The reports came in from all over the country — at least a half-dozen children, spread across the U.S., were suddenly sick with similar symptoms. NBC news reported one 14-year-old girl experienced stomach pain, her hair fell out in clumps, and she was hospitalized for elevated ammonia levels in her blood.
All the children had two things in common: each suffered from a rare genetic disorder requiring L-citrulline as part of their treatment, and each had taken L-citrulline supplied by the same New York facility.
In a matter of days, Medisca, Inc. would recall eight lots of its product when tests showed it had shipped the wrong product — a mistake that the U.S. Food and Drug Administration (FDA) called “serious and potentially life-threatening.”
L-Citrulline Critical For Ammonia Removal
The affected children all had a urea cycle disorder (UCD) — a rare genetic defect in which they were missing one of six enzymes necessary to remove ammonia from the blood. Without proper treatment, ammonia builds up in the blood — a condition called hyperammonemia, which can quickly lead to brain damage, coma, or death.
UCD requires a regimen of diet and drug treatment using the prescription drug Buphenyl (sodium phenylbutyrate) or sodium benzoate. But the drugs will not work without one of two amino acids — L-citrulline or L- arginine, depending on the patient’s particular missing enzyme.
Medisca did not manufacture L-citrulline. It is a chemical wholesaler that repackaged and distributed drug ingredients to compounding pharmacies and hospitals.
L-citrulline was shipped as a powder to pharmacies or hospitals where it could be compounded into tablets, capsules or liquids. It could also remain in powder form. But instead of shipping L-citrulline in this case, the company had filled bottles labeled as L-citrulline with powdered N-acetyl-leucine, a drug used in the treatment of vertigo.
The error would lead to a four-day flurry of tests, recalls and FDA warnings as the company and federal regulators raced to reign in a medical threat.
L-citrulline Recall Timeline:
At least 6 children develop health problems after taking L-citrulline
February 14, 2014
Medisca recalls eight lots of L-citrulline
February 14, 2014
FDA alerts health care professionals and patients of severe adverse events associated with Medisca L-citrulline
February 15, 2014
FDA announces Medisca’s tests show shipments contain no L-citrulline
February 17, 2014
FDA tests show products labeled L-citrulline actually contain N-acetyl-leucine
February 17, 2014
FDA launches 10 day inspection of Medisca’s New York facility, finding three major issues
FDA issues warning letter to Medisca for adulterated and misbranded drugs
L-citrulline Recall Prompts FDA Warnings, Probe
On February 14, 2014 the FDA alerted health care professionals, patients, and caregivers of what it thought at the time was “subpotent L-citrulline.” The agency reported that adverse effects experienced by UCD patients had been traced to L-citrulline shipped from Medisca’s Plattsburg, N.Y. facility.
The FDA recommended pharmacies, hospitals, and doctors quarantine lots of Medisca L-citrulline until the agency could “provide additional information.”
That same day, Medisca issued a recall of eight lot numbers of L-citrulline. The company had determined none of the packages actually contained L-citrulline and “therefore represent a potential health hazard.”
“These lots should not be used for any purpose,” the company said in a drug recall announcement.
Eight Lots of Medisca L-citrulline Recalled:
|1kg||96453/A, 95482/A||2.8 L white HDPE bottle|
|500g||96453/B, 95482/B||1,000 mL white HDPE bottle|
|100g||96453/C, 95482/C||300 mL white HDPE bottle|
|25g||96453/D, 95482/D||100 mL white HDPE bottle|
On February 15, the FDA announced it was investigating “the full scope” of the recall. The agency recommended pharmacists and clinic staff who dispense L-citrulline to examine their stock and immediately contact Medisca if they found any from the recalled lots.
Did you know
The FDA reported all samples from contaminated lots contained a different amino acid, N-acetyl-leucine, instead of L-citrulline.
On February 17, the FDA said it had received “several adverse event reports associated with Medisca’s L-citrulline product.” The agency reported it had tested samples from the recalled lots and found all samples contained a different amino acid, N-acetyl-leucine, instead of L-citrulline. No L-citrulline was found in any of the samples the FDA tested.
“The samples were analyzed by several laboratory methods to identify the ingredient present in the product that was repackaged by Medisca and labeled as L-citrulline,” the agency said in a statement.
The FDA said its test results served to “reinforce the FDA’s concern” about the mislabeled product. The agency said it was updating its recommendations to health care professionals “so that they can focus their attention on following up with the patients who are believed to be at greatest risk of receiving a mislabeled product.”
FDA recommendations included:
- Health care providers should stop dispensing L-citrulline from the affected lots, contact their patients, and return all unused stock to Medisca
- Patients and their caregivers should immediately stop using Medisca L-citrulline with the affected lot numbers
- Patients should direct any concerns to their health care professional
L-citrulline is not considered a drug, so the FDA’s regulation of the amino acid is limited. The agency considers it an active pharmaceutical ingredient (API) which can be included in the manufacture of drugs. The FDA also considers it a “medical food” defined by law as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”
The National Urea Cycle Disorders Foundation said the recall raised “reasonable concerns” about the potential future quality control failure for supplements that are not regulated by the FDA. The foundation suggested patients or parents speak to a doctor if they suspect problems.
“Quality issues could result in side effects, including but not limited to metabolic instability, hyperammonemia or other symptoms,” the foundation posted to its website.
FDA Inspection Finds Problems
On February 17, 2014 the FDA launched an inspection of Medisca’s Plattsburg, N.Y. facility. Inspectors would report three concerns by the time they wrapped up their review 10 days later.
The problems the FDA found were:
Incoming Powder Was Not Confirmed as L-citrulline
The FDA’s investigation observed that Medisca had not completed examination and testing of “incoming material.” Medisca purchased L-citrulline from a manufacturer and repackaged it. The inspection found that no tests had ever been performed to verify the “identity of each batch” of powder labeled as L-citrulline received at the facility between April 5, 2013 and February 3, 2014.
Medisca Failed to Adequately Investigate Complaints
The FDA report said the company provided “inadequate” investigations of customer complaints. Its investigator wrote that the company “failed to conduct comprehensive investigations to determine the root cause” of complaints. Customers first reported powder in some of the recalled lots did not match the product label as early as June 20, 2013 – nearly a full eight months before the company recalled the eight lots.
The report said Medisca did not launch a full investigation until February 7, 2014 — a week before the recall — and only then after mounting customer complaints.
Medisca Failed to Properly Certify L-citrulline Batches
As an active pharmaceutical ingredient (API), the FDA calls for each batch of L-citrulline to have a Certificate of Analysis from the company. These certificates are supposed to list the batch number, its grade and contact information for the original manufacturer. The certificates should also show each test performed, acceptance limits, and numerical results obtained from each test.
The FDA investigator reported that a single Certificate of Analysis had been created for L-citrulline lot 95482 on April 8, 2013. He said it was used as a template, copied, and used for other batches, and that it appeared none of the subsequent batches were ever individually verified.
The inspection also found that the certificates for the recalled lots, as well as two other lots of L-citrulline, did not include the name or contact information of the original manufacturer.
FDA Warning Letter Cites Adulterated, Misbranded Drugs
The FDA followed up its inspection with a warning letter to Medisca in November, 2015.
“Based on this inspection and sample analysis, it appears that your firm has produced drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA),” Lt. Cmdr. Catherine Beer, the FDA’s compliance officer, wrote.
The letter said the FDA’s investigation had turned up two serious violations of the law:
- Adulterated Drugs: Under federal law, a drug is adulterated if its strength, purity, and quality fall below what the label says. The FDA cited this violation because samples of repackaged APIs labeled as L-citrulline were found to actually be N-acetyl-leucine.
- Misbranded Drugs: A drug is considered misbranded under the law if its label is false or misleading. Again, because N-acetyl-leucine was labeled as L-citrulline, the FDA considered the recalled lots as misbranded.
In addition, the warning letter said the FDA had “received information” that Medisca may have been distributing domperidone illegally. Originally synthesized in the 1970s, the gastrointestinal drug has never received FDA approval in the U.S. due to serious side effects.
“If you are repackaging and distributing the API domperidone you should stop immediately,” the letter said.
Medisca’s Rise and Troubles
Medisca Pharmaceutique, Inc. was founded in 1989, as a small, three-person business in Canada. It has since become a leading supplier of pharmaceutical ingredients, supplements, and other chemicals for compounding pharmacies in North America and Australia.
Medisca founded in Montreal, Quebec
Medisca opens first U.S. facility in Plattsburgh, N.Y.
Medisca now has facilities in British Columbia; Las Vegas, Nevada and Dallas, Texas
Medisca and founder Antonio Dos Santos fined $15,000 and required to give up $1.7M in profits for unlawful sale of human growth hormone
Medisca expands operations to Australia with facility in Sydney
Wrong product is mislabeled as L-citrulline, triggering adverse health events and recall
FDA issues warning letter for “Adulterated Drugs” and “Misbranded Drugs” over L-citrulline recall
Medisca announces new process for testing ingredients
Previous Criminal Investigation of Medisca Results in Guilty Pleas, Fines
In 2011, Medisca and its president, Antonio Dos Santos, each pled guilty to misdemeanor counts of “introducing a misbranded drug, specifically somatropin, into interstate commerce using misleading labeling.”
Somatropin is a human growth hormone. In entering their guilty pleas in federal court, Dos Santos and the company admitted to importing somatropin from China and distributing it to pharmacies between 2004 and 2007. As part of the plea, they admitted to falsely representing somatropin in promotional literature to the pharmacies as being FDA approved, even though it wasn’t.
Though Dos Santos could have faced a year in prison and a $100,000 fine for his part, and the company another $200,000, they were fined a total of $15,000 and made to surrender $1,763,529 million in profits from the sales of somatropin. No prison time was ordered.
“These circumstances underscore the importance of following and enforcing the rules,” U.S. Attorney Richard Hartunian said at the time. “Circumventing them for financial gain increases the risk of illicit use and harm, and cannot be tolerated.”
Terry Turner is an Emmy-winning, former television journalist. He is an associate member of the American Bar Association, the ABA’s Health Law group and a member of the Alliance of Professional Health Advocates. He holds six certificates in Health Literacy for Healthcare Professionals from the Centers for Disease Control and Prevention. As a Washington-based investigative reporter, he routinely reported on health and medical policy issues before Congress, the FDA and other federal agencies. Terry received his B.A. in Media Arts from Lyon College.