Updated with the approval on Wednesday of an over-the-counter form of naloxone.
As the U.S. drug crisis has accelerated, the pharmaceutical industry has jumped into action — particularly when it comes to naloxone, the drug used to reverse opioid overdoses.
In recent years, companies have introduced a dizzying array of ambitious new naloxone products. They include a mechanized injector that gives robotic voice commands, a prefilled syringe pen, an ultra-high-dose nasal spray, and an autoinjector that the Pentagon has purchased for use in the event of a terrorist attack.
At first glance, the race to create stronger, more advanced overdose-reversal tools seems like a win-win: a case study in American pharmaceutical companies saving countless lives and turning a profit along the way.
A new STAT examination, however, captures a far different reality: One in which pharmaceutical companies have used the opioid crisis, and the nation’s fear of fentanyl, to aggressively market high-cost naloxone products that divert resources away from cheaper forms of the lifesaving medication. These expensive new products, according to researchers, harm-reduction groups, doctors, and pharmaceutical industry experts, don’t fill a legitimate public health need. Instead, they serve largely as an excuse to charge exorbitant prices for a medication that has been off patent for nearly 40 years.
“The average person would assume that a higher dose is stronger and perhaps can work better,” said Robert Ashford, a substance use researcher and advocate who runs Unity Recovery, an addiction recovery organization in Philadelphia. “The unfortunate truth is that’s just not supported by science. The industry is grasping at straws — I think for a profit motivation, not a scientific or medical one.”
Naloxone is perhaps the best tool available to prevent opioid deaths: It is used to reverse hundreds of thousands of overdoses each year, and has saved countless lives. With more than 80,000 Americans dying of opioid overdoses each year, experts say what’s needed is an abundant supply of cheap naloxone, packaged at reasonable doses and in simple, low-tech delivery systems like nasal sprays or syringes.
One such product, Narcan, hit a major milestone on Wednesday: the first-ever approval as an over-the-counter medication.
Other companies, however, have brought to market a glut of high-dose, mechanically complex naloxone products — all of which sell for far higher prices than their generic counterparts. Advocates say there’s a simple reason why: No company has held patent exclusivity over naloxone since 1985, and there’s little money to be made selling low-cost generic versions.
Recent examples of questionable new products include Kloxxado, a nasal spray nearly identical to Narcan but containing a dose twice as high; Zimhi, a prefilled syringe pen; and Evzio, the infamous mechanized auto-injector that was withdrawn from the market in 2020. Orexo, a Swedish company, is currently developing a product whose key features, as highlighted in a company press release, are “high-dose” and “protected by patents until 2039.”
The contrast, experts say, highlights a fundamental mismatch between public health needs and profit motives. And it demonstrates, too, how the fear of fentanyl, the ultra-potent synthetic opioid, has allowed companies to push the narrative that standard doses are no longer enough.
“Pharma did what pharma does,” said Michael Hufford, a longtime health technology executive who in 2017 founded Harm Reduction Therapeutics, a nonprofit currently awaiting approval for its own over-the-counter naloxone nasal spray. “They ran the patent space. … They had the opportunity to develop high-dose products, even though that wasn’t what was needed. So that’s what they did.”
Drug companies’ behavior in the naloxone market mirrors a longstanding pharmaceutical industry practice: protecting profit margins by continually offering medications in new — and therefore, patentable — formulations and delivery mechanisms.
But amid the devastating U.S. drug epidemic, the companies’ behavior comes at a cost. On an individual level, the new brand-name products threaten to shut out consumers: Kloxxado and Zimhi each retail for roughly $140 for a two-pack, according to the website GoodRx. A two-pack of Evzio, the auto-injector since withdrawn from the market, at one point retailed for $4,100.
Naloxone-access advocates, however, say the bigger issue lies in the way organizations like schools, nonprofits, police departments, and local public health agencies spend their money.
Buying a few doses of Zimhi or Kloxxado for the same price as hundreds of doses of generic naloxone would represent a “dangerous diversion of resources,”said Sarah Evans, a drug policy expert at the Open Society Foundations and the former director of a supervised injection site in Vancouver, Canada.
“I can only understand it as a fear-based market,” she said. “This should not be another opportunity for, essentially, pharmaceutical price-gouging — and the marketing of unnecessarily strong or fancy new products to state and county health departments that maybe don’t know better.”
Some local health organizations have already made the change. Alaska’s public health department, for instance, announced in 2022 that it was switching to exclusive use of Kloxxado.
In an interview, Jake Nichols, the director of medical affairs in the recovery division of US WorldMeds, Zimhi’s manufacturer, acknowledged concerns over cost and the risk of giving too high an initial dose. But it’s safer to err on the side of a higher dose, he argued, and the fact that Zimhi is an injection also increases the medication’s bioavailability and eliminates the risk of naloxone sprays not working because of potential nasal blockages.
“You’re getting 100% of the drug and you’re getting it quick, which is what people are postulating is necessary to get these fentanyl analogues off the receptor,” he said. “Do we need these? There are those of us, like myself, who feel right now that until we truly figure that out, we’d better err on the side of caution.”
Steven Weiss, a spokesman for Hikma, the manufacturer of Kloxxado, cited the drug’s FDA approval and a statement of support from the American Medical Association.
“Those on the frontlines of this public health epidemic need all FDA-approved treatment options available to them,” he wrote, “which is why Hikma provides 8 milligram nasal Kloxxado and generic injectable naloxone.”
Drug manufacturers’ aggressive marketing of new, higher-dose naloxone formulations comes amid heightened fears surrounding fentanyl.
Those concerns are largely justified: The compound’s presence in the U.S. drug supply has sent overdose rates soaring. Fentanyl is now sometimes found not just in opioids, like heroin, but also in other drugs like cocaine or counterfeit versions of stimulants, like Adderall, often causing overdose in unwitting, opioid-naive users.
The drug’s dangers have, however, have spawned a number of highly misleading, fear-driven narratives. The DEA warned last year of “rainbow fentanyl” disguised to appear like candy, implying that it was meant to target children (the drugs’ bright colors, experts said, have nothing to do with appealing to young people). Numerous police officers have claimed to have overdosed on fentanyl simply from touching it — medically speaking, a near-impossibility. Both claims have been widely refuted.
Amid the climate of fentanyl-driven fear, drug companies have worked to advance the narrative that only super-sized naloxone doses can reverse a fentanyl overdose. As one 2018 journal article argued: “Higher doses of naloxone are needed to combat the new era of overdoses due to more potent synthetic opioids such as fentanyl.”
The article’s authors were both employees of Adamis Pharmaceuticals, the company that licensed US WorldMeds to sell Zimhi, the prefilled injector pen.
Nora Volkow, the director of the National Institute on Drug Abuse, said in an interview that starting with a smaller dose is ideal. She argued, though, that the higher-dose products may be useful, especially in contexts where an overdose victim won’t necessarily have access to follow-up care. Given naloxone’s relatively short half-life, she said, higher doses can help ensure naloxone remains in an overdose victim’s system for longer, meaning they won’t overdose again.
“There are instances, absolutely, where an 8-milligram naloxone will make sense,” she said. But, she added: “People are afraid that it’s so costly that it could be diverting resources that could be better used. And that’s a reality.”
Besides being less expensive, advocates say the standard 4-milligram dose of intranasal naloxone continues to effectively reverse overdoses.
Several academic studies have reached the same conclusion. One review of emergency department admission records in 2017 and 2018 found no significant difference between the doses of naloxone used to reverse overdose in patients who had and had not consumed fentanyl. An earlier study of people who reversed overdoses in Pittsburgh found no increase in reported naloxone dosage from 2013 to 2016, even as fentanyl’s prevalence shot upward.
Related: Unlocking federal funding for fentanyl test strips will save lives
Other research paints a more nuanced picture. One recent review of naloxone-dose studies concluded that administering multiple naloxone doses has become “significantly” more common — but noted that EMS personnel administered additional doses at a significantly lower rate than responders without medical training.
Even in instances where more than a standard dose is needed, advocates say, responders can simply use more. Trained medical workers often titrate doses of injectable naloxone, and even people without medical training can easily administer a second nasal spray.
Ashford, the substance use researcher, said that in his experience in harm reduction, he could not recall a time when an 8-milligram dose would have been needed.
“I won’t say that there’s not a world at some point in the future where we see something we’ve never seen before, and they become medically necessary,” Ashford said of high-dose formulations like Kloxxado. “Anything is possible. But there is no current evidence, empirical or anecdotal, that they are ever medically necessary.”
Still, the increasingly toxic drug supply has muddied the landscape. Anecdotally, the presence of xylazine, a veterinary tranquilizer that is increasingly found in illicit fentanyl, appears to have made overdoses more difficult to reverse. In those cases, though, the key lies in techniques like rescue breathing and the use of oxygen masks. While xylazine can depress breathing, it is not an opioid — meaning it won’t respond to naloxone at any dose.
Related: Newly available test strips can detect lethal ‘tranq’ in drug supply
While naloxone has no real effect other than to displace opioid molecules from brain receptors, giving larger-than-typical doses is not without risk. Unnecessarily large naloxone doses can cause debilitating withdrawal symptoms in overdose victims soon after they regain consciousness. And those withdrawal symptoms can be so agonizing that they are driven to again use illicit substances, like fentanyl, sometimes leading to a repeat overdose.
“It’s true that people may give one dose, wait a few minutes, and give another — I’ve done that myself,” said Evans, the Open Society Foundations drug policy expert. “But I don’t know that there’s a proven need for this doubly strong dose out of the gate. And of course, it comes at a risk: It can push people into withdrawal, which is incredibly uncomfortable, and then they’re likely to want to run out and use drugs again, which is going to lead to a worse situation.”
For years, advocates, lawmakers, and health officials have called for naloxone to be made available without a prescription. The FDA’s approval this week of Narcan as an over-the-counter drug is a milestone. But it is not as large a victory as it may seem.
For one, naloxone products are already available to most Americans via a loophole known as a “standing order” — in essence, a blanket prescription written by a state or local health official. Thanks to coupons and discounts, naloxone is often entirely free to individuals who seek it out, especially if they have health insurance.
Strangely, the FDA granting over-the-counter status for Narcan may make cost more of a barrier for individual buyers. Emergent BioSolutions, Narcan’s manufacturer, has not said what the medication’s new price will be. Most insurance plans typically only cover prescription medications — meaning that individuals looking to buy naloxone at a pharmacy may soon be forced to pay dramatically more.
Related: FDA advisers recommend approval of over-the-counter naloxone to fight opioid overdose
It is telling, also, that no company applied for over-the-counter status until late 2022. The FDA had called for companies to create naloxone products that could be sold without a prescription as early as 2016. In 2019, the agency took the unprecedented step of creating its own drug facts label for naloxone, essentially begging companies to bring forward proposals for over-the-counter versions.
“I personally urge companies to take notice of this pathway that the FDA has opened for them, and come to the agency with applications as soon as possible,” Scott Gottlieb, the agency’s commissioner from 2017 to 2019, said then in a statement.
Still, nearly four years passed before Emergent applied for over-the-counter status — prompting criticism that the company was acting for the sake of preserving profit margins, not public health.
In a statement, Matt Hartwig, an Emergent spokesman, stressed that the company offers Narcan at a discount to public interest groups and that it “takes time” to conduct studies and develop the infrastructure required to launch an over-the-counter product.
The company’s critics — namely Hufford, the CEO of Harm Reduction Therapeutics, the nonprofit working on another nasal spray set to receive over-the-counter approval this year — aren’t buying it.
“It’s extraordinarily disingenuous to suggest that they pursued the switch for any altruistic or public health-motivated reasoning,” said Hufford. “They read the tea leaves, realized they had no space to run, and finally, seven years into this epidemic and despite multiple pleadings from regulators, public health authorities, harm reduction groups, and families, they submitted their OTC switch application.”
The FDA will likely issue its approval decision for RiVive, the nonprofit’s version of Narcan, in July, Hufford said.
Related: Overdose data, often scattered and siloed, pose challenges for researchers racing to predict risk
It is unlikely Emergent’s bottom line will suffer, even with the threat of over-the-counter competition. One recent market analysis published by the investment bank TD Cowen projected that despite the new competition, Narcan sales in 2023 will equal approximately $264 million.
Despite criticism, drug companies continue to market several brand-name, high-dose, technologically advanced overdose-reversal products.
There are more on the way: Orexo, the company developing a naloxone product it has only described as “high-dose,” is also developing a version that employs nalmefene, another medication that essentially kicks opioid molecules off of brain receptors.
Purdue Pharma, the company made infamous for aggressively marketing the pain drug OxyContin despite knowing of its addictive risks, has also introduced a nalmefene product, though it pledged not to exercise its 180-day patent exclusivity and to distribute the medication for no profit.
Even Evzio, the auto-injector controversial for its $4,100 sticker price, has found new life after a long-running controversy and high-profile investigation by Sens. Rob Portman (R-Ohio) and Tom Carper (D-Del.). Separately, the device’s manufacturer, Kaléo, agreed to pay the federal government $12.7 million to settle allegations of fraudulent billing practices.
But after being quietly withdrawn from the market in 2020, the product is back: this time as a 10-milligram auto-injector adapted for use by the military to be used in the event of a fentanyl-based bioweapon attack.
It is unclear how much of a threat fentanyl actually constitutes as a bioweapon. No such attack has been documented, other than a 2002 hostage crisis in Moscow where Russian security forces used an aerosolized compound to incapacitate the attackers.
Related: Nora Volkow: Leading a revolution against drug addiction
The chemical brought the crisis to an end, but killed 130 hostages in the process. The Russian government has never acknowledged using fentanyl, but one analysis published a decade after the incident concluded that the compound contained two fentanyl analogues.
The assessed threat led the Department of Defense to buy as many as 788,000 doses of the new product, rebranded as the Rapid Opioid Countermeasure System.
A spokeswoman for the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, the Pentagon office that procured the naloxone injectors, declined to comment on Káleo’s prior controversies, and said information about the size and cost of the Pentagon’s order could only be obtained via a Freedom of Information Act request.
A Káleo spokeswoman also declined to provide detailed information about the contract, but said the auto-injector was priced at $100 on the federal supply schedule.
Some public documents appeared to indicate an even higher price, however. The Pentagon paid the company at least $19 million to develop the product, and, according to a recent budget justification, has already bought 4,121 kits at a price of $349 each.
If the Department of Defense were to fulfill its entire 788,000 dose order at $100 per unit, the total would equal $78.8 million. At $349 apiece, the price indicated in the Pentagon budget justification, the total would come to almost exactly $275 million.
For all the high-dose, high-price naloxone products on the market, some companies do churn out cheap, generic versions. Pfizer, in particular, has won admirers in the harm-reduction world for donating millions of doses of intramuscular naloxone. Hikma, the Kloxxado manufacturer, also makes a generic intramuscular product — and earned plaudits, even from industry critics, for donating tens of thousands of doses.
The generic drugmaker Teva now sells a generic form of nasal naloxone, after an Emergent lawsuit failed to prevent the product from coming to market. And Sandoz, a former Novartis subsidiary, makes an “authorized generic” version of the nasal spray, meaning Emergent receives a cut of its sales.
Despite the market’s flaws, Volkow, the NIDA director, argued it is capable of self-correcting thanks to competition and public pressure. She cited, in particular, the example of Evzio and its withdrawal from the market in 2020.
More broadly, Volkow said, the public health world has no choice but to navigate the system as it currently exists.
“We need the companies, because without them we don’t have products,” Volkow said. “We have to learn to navigate these markets, whether we like it or not.”
STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.
Original Article: https://www.statnews.com/2023/03/28/opioid-overdose-naloxone-industry-profits/
