Invited Editorial: Advantages and Limitations of FAERS in Assessing Adverse Event Reporting for Eluxadoline

Irritable bowel syndrome (IBS) affects 10–20% of the population in developed countries⁽¹⁾ and is characterized by recurrent abdominal pain related to defecation on average one day per week in the last month associated with changes in bowel habits^{(2, 3)}. Approximately one-third of patients have diarrhea-predominant (IBS-D) symptoms⁽⁴⁾, which has a large impact on quality of life as well as socioeconomic burden^{(1, 2, 4)}. The main pharmacotherapies used in patients with IBS-D are μ-opioid receptor agonists, tricyclic antidepressants, rifaximin, and 5-HT₃ receptor antagonists⁽⁵⁾. Diphenoxylate and loperamide provide significant relief of diarrhea, but have limited efficacy for the abdominal pain in IBS-D^(6–9).

Eluxadoline is a novel, peripherally acting, mixed μ- and κ-opioid receptor (OR) agonist and δ-opioid receptor antagonist^{(10, 11)}. By targeting multiple ORs, it induces visceral analgesia and decreases motility through actions on μ-OR, while adverse side effects attributed to excessive inhibition of gut motility related to the μ-OR agonist effects are mitigated by the actions on the κ- and δ-ORs^{(12, 13)}. Eluxadoline was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with IBS-D in February of 2015⁽¹⁴⁾. In phase 3 trials, 2,427 participants with IBS-D were randomized to eluxadoline (75mg or 100mg) or placebo twice daily for 26 weeks or 52 weeks. There was significant improvement in the composite endpoint of abdominal pain and stool consistency with eluxadoline compared to placebo, but no improvement in abdominal pain alone⁽¹¹⁾.

Among 1,666 patients who received eluxadoline in the phase 3 trials, 5 developed acute pancreatitis: 2 on 75mg and 3 on 100mg⁽¹¹⁾. In March 2017, the FDA released a Drug Safety Communication warning about the increased risk of pancreatitis among patients with IBS-D with prior cholecystectomy who were treated with eluxadoline. Some of these episodes were reported after a single or few doses of eluxadoline; acute pancreatitis episodes were also recorded in patients who had not undergone prior cholecystectomy. The FDA had received 120 reports of pancreatitis or death in patients receiving eluxadoline, based on a publicly accessible reporting system, the Federal Adverse Events Reporting System (FAERS). FAERS is implemented by the FDA for post-marketing pharmacovigilance and surveillance of approved drugs⁽¹⁵⁾. These pancreatitis episodes were postulated to result from sphincter of Oddi spasm as defined by the Atlanta criteria and largely based on clinical judgement⁽¹⁶⁾.

In this issue of Clinical Gastroenterology and Hepatology, Gawron and Bielefeldt⁽¹⁷⁾ utilized the FAERS database to examine pancreatitis following treatment with eluxadoline and compared the risks associated with eluxadoline and with other medications used in IBS-D or abdominal pain: loperamide, diphenoxylate and atropine, oxycodone, and rifaximin. They noted that among adverse events (AEs) reported by those prescribed eluxadoline, pancreatitis accounted for 98/597 (16.4%) of reports, and sphincter of Oddi dysfunction (SOD) for 5%. In comparison, there were fewer reports of either pancreatitis or SOD for the other drugs studied: loperamide 12/3775 (0.32%), diphenoxylate and atropine 4/923 (0.43%), oxycodone 20/11,513 (0.17%), and rifaximin 2/209 (0.96%). The entities submitting reports to FAERS were predominantly consumers: for eluxadoline (80.6%) compared to the other drugs (<25%). Additionally, 99% of the reporters believed that eluxadoline was the cause of the pancreatitis, whereas 50% believed loperamide was the primary cause, and the remaining cases were perceived as largely coincidental.

Pharmacovigilance and FAERS

There are more than 1 million serious AEs (SAE) reported per year in the United States, and 5–10% can lead to death or significant morbidity⁽¹⁸⁾. Pharmacovigilance strategies are continued throughout the duration of product development until the post-marketing product lifecycle⁽¹⁸⁾. Pharmacovigilance is intended to assess risk-benefit and recognize and further investigate any SAEs, with the options of updating the product’s labeling information, restricting use of the drug, communicating new safety information to the public, or investigating whether the drug should be removed from the market⁽¹⁸⁾. FAERS includes information on adverse reactions (ADR) and medication error reports submitted to the FDA⁽¹⁹⁾. It complies with international safety reporting guidance; all reports are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Reporting to FAERS is mandatory by law for product manufacturers (who must report any AE to FAERS within 14 days of becoming aware of the AE) or voluntary for healthcare professionals (physicians, pharmacists, nurses) and consumers (patients, family members, and lawyers). The reports are not required to be detailed, medically sophisticated, or backed by evidence⁽¹⁹⁾.

Although post-marketing pharmacovigilance databases serve an important role, FAERS has several limitations, including: no definitive proof of the causal relationship between exposure to the product and the reported event; significant heterogeneity in the reports that depend on the individual reporting; potential for bias based on physician preference of one drug over others; a patient’s negative experience with a certain product; or a lawyer’s perceptions when defending a client prescribed that product. Finally, since FAERS is a voluntary reporting system, it is likely that not every ADR is reported, and since the denominator (number prescribed the product) is unknown, it is impossible to calculate the incidence of ADR using FAERS. Overall these limitations may lead to inflation of risk attributable to a medication based on the FAERS pharmacovigilance.

Gawron and Bielefeldt⁽¹⁷⁾ acknowledge some of the FAERS limitations; highlight that recently approved medications are expected to have more AE reports; and that lack of benefit on abdominal pain, as demonstrated in phase 3 trials⁽¹¹⁾, might increase reports of eluxadoline to FAERS if patients’ expectations are not met. Two missing comparators for rates of pancreatitis in response to opioid medications are morphine which, like eluxadoline, acts on all 3 ORs⁽²⁰⁾, and codeine, a precursor to morphine and a known cause of acute pancreatitis⁽²¹⁾.

Putative Mechanism of Pancreatitis

It is postulated that the pancreatitis is secondary to SOD, but it is unclear why pancreatitis occurs so soon after the first dose and, according to FAERS reports, at a much higher frequency compared to other opioids. The two ORs on the sphincter of Oddi are μ-OR, which mediates sphincter contraction upon stimulation, and δ-OR, which induces relaxation⁽²²⁾. Also, δ-receptor agonists and antagonists can increase the efficacy or potency of the μ-receptor⁽²³⁾. Eluxadoline activates μ-OR and blocks the δ-OR, and these effects could result in contraction of the sphincter of Oddi and prevention of the sphincter’s relaxation, respectively. These dual actions may conceivably potentiate the effects on sphincter of Oddi, potentially leading to spasm with eluxadoline treatment. A possible explanation for the greater risk of SOD associated pancreatitis in patients post-cholecystectomy is that cholecystokinin loses the ability to inhibit phasic contractions of the sphincter of Oddi after gallbladder removal⁽²⁴⁾.

Examples of instances where the FDA issued labeling information or other guidance for the period April to June 2017⁽²⁵⁾ are: updating of labeling for Ameluz® (aminolevulinic acid hydrochloride) gel 10% for topical use to include transient amnestic episodes; changing the labeling for Carafate® to include warnings of fatal complications with inappropriate intravenous administration of Carafate® oral suspension; and updating the Keytruda ® labeling to include Stevens-Johnson syndrome and toxic epidermal necrolysis. While IBS-D is a disorder with significant impact on quality of life, it is not associated with mortality.

With the availability of alternative medications to treat IBS-D, we believe the FDA has appropriately alerted both prescribers and patients to consider the benefits of eluxadoline treatment and to weigh the potential of life threatening complications associated with pancreatitis. We believe that the FAERS reporting system will be essential for further appraising the risk of acute pancreatitis; in addition, prospective studies that are registered in ClinicalTrials.gov (Identifier: NCT02959983) are likely to provide further structured information. Meanwhile, patients and prescribers should follow recommendations in the FDA prescribing information regarding dosing and contraindications: known or suspected biliary duct obstruction, or sphincter of Oddi disease or dysfunction; alcoholism, alcohol abuse, alcohol addiction, or drink more than 3 alcoholic beverages/day; a history of pancreatitis; structural diseases of the pancreas, including known or suspected pancreatic duct obstruction; severe hepatic impairment (Child-Pugh Class C); severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction.

Abbreviations

AE

Adverse events

ADR

adverse drug reaction

FAERS

federal adverse events reporting system

FDA

food and drug administration

IBS

irritable bowel syndrome

IBS-D

irritable bowel syndrome – diarrhea predominant

MEDRA

Medical Dictionary for Regulatory Activities

OR

opioid receptor

SAE

serious adverse events

SOD

sphincter of Oddi dysfunction