Drug Safety Alerts

Gabapentin and Pregabalin Drug Safety Communication

12/19/2019

On December 19, 2019, the United States Food and Drug Administration (FDA) issued a Drug Safety Communication warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin®, Gralise®, Horizant®) or pregabalin (Lyrica®, Lyrica CR) who have respiratory risk factors. These include the use of opioid pain medicines and other drugs that depress the central nervous system, and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function. The elderly are also at higher risk.

Gabapentin and pregabalin are FDA-approved for a variety of conditions, including seizures, nerve pain, and restless legs syndrome.

The FDA 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. The FDA will continue to monitor these medicines as part of our routine monitoring of all FDA-approved drugs.

The FDA is requiring new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids. The FDA has also required the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids, because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression. Special attention will be paid to the respiratory depressant effects during this abuse potential evaluation.

The FDA advises that 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.

The FDA recognizes 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 has provided the following additional information for healthcare providers:

• FDA is warning that serious, life-threatening, and fatal respiratory depression has been reported with the gabapentinoids, gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR). Most cases occurred in association with co-administered central nervous system (CNS) depressants, especially opioids, in the setting of underlying respiratory impairment, or in the elderly.

• Our evaluation of respiratory depression with the gabapentinoids provides some evidence contrary to the widely held belief that gabapentinoids lack drug interactions and have wide therapeutic indices. Published studies demonstrate these drugs can behave in an additive way to potentiate central nervous system (CNS) and respiratory depression.

• When co-prescribing gabapentinoids with another CNS depressant, particularly an opioid, or in patients with underlying respiratory impairment, initiate the gabapentinoid at the lowest dose.

• Adjust the dose of both gabapentin and pregabalin in patients with renal impairment and patients undergoing hemodialysis, because both drugs are excreted by the kidneys.

• Monitor for symptoms of respiratory depression and sedation, especially when co-prescribing gabapentinoids with an opioid or other CNS depressant such as a benzodiazepine or when prescribing to patients with underlying respiratory impairment, or elderly patients.

• The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants, including the gabapentinoid. Gabapentinoids used for analgesia or seizure control should be tapered prior to discontinuation. See the prescribing information for specific tapering guidance.

• Encourage patients to read the Medication Guide they receive with each gabapentinoid prescription, which explains the safety risks and provides other important information.

• To help FDA track safety issues with medicines, report adverse events involving gabapentin, pregabalin, or other medicines to the FDA MedWatch program.

CVS Caremark® Response:

Please note: These products have not been recalled. CVS Caremark® Mail Service Pharmacy will continue to fill prescriptions for these products subject to applicable laws and the professional judgment of its pharmacists.

For more information about this issue, health care providers may call the FDA consumer inquiry line at 1-888-INFO-FDA (1-888-463-6332) or visit https://www.fda.gov.