Quinidine Fades; Pharma Asked to Put Patients Before Profits

March 14, 2011

March 11, 2011 (Tel Aviv, Israel) — It is nobody's idea of a great drug, but the slow disappearance of quinidine from the pharmacies of countries around the world is causing some consternation among electrophysiologists who treat patients with rare arrhythmias. The situation has gotten so bad that one physician recently placed a few boxes of quinidine in the mail, shipping the drug halfway across the world to a Canadian colleague who needed the antiarrhythmic medication.

"Quinidine used to be a popular drug, and everybody used it, but they used it primarily for atrial arrhythmias. As new medications came out, it was used less and less, and it was brought into fewer countries," Dr Sami Viskin (Tel Aviv Medical Center, Israel) told heartwire . "At the same time, we discovered new diseases not known before, like Brugada syndrome, a disease that affects young males and causes sudden death and was described only 16 years ago. By the time we realized that quinidine was the only drug that is effective for these diseases, it was already gone from many countries."

The issue of a quinidine shortage was first raised by Viskin and colleagues in a 2007 editorial in Europace [1] and then by Viskin and Drs Bernard Belhassen (Tel Aviv Medical Center, Israel) and Arthur Wilde (Academic Medical Center, Amsterdam, the Netherlands) in a letter to the editor of Heart Rhythm in 2010 [2].

However, the case of the disappearing quinidine was brought to the forefront when Viskin recently shipped "bootleg samples" to Dr Andrew Krahn (University of Western Ontario, London), a Canadian electrophysiologist.

By the time we realized that quinidine was the only drug that is effective for these diseases, quinidine was already gone from many countries.

"If you think about a patient in Canada with Brugada syndrome who goes into arrhythmic storm and then requires quinidine from a physician in Tel Aviv to put it into an envelope and send by Federal Express, that's an issue," said Viskin. "I understand that drug companies are businesses, but I think they have a responsibility to continue to manufacture medications known to be effective, even if they are not good business."

Speaking with heartwire , Krahn put the quinidine shortage into perspective. "If you're taking a population health perspective, the problem with this particular drug not being available is a trivial problem," said Krahn. "If you're looking at the cardiac world, it's a minor problem, but if you're looking at the electrophysiology world, this is a significant problem. That's because these patients gravitate toward our care and their conditions are life-threatening. From that aspect of things, this is definitely a problem."

AstraZeneca Stopped Making Quinidine in 2006

Speaking with heartwire , Viskin said that quinidine is the most effective treatment for patients suffering from unique ventricular arrhythmias, such as short-QT syndrome and Brugada syndrome and some arrhythmias associated with organic heart disease. In nearly one-third of patients with idiopathic ventricular fibrillation and one in five patients who receive an implantable cardioverter-defibrillator (ICD) for Brugada syndrome, arrhythmic storms develop and are terminated with shocks. These storms recur often and fail to respond to other medications but are responsive to intravenous isoproterenol and quinidine.

"Patients who are diagnosed with Brugada syndrome usually end up with defibrillators, but the problem is that once they have the arrhythmia, some go on to develop ventricular storm," said Viskin. "They will go into ventricular fibrillation, the device will shock them, then they go into ventricular fibrillation again, and the device will shock them again. They can have hundreds of episodes requiring shocks, and they die with the defibrillator in place. There are two drugs effective for this--one is isoproterenol, which is given intravenously and can't be given at home, and the other is quinidine. That's it."

We run into these unique situations where people with these relatively uncommon causes of life-threatening arrhythmias are unable to access the drug.

AstraZeneca stopped manufacturing quinidine in 2006. As a class 1a antiarrhythmic medication, the drug wasn't very popular even when it was available. It required frequent dosing, was associated with side effects, including loose bowels and diarrhea, and wasn't considered very effective. Like most of the early antiarrhythmic drugs, it fell out of favor in light of nondrug approaches, such as ICDs and ablation therapy. ICDs, however, only treat the arrhythmias in patients with Brugada or idiopathic ventricular fibrillation and don't prevent the arrhythmia from occurring in the first place, say experts. Another class 1a antiarrhythmic drug, disopyramide, is not as effective as quinidine, while oral procainamide is no longer manufactured.

In response to Viskin et al's letter to Heart Rhythm last year [2], AstraZeneca said the decision to stop manufacturing quinidine was based on the "consistent decline in the demand of the product over several years." When it stopped making the drug, other companies were still making it, and there were other oral antiarrhythmic agents in the same class. One company still making quinidine is Sanofi-Aventis, but despite this, the drug is not widely available throughout Europe and is no longer available in Canada, likely because the costs associated with clearing the bureaucratic and regulatory hurdles don't make it cost-effective. It is still available in the US, but experts are not sure how much longer that will be the case.

Diminishing Economic Returns

Dr Dan Roden (Vanderbilt University School of Medicine, Nashville, TN) said quinidine is still available at his institution's pharmacy in 200-mg and 300-mg doses, as well as 300-mg and 324-mg extended-release formulations. He said that while the number of patients who are candidates for the drug is small, there are no real alternatives for these patients.

"There are no randomized trials in patients with Brugada syndrome and [ventricular tachycardia] VT storm. That's a pretty unusual entity," Roden told heartwire . "There is pretty good basic-science evidence and corroborating clinical data that quinidine is an effective therapy in this pretty devastating disease. That's what people would reach for, and it's what many clinicians in this country would reach for, but they don't have that option in parts of Europe or Canada."

Given the diminishing economic returns of making a drug for a niche population, Roden said he doesn't expect quinidine to be around forever. Even convincing a generic company to make the drug would require testing to ensure it was made to standard, but given the "boutique" nature of quinidine in treating small numbers of patients, Roden is not sure that will happen.

Krahn said that quinidine stopped being available in Canada about two years ago, and while he has some samples stockpiled, most clinicians who treat patients with short-QT syndrome, Brugada syndrome, or an idiopathic ventricular fibrillation do not.

"We run into these unique situations where people with these relatively uncommon causes of life-threatening arrhythmias are unable to access the drug," said Krahn. "Let's say somebody came into our emergency room at this instant and was in one of these unstable states, we could attempt to get compassionate release of the drug. But in most regulatory environments, that's going to take more than 24 hours, and that's working with people pulling out all the stops."

Doing Good or Making Money

To heartwire , Dr Douglas Zipes (Indiana University School of Medicine, Indianapolis), the editor-in-chief of Heart Rhythm, also said he doesn't expect quinidine to be available much longer in the US. However, he is calling on companies to continue manufacturing it given its unique ability to treat these small numbers of patients.

What we need is a company that will say, 'We're doing a good deed, even though there isn't a lot of money in it.'

"What we need is a company that will say, 'We're doing a good deed, even though there isn't a lot of money in it,' " said Zipes. Companies exist, he added, for two reasons: either to do good things or to make money, and ideally for both. "Sometimes you've got to do good things even though it doesn't make money."

Krahn agreed, and while the thought of such a situation occurring might seem blindly optimistic, he is hopeful it might change. Another possibility is that the drug gains orphan-drug status, meaning the Food and Drug Administration provides incentives for the development and marketing of quinidine. Orphan-drug status is intended for drugs that treat fewer than 200 000 people in the US or that affect more than 200 000 people but the company is not expected to recover the cost of developing and marketing the drug. Still, quinidine doesn't even fit into this category, given that it's already been developed. Although nobody is sure how many patients require quinidine, some suspect there are fewer than 200 000 patients. Krahn said he might see one patient per year where quinidine would be strongly considered if it were available.

"The world needs the big drivers--drugs like our ACE inhibitors and amiodarone--but we shouldn't forget about situations where drugs like quinidine are really critical for the odd life-saving clinical emergency," said Krahn. The authors report no conflicts of interest.