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FDA discusses REMS safety programs for new drug therapy advances in depression

by Tiffany R. Farchione, MD, and Cynthia LaCivita, PharmD

Drug safety programs called Risk Evaluation and Mitigation Strategies (REMS) helped ensure the availability of two recent and highly significant advances in drug therapies in the U.S. for patients with postpartum depression and treatment-resistant depression.

Zulresso (brexanolone, Sage Therapeutics) injection for intravenous (IV) use, approved in March 2019, is the first drug approved by the FDA specifically for the treatment of postpartum depression (PPD) in adult women. Spravato (esketamine, Janssen) nasal spray, also approved in March, is an antidepressant indicated for use in conjunction with an oral antidepressant for adults with treatment-resistant depression. Both drugs have unique mechanisms of action and unique routes of administration, and both are hoped to lead to important advances for patients with depression.

Because of preliminary clinical evidence demonstrating potential for substantial improvement on a clinically significant endpoint, both drugs received the FDA’s “Breakthrough” designation, which helped to expedite their review and approval. In clinical trials, both drugs demonstrated the ability to confer rapid benefit, but both had important safety issues. Some trial participants using brexanolone experienced a sudden loss of consciousness, and most trial participants who received esketamine experienced sedation and dissociation. In addition, esketamine was found to have the potential for abuse and misuse. During FDA’s review of the new drug applications for both drugs, we determined that a REMS would be needed to ensure that the products would be used safely. A REMS is a drug safety program that FDA can require for certain medications when there are serious safety concerns. REMS programs help ensure that the benefits of a drug outweigh its risks. When prescribing or dispensing a drug with a REMS, prescribers may be required to take specific steps before the drug can be administered.

Zulresso REMS

Zulresso is available only through a restricted program called the Zulresso REMS, which requires that the drug be administered by a health care provider in a health care facility certified in the REMS. Patients must be enrolled in the REMS program prior to administration of Zulresso, which is administered as a continuous IV infusion over a total of 60 hours (2.5 days). While receiving the infusion, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. Prior to administration, patients must be counseled on the risks of Zulresso treatment and instructed that they must be monitored at a health care facility for the entire 60-hour infusion. Because of the risks of excessive sedation and sudden loss of consciousness during the infusion, patients must be accompanied during interactions with their child(ren). The drug’s prescribing information includes a Boxed Warning that addresses the need for these steps. A Medication Guide informs patients they should not drive, operate machinery, or perform other dangerous activities until feelings of sleepiness from the treatment have completely resolved.

Spravato REMS

The Spravato prescribing information contains a Boxed Warning cautioning that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Spravato labeling also includes a Medication Guide for patients.

The Spravato REMS is a restricted distribution program that requires the drug be administered in a health care setting that is certified in the REMS program where the health care provider can monitor the patient. Because of the risk of sedation and dissociation, patients must be monitored for at least 2 hours after receiving their Spravato dose.

The Spravato REMS program also requires that the prescriber and the patient both sign a Patient Enrollment Form clearly stating that the patient knows he or she should make arrangements for safe transportation home after receiving the drug. The patient must also acknowledge that he or she should not drive or use heavy machinery for the rest of the day after receiving the drug. The patient self-administers Spravato nasal spray under the supervision of a health care provider in a certified doctor’s office or clinic, and the spray cannot be taken home. The health care provider will instruct the patient on how to operate the nasal spray device. During and after each use of the nasal spray device, the health care provider will monitor the patient for at least 2 hours and determine when the patient is ready to leave.

Why REMS?

REMS programs are designed to help reduce the occurrence and/or severity of serious adverse events and help support the safe use conditions described in the product’s FDA-approved prescribing information.

Once the FDA determines a REMS is necessary for a drug, pharmaceutical companies must develop, implement, and assess the specific REMS program for their drug product.

 

Although the REMS requirements for Zulresso and Spravato include restrictions on prescribing, dispensing and use of these medications, it is important to remember that REMS can provide patients with safe access to certain drugs with serious risks that might not otherwise be approved and available on the market.

The FDA has implemented many REMS programs, each designed to target a specific risk or risks associated with a particular drug or drug class. Depending on the risk(s) involved, a REMS program can be simple or complex, ranging from providing an information sheet to a patient or health care professional, to enrolling a patient in a registry prior to taking the drug, or monitoring a patient’s lab values during treatment. Some REMS may require patients to take preventive measures, such as requiring that women ensure that they use effective birth control if taking a drug that has embryofetal toxicity. Sometimes, the FDA may remove a REMS if — after a review of data — we determine that a drug can be safely used without extra safety measures. The FDA may also remove certain components of a REMS if they are deemed to be no longer necessary. For instance, the FDA has removed either part of or all of the REMS for Tikosyn (dofetilide, Pfizer), Lotronex (alosetron hydrochloride, Sebela Pharmaceuticals Inc.), and erythropoietin stimulating agents.

We recognize that REMS requirements place administrative burdens on already busy health care providers. The FDA makes every effort to require REMS programs that contain only elements that are specifically necessary to help ensure the drug’s benefit outweighs its risks. Our goal is to maintain patient access while still assuring safe use of a drug.

The FDA’s web page, REMS@FDA, lists every drug for which the FDA requires a REMS, along with all of the details for that drug’s REMS requirements. Visit https://www.accessdata.fda.gov/scripts/cder/rems/ for more information.

Tiffany Farchione is acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research.

Cynthia LaCivita is director of the Division of Risk Management in the FDA’s Center for Drug Evaluation and Research.