynamics, i.e. the study of a drug's pharmacological effect on the body.



BACKGROUND: 4-Aminopyridine (4-AP) is a potassium channel-blocking drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction. It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from compounding pharmacies with a physician's prescription. Dose-related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, tremor, delirium, choreoathetosis, and seizures.

OBJECTIVES: To report a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error.

CASE REPORT: A 42-year-old man with a history of C3 spinal cord injury with residual left-sided weakness and anesthesia, taking 4-AP, presented to the Emergency Department with the sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation, and choreoathetosis, followed by status epilepticus. Toxicity due to 4-AP was suspected and the patient was treated symptomatically. He recovered with permanent short-term memory loss after a prolonged and complicated hospital course. Analysis of the pills, which had been prescribed for him by a physician and specially compounded by a pharmacist, showed that they contained approximately 10 times the dose indicated on the label, a dose that reliably produces severe toxicity.

CONCLUSION: Emergency physicians should be familiar with the signs of 4-AP toxicity. Additionally, they should be aware that 4-AP and other non-FDA-approved medications may be available to patients from compounding pharmacies, and that quality control of made-to-order drug compounding may not be up to the standard that is expected with mass-produced pharmaceuticals.

CoI: multiple

3 comments:

  1. Thanks for providing this explanation - if this had been provided by my neuro I would not have pursued the route of finding a cheaper alternative via a compounding pharmacy. It would still be good to have it funded by the NHS to a greater degree.

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  2. Making the unlicensed preparations illegal is no protection for patients who cannot afford the licensed versions. They should at least have the option of getting the compounded pharmacy version. Let them decide based on the risk-benefit ratio

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  3. Patient choice is a bit of a conundrum, ain’t it? It seems some ill people are seriously willing to play Russian roulette with these drugs, opting to risk life and limb(s) for the small chance of minimal improvement. I thought that life was more precious than that.

    Don Giovannoni says that with new designer MS drugs you are: “paying for innovation; innovation costs money.” I guess he’s right but surely research and development costs can be recouped in a less fascist way than what exists currently. When DVD players first came on the market they cost a fortune but their price plummeted within a couple of years once manufacturers clawed back R&D investments. This doesn’t happen in the Big Pharma game. Patents last more than a generation and then Big Pharma seeks licence extensions to please its share holders further. It’s terrible.

    The evilness of Big Pharma aside, will Don Giovannoni agree with me when I say one of the hugest issues we face in the West is that of our culture of privilege and entitlement? MSers are convinced they have a right to the very best over everyone else because they ‘deserve it’, which kinda sucks for them when Big Pharma overprices its products and then NICE goes into one. Do we need, in the age of austerity and discrimination, to alter our notions of just how much we are really worth to society? Are we all in it together or in a pack of one?

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