COMMENTARY

IV Diltiazem and Other Shortages at Crisis Level

Melissa Walton-Shirley, MD

Disclosures

May 23, 2018

A severe flu season on the heels of a Category 5 Hurricane in September 2017 in Puerto Rico has caused a complete revamping of treatments for rapid atrial fibrillation, dehydration, and hypotension in the United States. I became concerned in January of this year when I could not get intravenous (IV) diltiazem for a patient in the intensive care unit, and the issue is unresolved.

Pharmacists have been grappling with parenteral shortages far longer than we physicians have. They have been rationing normal saline and lactated Ringer's and monitoring substitutions with less than ideal drug therapies. Extreme measures, such as "borrowing" sterile water from alteplase kits to dilute other, more commonly required parenterals, are becoming commonplace. Was this crisis avoidable? Absolutely. Is it dangerous? No doubt. Is it correctable? Not overnight. Only legislation and regulation can move the needle forward on four decades worth of corporate complacency.

Hurricane Maria

When Hurricane Maria crushed power lines to pharmaceutical manufacturing facilities in Puerto Rico, it affected the availability of up to 10% of all drugs consumed by Americans, according to the Food and Drug Administration (FDA).[1] About 80 firms make medical products there.

Nearly half of the IV saline used in the United States comes from Puerto Rico. But for reasons unclear, the United States was running below optimal levels of saline and other products before Hurricane Maria hit. Industries that long relied on "just in time" deliveries instead of large shipments ran out. Adequate backup plans to make larger stockpiles required to offset natural disasters and epidemics still aren't in place. Most average citizens and many physicians are unaware of how alarmingly vulnerable we are.

Someone please bring back the diltiazem drip. The IV diltiazem shortage affects cardiac patients who require treatment for rapid atrial fibrillation. We don't have the basic mechanics essential to formulate a drip to sustain conversion to sinus rhythm or rate control, resulting in longer hospital stays for patients as well as anxiety and discomfort. From a clinical perspective, I've seen cardiac stress with rising troponin levels and heart failure secondary to reduced diastolic filling time because of the IV diltiazem shortage.

Cardiologists are late to this pharmaceutical version of The Hunger Games, but Mike Ganio, PharmD, a medication safety expert at the American Society of Health-System Pharmacists (ASHP), is familiar with it. Via phone, he described what is happening with opioids in the United States. "Pfizer is responsible for 50% to 60% of injectable opioids…. When they detected a quality issue in their Kansas plant involving glass syringes, they shut down production abruptly. The other two manufacturers, West-Ward and Fresenius Kabi, could not cover the shortages," he explained. This crisis is still boiling, resulting in the postponement of elective surgeries in some venues because of the lack of injectable opioids and anesthetics.

Additionally, the Drug Enforcement Administration is calling for a reduction in the manufacture of opioids to curtail illegal consumption, which will further fuel the legal opioid crisis and likely result in more patients in pain. Two IV morphine shortage–related deaths were reported  when doses of the substitute drug, hydromorphone, were miscalculated during the crisis of 2010.[2]  The opioid crisis is raging on the streets and in the operating room.

Poor Substitutions

What about substitutions for cardiac drugs? Less-than-ideal treatments to control heart rate in patients in atrial fibrillation, such as esmolol, can induce hypotension, which can further cut into supplies for normal saline or lactated Ringer's for correction. Digitalis, a first-line therapy for decades, is rarely a first option now because of fear-mongering based on studies that demonstrate higher mortality in elderly women with heart failure.[3]

IV amiodarone, a drug with long-term toxicities, is being used more often in the acutely ill and in younger patients. Semi-elective cardioversion is cumbersome in the middle of the night because of the need for transesophageal echocardiography.

And there you have it: the status of acute atrial fibrillation treatment in the United States in 2018, post-Maria, post-flu season, and in the wake of poor preparation with corporate manufacturing practices run amuck. Unfortunately, it's only the micrometer-sized tip of the iceberg in a sea of shortages that many of us never thought about previously.

ASHP's Solutions

I spoke with a panel of experts* at ASHP regarding the parenteral shortage crisis. They not only understand the issues but have the answers. What they need now is a public outcry to bring their suggestions to action before more harm comes to the US public. Chris Topoleski, a legislative consultant for ASHP, informed me that the following suggestions  for Congress are being floated on Capitol Hill

  • Manufacturers should provide the FDA with more information on the causes of the shortages and their expected duration:

  • Require manufacturers to establish contingency plans and/or redundancies, including more transparency from the manufacturers with regard to location of production (ie, some of them use contract pharmacies without revealing their strategies for supply lines).

  • Examine drug shortages as a national security initiative with a requirement for publication of preparation strategies for disaster response.

  • The Federal Trade Commission should include in its review of drug company merger proposals the potential risk for drug shortages.

  • Provide incentives to foster new competition among drug manufacturers.

I reached out to Baxter International regarding their role in correcting the current crisis. Global Corp Communication responded by email stating that, "All manufacturing facilities in Puerto Rico are operating fully at prehurricane levels and have been throughout 2018." They also pointed out that "small volume parenterals, mini-bag plus, amino acids and certain pre mixed products are available to customers and allocations range from 100-120% depending upon the product." They added that

"Baxter's large volume parenterals (LVPs) which are not made in Puerto Rico are also available" and that "Baxter will bring millions of additional units of LVPs into the US through a permanent FDA approval for products made at a Baxter facility in Mexico."

They also told me that they were granted regulatory discretion from the FDA for the temporary special importation of certain products from Baxter facilities outside the United States to support the product supply stateside and have imported millions of units that have been provided to hospitals across the nation since October 2017.

That's all very well, but we are still in trouble. The posthurricane, postflu season efforts haven't been adequate for some parenterals. A Tennessee hospital facility pharmacist confirmed by phone that amiodarone is currently being used at a 4-fold higher rate than in the first quarter of 2017. Use of esmolol is 3.5-fold higher than last year. Recently, I heard of a patient who received an undiluted bolus of ceftriaxone for treatment of bronchitis, resulting in dry heaves and sinus tachycardia, which led an emergency department doc to note that, "This happens to a lot of people when we don't dilute it" — and they didn't dilute it because the patient was normotensive and they didn't want to waste the diluent on a stable patient.

Despite magnanimous efforts post-Maria from entities, such as Baxter, that delivered food, water, fuel, gas-powered generators, propane cook tops, and laundry stations to employees in Puerto Rico, IV drug and diluent shortages continue and are unacceptable. What will it take to get our legislators' attention?

The participants in my call with ASHP bemoaned the fact that the FDA has little leverage over the pharmaceutical companies other than ensuring that quality standards are in place. They suggested that tax exemptions might help bring the industry back to the mainland, but that still leaves the issue of diminishing competition. The ASHP encourages its members to contact their congressmen and -women to educate them on the issue, and the agency has asked for a hearing. "They aren't aware of the shortages," and  "It's going to take a fatality to get Congress's attention," the callers warned. There have been two drug summits and another is scheduled, but no  hearing is set.

That's where physicians and providers can help. We've long been complacent when it comes to driving legislation. We need to pick up the phone, call in a few favors, and let the donations we've made to local, state, and federal campaigns start to work for us and for the public good. At this point, we are in reactive mode.

We should have been proactive decades ago. The ASHP needs our help. Our patients need our help. Now.

*ASHP conference call participants: Michael Ganio, PharmD, MS, FASHP, director, pharmacy practice and Quality Center on Medication Safety and Quality; Christopher Topoleski, director, federal legislative affairs, Government Relations Division; Jillanne Shculte Wall, JD, director, federal regulatory affairs, Government Relations Division; Aretha Hankinson, JD, director, advocacy communications.

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