FDA Sends Back PharmaTher’s Ketamine Application

Canada drugmaker PharmaTher received a complete response letter from the Food and Drug Administration (FDA) for its abbreviated new drug application (ANDA) for racemic ketamine, the company announced yesterday.

The company is pursuing approval of its generic ketamine product—Ketarx—to shore up global demand and as part of its research program testing ketamine for mental health and other indications. According to an FDA database, ketamine hydrochloride 50 mg and 100 mg injections have been in short supply in the United States since February 2018, owed to increased demand for psychiatric and acute pain indications.

“As noted by the FDA in the [complete response letter], the resubmission … will be considered to represent a minor amendment, given that the deficiencies have been classified as minor,” PharmaTher wrote. “The FDA requested new and updated information and clarifications related to drug substance, drug product, manufacturing, and microbiology.”

The company noted that the FDA did not express concern about the stability of the ketamine submission batches and no new preclinical and clinical studies were requested; they stated they will work with their third-party manufacturing partner to resolve these deficiencies and respond to the FDA in a timely fashion.

In May 2023, PharmaTher sought fast-track designation from the FDA for Ketarx to treat levodopa-induced dyskinesia in Parkinson’s disease. The company’s clinical trial results showed that ketamine was safe and well-tolerated, and that 100% of subjects treated with ketamine had a reduction in dyskinesias.

ANDAs allow drugmakers to apply to market generic drugs that are comparable to brand-name drugs in terms of safety, effectiveness, and cost. Drugmakers must demonstrate that their generic is bioequivalent to the brand-name drug, meaning it has the same properties and acts in the same way. A complete response letter is not a rejection of an application, but rather a way for the agency to provide drugmakers with guidance on how an application might be improved.

Ketamine was FDA approved in 1970 as a general anesthetic and is still widely used for this indication.

Though used off-label for conditions like depression, the FDA has not approved ketamine for the treatment of any psychiatric disorder. In October 2023, the FDA published an alert warning of the potential risks associated with unapproved compounded ketamine products for psychiatric disorders, specifically from telehealth providers that provide in-home ketamine services.

For related information, see the Psychiatric News feature “Ketamine: Miracle Drug or Double-Edged Sword?”

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Very Young Children Exposed to Anesthesia May Be at Higher Risk of Childhood Bipolar Disorder

Infants and toddlers who are exposed to general anesthesia may be at increased risk for bipolar disorder later in childhood compared with infants and toddlers who are not exposed, according to a report in Schizophrenia Bulletin. The association remained after adjusting for other childhood comorbidities and parental psychiatric diagnoses.

“In the context of pediatric care, it is essential to recognize the substantial perioperative trauma experienced by children, both physically and psychologically,” wrote Mingyang Sun, M.D., of the People’s Hospital of Zhenghzou University in Henan, China, and colleagues. “Emerging evidence underscores the significant impact of early-life exposure to multiple anesthetics on neurodevelopment.”

The researchers compared the incidence of pediatric bipolar disorder in 7,535 children in Taiwan who were exposed to general anesthesia at age 3 or younger between 2004 and 2014 with that of an equal number of children who were not exposed. Data were drawn from the Taiwan Maternal and Child Health Database. The two groups of children were matched for other variables associated with bipolar risk, including premature birth, head injury, sexual abuse, malnutrition, toxic exposure, congenital abnormalities, and parental psychiatric illness.

A total of 223 (3%) of the children who were exposed to general anesthesia were diagnosed with bipolar disorder before age 12 compared with 178 (2.4%) of those who were not exposed. Children exposed to general anesthesia were 1.26 times more likely to develop bipolar disorder before age 12.

Sun and colleagues noted that general anesthesia’s potential to increase the risk of developing bipolar disorder involves intricate mechanisms, including neurotoxicity associated with specific anesthetic agents and disruptions in neural pathways. Sevoflurane, a commonly employed inhalation anesthetic, has garnered particular attention due to its neurotoxic effects, they wrote, but adding, “our study didn’t examine specific anesthetic agents’ effects on [bipolar disorder] development, an area ripe for future research to inform precise anesthesia choices and mitigate [bipolar disorder] risk in children.”

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Obstructive Sleep Apnea May Raise Post-Op Heart Risk

Obstructive sleep apnea (OSA), a condition in which the soft tissues of the throat relax and narrow the airways during sleep, may raise the risk of developing heart problems after surgery, according to research published this week in JAMA. In OSA, breathing stops and starts multiple times during sleep, resulting in snoring, gasping for air, poor sleep quality, morning headaches, daytime fatigue, irritability, and difficulty concentrating.

The study, led by Matthew T. V. Chan, Ph.D., M.B.B.S., of the Chinese University of Hong Kong included 1,218 patients aged 45 years or older who had abdominal, vascular, or major orthopedic surgeries and were at risk for post-surgery heart-related complications. The patients underwent sleep studies at home or in the hospital the night before their procedures.

Although none of the patients had been diagnosed with OSA previously, the sleep studies revealed that 67.6% of them had the condition. Among all patients, 11.2% had a severe form of OSA in which their breathing stopped and started at least 30 times during the night.

In the 30 days after their surgeries, 21.7% of the participants with OSA developed heart and blood vessel complications, such as injury to their heart muscles, congestive heart failure, atrial fibrillation (an irregular, fluttering heartbeat), and thromboembolism (clots that block blood vessels). Only 14.2% of those without OSA developed these complications. This represents a 50% greater risk in people with OSA, regardless of the condition’s severity. However, after the researchers accounted for other factors, they determined the increased risk to be statistically significant only in patients with severe OSA, not mild or moderate OSA. Those with severe OSA had more than double the risk of those without OSA. Severe OSA was also associated with a nearly 14-fold increase in cardiac death, a nearly 7-fold higher risk of heart failure, and an 80% higher risk of heart injury.

The researchers noted that episodes of apnea and higher sedation either during or after the surgeries may have prompted health care professionals to make adjustments to the patients’ care such as lowering doses of opioids or keeping the patients on supplemental oxygen longer than usual.

“It is unclear how these interventions may affect perioperative outcomes. Nevertheless, the event rates reported in this study would represent the expected perioperative outcomes associated with untreated OSA in contemporary anesthetic practice for major noncardiac surgery,” the researchers wrote.

For more information, see the Psychiatric News article “Sleep Apnea Linked With Hard-to-Treat High Blood Pressure in Blacks.”

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Ketamine Clinics Attract Patients Despite Unknowns

Even as researchers continue to investigate how a single dose of the anesthetic ketamine reduces symptoms of treatment-resistant depression within hours and what the risks of long-term, repeated ketamine infusions might be, a growing number of patients are turning to ketamine clinics in the United States.

The most recent issue of Psychiatric News PsychoPharm features an article exploring the off-label use of this medication in special clinics. The piece describes what patients can expect at ketamine centers, including the physicians running them and the course and cost of standard treatment regimens.

The majority of the ketamine clinics in the United States are run by anesthesiologists, who tend to have firsthand experience with using ketamine and managing side effects. Psychiatric News spoke with anesthesiologists at ketamine clinics in New York and Arizona, where patients are initially given four infusions of ketamine within about two weeks.

Such procedures can be expensive, with most clinics charging $400 to $800 for a single infusion of ketamine, Dennis Hartman of the Ketamine Advocacy Network told Psychiatric News. (The Ketamine Advocacy Network is a website whose mission is to spread awareness about ketamine therapy for treatment-resistant depression.)

Although ketamine works for many patients, an estimated one-third of all patients in clinical trials do not respond to the medication.

“We need to find particular characteristics that can predict response,” APA President Maria A. Oquendo, M.D., Ph.D., told Psychiatric News. Oquendo is involved with a clinical trial evaluating the safety and effectiveness of ketamine in patients with refractory depression.

Anesthesiologists Glen Brooks, M.D., medical director of the New York Ketamine Infusions LLC, and Mark Murphy, M.D., the medical director of the Ketamine Wellness Centers in Mesa, Ariz., noted that patients at their clinics undergo mental health screening before receiving ketamine infusion, and they recommend that patients receive ongoing psychiatric or psychological care during treatment. Additionally, staff at the clinics routinely communicate with referring psychiatrists.

For related information, see “APA Task Force to Address ‘What’s Next?’ for Ketamine.”

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Primitive Brain Responds First

When people return to consciousness after receiving anesthesia, a more primitive area of their brains--the brainstem--becomes active first, followed by the thalamus, the hypothalamus, and the anterior  cingulate cortex in the frontal lobe, a study reported April 4 in The Journal of Neuroscience has found. These brain structures thus appear to form a foundation for the conscious state, the scientists believe. The same structures also activate upon awakening from natural stage-two sleep. Other researchers have found that restored activity in the anterior cingulate cortex correlates with the level of responsiveness in brain-injured patients.

More information about the brain function of traumatic brain-injured patients can be found in Psychiatric News here. More information about traumatic brain injury in general can be found in the American Psychiatric Publishing Textbook of Traumatic Brain Injury, Second Edition.

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