The amino acid L-citrulline is critical for treating people with urea cycle disorder – a rare genetic condition. Without L-citrulline, certain people with UCD can suffer brain damage or death. In 2014, a company shipped another product mislabeled as L-citrulline, resulting in severe adverse reactions before it was recalled.
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.”
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.
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.
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.
|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.
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.”
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.
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 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.
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 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.
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.”
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