A joint US Food and Drug Administration (FDA) advisory committee has voted against approving a novel drug for acute pain that combines hydrocodone, acetaminophen, and promethazine.
Many committee members expressed concern about the lack of data on its use in the elderly, inadequate plans for abuse and misuse deterrence, and the inflexibility of the single-dose product, which has the proposed trade name Hydexor.
“This drug, while a good idea, wasn’t really well thought-out in terms of how we use these drugs clinically,” said Edward Michna, MD, director, Pain Trials Center, Brigham Women’s Hospital, and assistant professor, Harvard Medical School, Boston, Massachusetts.
If the FDA does approve this opioid product, it would be the first to include an agent with antiemetic properties.
The joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee met to discuss a new drug application for Hydexor.
The immediate-release product would be indicated for the short-term (generally less than 2 weeks) management of acute pain severe enough to require an opioid analgesic, while preventing and reducing opioid-induced nausea and vomiting (OINV). Hydexor would be indicated when alternative treatments for pain are deemed inadequate.
The novel, bilayered tablet has three active ingredients:
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Hydrocodone (7.5 mg), a narcotic analgesic that blocks pain perception in the cerebral cortex by binding to mu-, kappa-, and delta-opioid receptors;
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Acetaminophen (325 mg), a nonopioid analgesic; and
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Promethazine (12.5 mg), which inhibits the histaminic, dopaminergic, and muscarinic receptors that stimulate the vomiting center.
The addition of low-dose promethazine to a hydrocodone/acetaminophen combination is intended to reduce or prevent OINV.
Many patients experience burdensome symptoms of nausea and vomiting induced by anesthesia after surgery while being treated for an acute medical condition or while undergoing chemotherapy.
About 40% of patients prescribed an opioid report nausea and about 20% report vomiting, Tong Joo Gan, MD, professor and chairman, Department of Anesthesiology, Stony Brook University School of Medicine, New York, told committee members.
Increased Risk for Postop Complications
OINV can complicate surgical recovery, increase postoperative complications, and negatively affect a patient’s nutrition and healing, said Gan.
There is currently no approved or proven therapy for acute pain that also prevents and reduces OINV.
During the meeting, committee members learned details of the applicant’s (Charleston Laboratories Inc) clinical program, which enrolled more than 1300 patients and participants.
The program included seven clinical studies:
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Three phase 1 relative bioavailability studies (one against a reference listed drug, one comparing it to Norco (Actavis), a combination acetaminophen/hydrocodone product [fasted]; and one to Norco [fed]);
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Two phase 3 studies of safety and efficacy for intended treatment uses;
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One study of safety in actual use; and
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One human abuse liability study.
All three active ingredients of Hydexor demonstrated bioequivalence to the respective components in the reference listed drugs. Over the first hour after ingestion, exposure to promethazine was 59% higher with Hydexor than with the commercial product.
This greater early bioavailability may contribute to the efficacy of the product in preventing and reducing OINV, according to background information provided by Charleston.
In the open-label, randomized crossover trials, 32 healthy persons received a single dose of Hydexor in one period and a separate single dose of Norco in another period. The studies compared the bioavailability of hydrocodone and acetaminophen in Hydexor with that in Norco.
Results from these two pharmacokinetics studies showed that the hydrocodone and acetaminophen components of the products are bioequivalent under both fed and fasted conditions.
Under fasted conditions, time to maximum concentration (Tmax) was longer with Hydexor than with Norco (1.5 vs 1 hour). As a result, the abuse quotient (maximum concentration divided by Tmax) is lower than for Norco (12.9 vs 17.2) in healthy persons.
The multicenter, randomized studies (002 and 003) used common acute pain models. Enrolled patients had moderate to severe pain after surgery: in one case, oral surgery, and in the other, bunionectomy. Study participants, who were deemed to be prone to OINV, were randomly assigned to receive Hydexor, Norco, or placebo.
There were two co-primary endpoints in each study. These included pain reduction by Hydexor compared with placebo and reduction in the incidence of OINV compared with Norco.
Unwanted Side Effects
In one of the studies (002), pain reduction was measured on a 0-to-3 pain intensity scale and analyzed by using the summed pain intensity differences from baseline over 24 hours (SPID24). In this study, participants getting Hydexor had a significantly greater reduction in SPID24 compared with those receiving placebo (16.2 vs 3.5; P < .001).
In the second study (003), an analysis of summed pain intensity differences from baseline over 48 hours using a 0-to-10 numeric scale showed similarly significant results (118.4 vs 53.1; P < .001).
Patients recorded the incidence of nausea and frequency of vomiting. OINV was defined as having any vomiting, use of any rescue antiemetic, or any report of greater than mild nausea.
In absolute terms, the incidence of OINV was 22% lower at 24 hours in the Hydexor group than in the Norco group in study 002 (36% vs 58%; P < .001). This, said Bernard P. Schachtel, MD, chief scientific officer, Charleston Laboratories, represents a 38% relative reduction in the risk for OINV.
According to the definition of OINV that has only two components — use of any rescue antiemetic and any vomiting — the relative reduction in the risk for OINV in study 002 was 64%.
However, patients receiving Hydexor in these studies had an increased rate and severity of some central nervous system–related adverse events.
For example, in the 002 study, 46% of this group experienced drowsiness compared with 37% in the Norco group. In the 003 study, there were more incidents of confusion, difficulty with concentration, and drowsiness in the Hydexor group.
Study 006 was an open-label, actual-use safety study in patients with moderate to severe acute pain associated with osteoarthritis of the knee or hip.
Opioid-naive patients took Hydexor as needed in the outpatient setting when they experienced a flare after discontinuing nonsteroidal anti-inflammatory drug treatment. Of the 179 patients enrolled, all but 1 got the drug; of these, 97% completed the study
In this study, 185 adverse events were reported by 81 patients, most of which were of mild to moderate severity. Drowsiness and dizziness were the most frequent adverse events.
Committee members were concerned not only about drowsiness and dizziness associated with Hydexor but also about the increased incidence of hypotension in some recipients of this drug.
Unnecessary Exposure
Brian T. Bateman, MD, an anesthesiologist and associate professor, Harvard Medical School, said he’s concerned about patients having to endure such symptoms associated with the addition of promethazine “when it’s being used in a prophylactic fashion such that many patients are potentially exposed to that medicine unnecessarily.”
Such side effects, said Bateman, could be particularly problematic in older, frail patients and those receiving concomitant medications, populations he said were underrepresented in the studies.
He also pointed out that the drug contains 7.5 mg of hydrocodone, which is higher than the typical starting dose of 5 mg.
The human abuse liability study (007) included nondependent recreational drug users and measured their “drug liking,” feeling of being “high,” and likelihood of taking the drug again. It showed no increased risk for abuse.
According to Ellen Fields, MD, deputy director, Division of Anaesthesia, Analgesia and Addiction of the FDA, results of the human abuse liability study suggest that “the presence of promethazine does not alter the abuse potential” for this drug.
As with all opioids, the label for this new product would carry the same black box warning regarding its potential for abuse, misuse, and diversion.
The FDA is in general agreement with the findings of the sponsor’s studies regarding efficacy and safety, said Fields.
If the drug is approved, the company plans to market only one strength of Hydexor: hydrocodone 7.5 mg/acetaminophen 325 mg/promethazine 12.5 mg.
Committee members were generally unhappy with this inflexible approach, with one noting that “in clinical reality, one dose does not fit all.”
The proposed dosing schedule is one tablet every 4 to 6 hours as needed, for a maximum daily dosage of six tablets. The intended population is adults at risk for OINV.
REMS
Because this is an immediate-release opioid analgesic expected to be used in the outpatient setting, the FDA had determined that it will need a risk evaluation and mitigation strategy (REMS) to ensure that the benefits outweigh the risks.
Although Hydexor is not an abuse-deterrent formulation, the company has plans to implement a comprehensive abuse mitigation program.
Part of that plan is to have the tablets available only in 3-, 5-, and 7-day packaging (with a total of 18, 30, and 42 tablets, respectively) using child-resistant containers, Thomas Smith, MD, chief medical officer, Charleston Laboratories, told the meeting attendees.
The company also intends to implement a buy-back program to reduce availability of unused tablets and ensure proper disposal.
In addition, it plans to introduce educational initiatives and distribution, monitoring, surveillance, and pharmacovigilance programs.
Although some committee members applauded the company for attempting to address issues of misuse, abuse, and divergence, some said the plans were not well formulated and one called it a “vague promise.”
While the limited amount of medication in the proposed packaging may result in less overall use of the opioid, the packaging might encourage some patients to take the entire dose whether they really need it or not, said Mary Ellen McCann, MD, associate professor of anesthesiology, Harvard Medical School, and acting chair of the meeting.
Some members wondered whether the buy-back program would actually be used since many patients like to hang on to leftover pills in case they need them in future. Others worried the buy-back program would be difficult to implement.
The program, said McCann, “is just very, very briefly sketched out at this point.”
Other members questioned who exactly the product would be aimed at — only surgeons and pain management specialists or other medical professionals as well?
Slippery Slope?
Steven B. Meisel, PharmD, director of medical safety, Fairview Health Services, Minneapolis, Minnesota, expressed concern that this combination drug might represent “a very dangerous slope.”
“We’re asking people to take a drug to prevent the side effect of another drug, but itself is causing more side effects, and pretty soon, we will have another drug proposed to us that will mitigate the adverse effect of the second drug. That’s not the way to practice medicine.”
Meisel also noted that when patients do experience nausea and vomiting linked to opioid use, these symptoms often disappear, and the body adjusts, after about the third or fourth dose. He, too, said he was averse to patients being exposed to medications they don’t need.
One committee member commented that it’s possible the drug would be prescribed to patients who might meet the criteria for increased risk for OINV, including being older, female, and a nonsmoker and/or with a history of motion sickness, but who won’t in fact experience these symptoms. This, in turn, would again introduce unnecessary exposure.
McCann noted the general feeling among committee members is that the ingredients in Hydexor might not be the “right combination” or what would have been chosen by pain specialists.
David S. Craig, PharmD, clinical pharmacy specialist, Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, for example, told the committee that promethazine is the “wrong choice of antiemetic” because of its risk for central nervous system complications.
Kevin L. Zacharoff, MD, faculty and clinical instructor, Pain and Medical Ethics, State University of New York Stony Brook School of Medicine, wondered whether “bundling” medications is appropriate and signals a “less tailored” approach.
Daniel Ciccarone, MD, professor of family and community medicine, University of California, San Francisco, also applauded the company’s risk mitigation efforts using dose restricting packaging and the return program.
“But since no data was presented showing that they would actually work in the real world, it remains a theoretical protective mechanism.”
Opioid Crisis
Some committee members wondered about the appropriateness of approving yet another opioid in view of the ongoing opioid crisis.
Sandra D. Comer, PhD, professor of neurology, College of Physicians and Surgeons, Columbia University, New York City, provided data showing that while hydrocodone prescriptions declined from 2012 to 2017, the number of pills per prescription has increased.
Of the 21 voting members, only 2 wanted to approve the drug. One was Margaret Kotz, DO, professor of psychiatry and anesthesiology, Case Western Reserve University School of Medicine, and director, Addiction Recovery Services, Cleveland Medical Center, Ohio.
Kotz said that from the data presented at the meeting and her own clinical experience, adding promethazine won’t make “a big difference in abuse liability.”
She added that she understood that the FDA recommends that the drug be indicated only for those who are prone to OINV.
Ronald S. Litman, DO, professor of anesthesiology and pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, also voted to approve the drug but had some “caveats.” One of these was the need for additional data for populations such as older patients.
Another of his concerns is use of this product by intravenous drug users. Dr Litman pointed out that promethazine is a “highly caustic irritant to skin tissues” and that intravenous drug users who inadvertently inject the drug subcutaneously or intra-arterially risk loss of a limb.
Gan is a consultant to the applicant but had no financial interest in the outcome of the meeting; Comer is a consultant for the company but had no financial interest in the outcome of the meeting
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