Ketamine FDA Alerts

FDA Warns Patients and Health Care Providers About Potential Risks Associated With Compounded Ketamine Products

October 10, 2023 -- There is increased interest in compounded ketamine products (including oral formulations) for the treatment of psychiatric disorders. When considering use of compounded ketamine products, patients and health care providers should know:

• Ketamine is not FDA approved for the treatment of any psychiatric disorder. FDA is aware that compounded ketamine products have been marketed for a wide variety of psychiatric disorders (e.g., depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder); however, FDA has not determined that ketamine is safe and effective for such uses.
• Compounded drugs, including compounded ketamine products, are not FDA approved, which means FDA has not evaluated their safety, effectiveness, or quality prior to marketing. Therefore, compounded drugs do not have any FDA-approved indications or routes of administration. Although compounded drugs can serve an important medical need for certain patients when an FDA-approved drug is not medically appropriate, they also present a risk to patients and should only be used under the care of a health care provider.
• Use of compounded ketamine products without monitoring by a health care provider for sedation (sleepiness), dissociation (disconnection between a person’s thoughts, feelings, and sense of space, time, and self), and changes in vital signs (such as blood pressure and heart rate) may put patients at risk for serious adverse events.
• Known safety concerns associated with the use of ketamine products include abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression (slowed breathing), and lower urinary tract and bladder symptoms. For FDA-approved ketamine (see Ketalar prescribing information), the expected benefit outweighs these risks when used at appropriate doses for FDA-approved indications and routes of administration.
• Despite increased interest in the use of compounded ketamine, we are not aware of evidence to suggest that it is safer, is more effective, or works faster than medications that are FDA approved for the treatment of certain psychiatric disorders.

Background

Ketamine hydrochloride (referred to here as “ketamine” interchangeably) is a Schedule III controlled substance that is FDA approved as an intravenous or intramuscular injection solution for induction and maintenance of general anesthesia. Ketamine, like many drug products, is a mixture of two mirror-image molecules, R-ketamine and S-ketamine (arketamine and esketamine, respectively). Spravato (which includes only the esketamine molecule), is approved as a nasal spray for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior (in conjunction with an oral antidepressant).

On February 16, 2022, FDA published a compounding risk alert describing the potential risks associated with at-home use of compounded ketamine nasal spray and several adverse event reports. The February 2022 compounding risk alert also provided information about Spravato, which is subject to a Risk Evaluation and Mitigation Strategy (REMS) as part of its FDA approval. A REMS is a drug safety program that FDA can require for certain approved medications with serious safety concerns to ensure the benefits of the medication outweigh its risks. The Spravato REMS requires esketamine to be dispensed and administered in medically supervised health care settings that are certified in the REMS and agree to monitor patients for a minimum of two hours following administration because of possible sedation and dissociation and the potential for misuse and abuse. Compounded ketamine products are not FDA approved for any indication, including psychiatric disorders, and are, therefore, not part of a REMS program. This does not mean compounded ketamine products are safer for patients. In fact, because compounded ketamine products are not subject to monitoring requirements under a REMS, they may be less safe.

Since the publication of the February 2022 compounding risk alert, FDA has become aware of increasing public interest in the use of sublingual and oral dosage forms of compounded ketamine for the treatment of psychiatric disorders. FDA understands that the ability to obtain such products through telemedicine platforms and compounders for at-home use may be attractive to some patients. However, the lack of monitoring for adverse events, such as sedation and dissociation, by an onsite health care provider may put patients at risk. Additionally, FDA has identified safety concerns associated with compounded ketamine products as discussed below. Furthermore, FDA has not established safe or effective dosing of ketamine for any psychiatric indication because ketamine has not been approved for these uses. These factors may place the patient at risk for serious adverse events, misuse, and abuse.

Potential Safety Risks Associated with Compounded Ketamine Products

Patients who receive compounded ketamine products from compounders and telemedicine platforms for the treatment of psychiatric disorders may not receive important information about the potential risks associated with the product. As previously noted, safety concerns that may be associated with ketamine products include, but are not limited to, risks of sedation, dissociation, psychiatric events or worsening of psychiatric disorders, abuse and misuse, increases in blood pressure, respiratory depression (breathing becomes slower and shallower and the lungs fail to exchange carbon dioxide and oxygen efficiently), and lower urinary tract and bladder symptoms. At-home administration of compounded ketamine presents additional risks because a health care provider is not available onsite to monitor for serious adverse outcomes resulting from sedation and dissociation.

In April 2023, FDA received an adverse event report of a patient who experienced respiratory depression after taking compounded oral ketamine outside of a health care setting for the treatment of PTSD. The patient’s ketamine blood level appeared to be twice the blood level typically obtained for anesthesia.

In addition to the potential risks associated with compounded ketamine products, patients and health care providers should be aware that information about use of these products is lacking. For example, FDA has not established safe or effective dosing of ketamine for any psychiatric indication. Furthermore, the dosages of the sublingual and oral compounded ketamine products marketed by compounders and telemedicine platforms may vary, which makes it challenging to predict which potential risks may be associated with these products. In addition to the concerns regarding the short-term use of compounded ketamine, the overall benefit-risk profile of ketamine for treatment of psychiatric disorders is unknown.

Conclusions

FDA is aware of increased interest in the at-home use of compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. Patients and health care providers should be aware that FDA has identified potential safety concerns associated with the use of compounded ketamine products from compounders and telemedicine platforms, including abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression, and lower urinary tract and bladder symptoms. Home use of compounded ketamine products presents additional risk because onsite monitoring by a health care provider is not available. Ketamine is not FDA approved for the treatment of any psychiatric disorder, and additional clinical studies are needed to adequately investigate ketamine’s benefit-risk profile and safe-use conditions in the treatment of psychiatric disorders.

FDA encourages compounders, patients, and health care providers to report adverse events associated with compounded ketamine products to FDA’s MedWatch Adverse Event Reporting program.

• Complete and submit the report online at MedWatch: The FDA Safety Information and Adverse Event Reporting Program; or
• Download and complete the form, then submit it via fax at 1-800-FDA-0178.

Source: FDA

General Anesthetic and Sedation Drugs: Drug Safety Communication - FDA Approves Label Changes for Use in Young Children

ISSUE: FDA has approved previously announced label changes regarding the use of general anesthetic and sedation medicines in children younger than 3 years. These changes include:

• A new Warning stating that exposure to these medicines for lengthy periods of time or over multiple surgeries or procedures may negatively affect brain development in children younger than 3 years.
• Addition of information to the sections of the labels about pregnancy and pediatric use to describe studies in young animals and pregnant animals that showed exposure to general anesthetic and sedation drugs for more than 3 hours can cause widespread loss of nerve cells in the developing brain; and studies in young animals suggested these changes resulted in long-term negative effects on the animals’ behavior or learning.

General anesthetic and sedation drugs are necessary for patients, including young children and pregnant women, who require surgery or other painful and stressful procedures. In the U.S., surgeries during the third trimester of pregnancy requiring general anesthesia are performed only when medically necessary and rarely last longer than 3 hours. FDA is advising that in these situations, pregnant women should not delay or avoid surgeries or procedures during pregnancy, as doing so can negatively affect themselves and their infants.

Similarly, surgeries or procedures in children younger than 3 years should not be delayed or avoided when medically necessary. Consideration should be given to delaying potentially elective surgery in young children where medically appropriate.

BACKGROUND: This is an update to the MedWatch alert "General Anesthetic and Sedation Drugs: Drug Safety Communication - New Warnings for Young Children and Pregnant Women" issued on December 14, 2016. 

RECOMMENDATION: Health care professionals should continue to follow their usual practices of patient counseling including discussing the benefits and risks of surgeries or procedures that require general anesthesia and sedation drugs. FDA will continue to monitor the use of these drugs in children and will update the public if additional information becomes available.

Parents, caregivers, and pregnant women should talk to their health care professionals if they have any questions or concerns about general anesthesia and sedation drugs.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[04/27/2017 - Drug Safety Communication (Update) - FDA]
[12/14/2016 - Drug Safety Communication - FDA]

General Anesthetic and Sedation Drugs: Drug Safety Communication - New Warnings for Young Children and Pregnant Women

ISSUE: FDA is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

Consistent with animal studies, recent human studies suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning. However, further research is needed to fully characterize how early life anesthetic exposure affects children’s brain development.

To better inform the public about this potential risk, FDA is requiring warnings to be added to the labels of general anesthetic and sedation drugs (see List of General Anesthetic and Sedation Drugs Affected by this Label Change). FDA will continue to monitor the use of these drugs in children and pregnant women and will update the public if additional information becomes available.

See the FDA Drug Safety Communication for a data summary and listing of general anesthetic and sedation drugs affected by this label change.

BACKGROUND: Anesthetic and sedation drugs are necessary for infants, children, and pregnant women who require surgery or other painful and stressful procedures, especially when they face life-threatening conditions requiring surgery that should not be delayed. In addition, untreated pain can be harmful to children and their developing nervous systems.

FDA has been investigating the potential adverse effects of general anesthetic and sedation drugs on children’s brain development since the first animal study on this topic was published in 1999. FDA held advisory committee meetings in 2007, 2011, and 2014. To coordinate and fund research in this area, FDA also formed a partnership with the International Anesthesia Research Society (IARS) called SmartTots (Strategies for Mitigating Anesthesia-Related neuroToxicity in Tots). More research is still needed to provide additional information about the safe use of these drugs in young children and pregnant women.

RECOMMENDATION: Health care professionals should balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risks, especially for procedures that may last longer than 3 hours or if multiple procedures are required in children under 3 years. Discuss with parents, caregivers, and pregnant women the benefits, risks, and appropriate timing of surgery or procedures requiring anesthetic and sedation drugs.

Parents and caregivers should discuss with their child’s health care professional the potential adverse effects of anesthesia on brain development, as well as the appropriate timing of procedures that can be delayed without jeopardizing their child’s health. Pregnant women should have similar conversations with their health care professionals. Also talk with them about any questions or concerns.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[12/14/2016 - Drug Safety Communication - FDA]

Olympia Pharmacy Sterile Compounded Products: Recall - Concerns About Sterility Assurance

[Posted 05/30/2013]

ISSUE: Lowlite Investments d/b/a Olympia Pharmacy ("Lowlite") notified the public of a voluntary multi-state recall of all sterile drug products compounded by the pharmacy that have not reached the expiration date listed on the product. The recall is being initiated due to concerns associated with prior quality control procedures that impacted sterility assurance. In the event a sterile product is compromised patients are at risk for serious and possible life threatening infections.

The recall includes all sterile products that Olympia Pharmacy supplied to patients and offices of licensed medical professionals with a use by date of 09/25/2013 or earlier. Olympia Pharmacy will be notifying customers by phone, fax, or mail to return the products to the pharmacy.

BACKGROUND: To date, Lowlite has received no reports of injury or illness associated with the use of the affected products.

RECOMMENDATION: Consumers or health care providers with questions regarding this recall may contact Lowlite by phone at 888-323-7788 or 407-673-2222 from the hours of 9:00AM- 6:00PM Eastern Daylight Time Monday through Friday, or at the following e-mail address: Brian@olympiapharmacy.com. Patients who have received any product furnished by Lowlite and have concerns should contact their healthcare provider.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[05/30/2013 - Press Release - Olympia Pharmacy]
[05/30/2013 - Recalled Product List - Olympia Pharmacy]