The emergence of a risk with loperamide (e.g., IMODIUM A-D), a 40-year-old antidiarrheal drug available over-the-counter, begins in the medical literature with stories about fatal and near-fatal cardiac disorders linked to intentional overdoses. One story involved a 39-year-old woman who presented to an emergency department (ED) after experiencing episodes of seizure-like activity (Katz et al., 2017). While being evaluated in the ED she experienced two more seizures, one while connected to a cardiac monitor that exposed a life-threatening dysrhythmia. A loperamide overdose was the cause. In this case, the woman had a substance abuse disorder and had been taking 50 to 100 loperamide (2 mg) caplets a day, instead of the recommended maximum dose of 4 caplets (8 mg total).
Loperamide is an opioid that is 40 to 50 times more potent than morphine in the gastrointestinal tract. But absorption from the gut is poor, and little drug passes the blood-brain barrier at normal doses; thus, it takes a large amount of loperamide to induce a euphoric high or cope with withdrawal symptoms. Thus, substance abusers may take 10 to 20 times the recommended dose to achieve effects that would be similar to taking an opioid such as morphine or oxyCODONE. The primary medical problem with a loperamide overdose is that it can cause potentially fatal cardiac events including QT interval prolongation, torsades de pointes or other ventricular arrhythmias, and cardiac arrest.
An event in which a 19-year-old was found dead at home after hosting a party revealed another problem: standard toxicology screens detected loperamide, but not loperamide overdoses (Mukarram et al., 2016). When the medical examiner reviewed 21 deaths where loperamide had been detected, mass spectrometry established that loperamide overdoses contributed to 19 of the 21 deaths (Bishop-Freeman et al., 2016). Poison control centers also reported that loperamide overdoses had doubled between 2009 and 2015 (Borron et al., 2017).
In June 2016 (updated 2017), the U.S. Food and Drug Administration (FDA) released a Drug Safety Communication (http://www.ismp.org/ext/53) that loperamide abuse was causing serious and fatal cardiac events. The warning was apparently based on 48 case reports the FDA received over 39 years-a small number in the FDA reporting system that typically captures more than 75,000 serious and fatal injuries per quarter. In January 2018, FDA issued an updated Drug Safety Communication (http://www.ismp.org/ext/54), reporting that it was working with the manufacturers to develop abuse-resistant packaging with fewer doses. In September 2019, FDA approved new packaging limits for brand name loperamide. Each carton will contain no more than 48 mg of loperamide and each tablet or capsule will be packaged in individual doses.
Although FDA acted promptly, published a detailed risk assessment, and followed up with additional action to reduce those risks, it took years to identify the problem of abuse. Even today, the true incidence of overdoses remains unknown. Whether this is a rare but novel form of abuse or a substantial safety issue cannot be determined.
Ear Wax Removal Drops Bottle Looks Like Eye Drops
A patient told us about an administration error she made in part due to look-alike packaging. The woman inadvertently instilled ear wax removal drops (carbamide peroxide 6.5%) into her eye causing irritation and redness that persisted after rinsing her eye for 15 minutes. The product bottle (Figure 1) looks like containers used for ophthalmic solutions. Neither the product carton nor the bottle contains prominent warnings that the solution is for the ears only. On the back of the carton, the statement "When using this product, do not get into eyes" is included in the middle of the Drug Facts table but it does not stand out. This same language also is included on a side panel of the container label but it appears in the middle of a paragraph of text in a very small font size.
This is not the first time we have received reports of nonophthalmic products packaged in containers that look like eye drop bottles. For example, patients or their caregivers have inadvertently instilled glucose control solution, clotrimazole topical solution, and even super glue into the eye. Any nonophthalmic substance packaged in bottles (or tubes) that look like eye drops or ointments might pose a problem, particularly if the products are left in areas where ophthalmic medications are stored. We contacted Walgreens and asked them to better differentiate this product from ophthalmic products and improve the visibility of the warnings.
Educate Fluorouracil Home Infusion Patients About Accidental Overinfusion
We received a call from the family of a patient with cancer who was to receive a 7-day infusion of fluorouracil at home via an ambulatory elastomeric infusion pump. For an unknown reason, the entire infusion ran in over 4 days. The patient was very sleepy for the next 2 days and had "terrible diarrhea." Even though the infusion was empty, they waited until the patient's scheduled appointment 4 days later to report the mishap. The doctor hospitalized and treated the patient. The patient was discharged after 7 days of hospitalization.
This incident points to the need to educate patients with ambulatory infusion pumps about specific details on how the pump works, what to expect over the course of the treatment, infusion rates, how long the infusion should last, how much should be left in the container each day, and the need to immediately report any incident to their care team should the container empties sooner than anticipated. Dangerous delays have been known to occur because patients are often asymptomatic in the first few hours and days. But rapid identification of an overdose allows prompt treatment with the antidote to minimize serious side effects and the risk of a harmful or fatal outcome. Patients need to be educated about rapidly reporting events so an antidote can be administered.
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