FDA Requires New Gabapentin Warnings

The FDA reported in December that it will require new warnings about the risk of respiratory depression to be added to prescribing information of gabapentinoid medications including gabapentin and pregabalin. The brand names mentioned in the advisory include Neurontin, Gralise, Horizant, Lyrica, and Lyrica CR.

According to the FDA, serious breathing difficulties may occur in patients taking these medications who also have respiratory risk factors. These risk factors include the use of opioid pain medicines and other drugs that depress the central nervous system (CNS), and conditions such as chronic obstructive pulmonary disease that reduce lung function. The elderly are also at higher risk. (https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-b.)

According to the FDA communication, "Our evaluation shows that the use of these medicines, often referred to as gabapentinoids, has been growing for prescribed medical use, as well as misuse and abuse. Gabapentinoids are often being combined with CNS depressants, which increases the risk of respiratory depression. CNS depressants include opioids, anti-anxiety medicines, antidepressants, and antihistamines. There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone. We will continue to monitor these medicines as part of our routine monitoring of all FDA-approved drugs."

In its advice to health care professionals, the FDA wrote:

Health care professionals should start gabapentinoids at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when co-prescribing gabapentinoids with an opioid or other central nervous system (CNS) depressant such as a benzodiazepine. Patients with underlying respiratory disease and elderly patients are also at increased risk and should be managed similarly.

Further, "We recognize that incorporating one or more medications with non-drug therapies is the prevailing approach for optimizing analgesia. However, pairing an opioid with any CNS depressant-a gabapentinoid, benzodiazepine, sedating antidepressant, sedating antipsychotic, antihistamine, or other product-will increase the risk of respiratory depression. Shifting treatment from one CNS depressant to another may pose similar risks. Be aware of the potential additive effects of all these CNS depressants and plan accordingly, by starting with low doses, titrating carefully, and informing patients of the potential for CNS and respiratory depression and their symptoms. The gabapentinoid prescribing information already includes guidance for health care professionals to caution patients about dizziness, somnolence, and the potential for impaired ability to operate a car or complex machinery."

The FDA is requiring manufacturers of these drugs to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids. Misuse and abuse of these products together is increasing, the FDA says, and may increase the risk of respiratory depression. "Special attention will be paid to the respiratory depressant effects during this abuse potential evaluation," according to the FDA communication.

The FDA based its warning on reports submitted to the FDA and data from the medical literature:

Among 49 case reports submitted to FDA over the 5-year period from 2012 to 2017, 12 people died from respiratory depression with gabapentinoids, all of whom had at least one risk factor. This number includes only reports submitted to FDA [via the FDA Adverse Event Reporting System (FAERS) database], so there may be additional cases about which we are unaware.

In addition, "We also reviewed the results of 2 randomized, double-blind, placebo-controlled clinical trials in healthy people, 3 observational studies, and several studies in animals. One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. The other trial showed gabapentin alone increased pauses in breathing during sleep. The 3 observational studies at 1 academic medical center showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after different kinds of surgeries. We also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function."

The FDA communication provides citations for the studies mentioned earlier.