Essential Drug Supplies for Virus Patients Are Running Low

By Knvul Sheikh, The New York Times, Apr 02, 2020.

Across the country, as hospitals confront a harrowing surge in coronavirus cases, they are also beginning to report shortages of critical medications — especially those desperately needed to ease the disease’s assault on patients’ respiratory systems.

The most commonly reported shortages include drugs that are used to keep patients’ airways open, antibiotics, antivirals and sedatives. They are all part of a standard cocktail of medications that help patients on mechanical ventilators, control secondary lung infections, reduce fevers, manage pain and resuscitate those who go into cardiac arrest.

Demand for these drugs significantly increased in March as the pandemic took hold in the United States. Orders for antibiotics like azithromycin and antiviral medicines like ribavirin nearly tripled. Medicines used for sedation and pain management, including fentanyl, midazolam and propofol, increased by 100 percent, 70 percent and 60 percent respectively.

Demand for albuterol, a common asthma inhaler medication, has also risen significantly, given its importance in easing the breathing of patients with severe infection.

At the same time, the rate at which these prescriptions are filled and shipped to hospitals has dropped considerably, down by half to more than three-fourths in the last month, according to data collected by Premier Inc., a health care improvement company that provides group purchasing, analytics, consulting and various services to more than 4,000 hospitals and approximately 175,000 other providers in the United States.

“Just like we’re seeing shortages of other materials, like masks and ventilators, medications are right there in the mix of things that we don’t always have enough of on hand,” said Erin Fox, a drug shortage expert at the University of Utah. “So we were not prepared for this kind of surge.”

Hospitals in particular are feeling the pinch in supplies. In a recent survey of 377 hospitals and 100 long-term care, home infusion and retail pharmacies, Premier found that drug shortages were pervasive in acute care settings, where 70 percent of respondents reported at least one shortage for coronavirus drugs. Among long-term care facilities, home care settings and retail pharmacies, 48 percent reported shortages.

Demand is even higher in coronavirus hot spots like New York, California and Washington.

A senior doctor at one large New York City hospital said the institution, like some others, was running low on the drugs they commonly use to induce anesthesia and then paralysis in patients on ventilators. “We’re running out of all the drugs,” the doctor said. “So we’re on second line, third line, fourth line medications. We’ve run out of the ability to monitor these people the way we conventionally monitor them. So we’re just sort of flying blind a little bit.”

Doctors at several hospitals have been using a combination of midazolam, hydromorphone and ketamine. Under normal circumstances, they would use propofol and fentanyl because they are short-acting, the doctor said. The others have a longer duration and that makes it harder for patients to emerge from sedation later.

And with the peak in cases and resource use still projected to be several weeks away, the run on these drugs only highlights weaknesses in the current supply chain.

“The pharmaceutical supply chain is one of just-in-time production,” Ms. Fox said. “Manufacturers tend to make just enough product, and they forecast out their manufacturing cycles based on how much they sold in the past. Nobody expects to sell, you know, 10 times the amount of something, and so nobody has that on hand.”

Even before this crisis emerged, the Food and Drug Administration noted shortages of well over 100 drugs in the United States. And factory shutdowns in China, India and other countries may have exacerbated the shortage of some ingredients and generic drugs during the pandemic.

“Out of 21 antibiotics that would be critical for treating secondary infections in Covid-19 patients, 18 antibiotics have greater than 80 percent of their supply coming out of either China, India or Italy — all places that have had production disruptions,” said Stephen Schondelmeyer, a professor at the University of Minnesota’s College of Pharmacy who is a co-leader of the Resilient Drug Supply Project, which aims to provide a detailed map of the supply chain for important drugs used in the United States.

Another factor that can affect the global supply chain is when countries ban export of certain drugs, either because of trade wars or because they want to ensure supply for their own citizens, Mr. Schondelmeyer said. India, for example, has put a ban on the exports of 26 drugs and drug ingredients, including hydroxychloroquine, an old malaria drug that is being used around the world as a potential treatment.

“So, politics is beginning to lay into the supply chain issues,” Mr. Schondelmeyer said.

The U.S. government could provide incentives to drug manufacturers to increase domestic production to solve some of the supply problems. But ramping up production may take two to three months and would not be able to fill immediate gaps, Mr. Schondelmeyer said. “It’s not a process where we could have the tablets next Friday.”

Increasing production is also dependent on quotas for controlled substances and ingredients that are set by the Drug Enforcement Administration. On Tuesday, the American Hospital Association and four other medical groups sent a letter requesting that the D.E.A. temporarily increase quotas to add flexibility for domestic manufacturing, but the agency has not done so yet, Ms. Fox said.

Hospitals have to start looking for alternatives that work almost as well as the current standard treatments.

“Many places are already shifting to using medications that we tried to avoid,” said Dr. Lewis J. Kaplan, president of the Society of Critical Care Medicine, a nonprofit involved in research and advocacy for patients. “We had cut down tremendously on the amount of benzodiazepines, which you may be familiar with as Ativan or Valium, because they may induce delirium, especially in people who are having trouble sleeping. But we’re now using those medications where our standard sedatives are running low.”

Some hospitals are purchasing alternative antibiotics, crushing up pills instead of using IV fluids, and reducing nonessential surgeries and treatments to prioritize patients with coronavirus infections, Dr. Kaplan said.

“There isn’t a hard and fast rule,” he said. “It is, what do I have? Can this work for this patient? And do I need to ask someone about whether or not the drugs that are mixing are reasonably safe?”

One change that has further strained drug supplies is a switch to buying albuterol inhalers for individual patients rather than using nebulizers, a shift that doctors hope will decrease the spread of the virus through the air. But that move heightens the problem of depleting supplies for people with asthma and chronic obstructive pulmonary disease, who routinely rely on the inhalers and have been encouraged to buy 90-day supplies of their medicine.

“In general, that’s good advice up front,” Mr. Schondelmeyer said. “But with drugs like albuterol, we’re not going to be able to sustain that because we’re already on short supply.”

Two pharmaceutical companies that make albuterol inhalers — GlaxoSmithKline and Teva Pharmaceuticals — have said they are facing unprecedented demand but did not have any supply chain issues at the moment. Kelley Dougherty, a spokeswoman for Teva Pharmaceuticals, said the company was “producing as much albuterol as possible as quickly as possible.”

Pfizer, which makes several versions of the sedative midazolam, also noted that its distribution network continues to operate without significant disruption. “For many of these critical medicines, we have ample supply. For some, the unprecedented surge in demand for these products is limiting our ability to fully satisfy customer orders in the short-term,” said Kimberly Bencker, a spokeswoman for the company.

Pharmacy benefit managers, such as CVS Caremark, are also trying to balance the growing interest in prescription medications for the coronavirus response with the needs of patients who take them for chronic conditions like asthma, H.I.V., rheumatoid arthritis and lupus.

“Our goal is to limit stockpiling of medication that could result in future shortages and gaps in care,” said Mike DeAngelis, a spokesman for CVS. Retail pharmacies are following state dispensing guidelines, and limiting the dispensing for coronavirus treatments to a 10-day supply in states without set recommendations, Mr. DeAngelis said. People who already take these medications for approved uses will be able to bypass any new quantity limits agreed to by their plan sponsor.

Experts still advise that patients avoid hoarding medications because the regional shortages could soon turn into national shortages as coronavirus infections continue to spread.

While the pandemic has sparked innovations in mechanical breathing machines, and some medical supplies can be sourced from the national stockpile, drugs are not as easy to replace. “If you get past a peak in a certain area, you could move resources like ventilators somewhere else, but drugs are consumables,” Mr. Schondelmeyer said. “They’re gone once they’re used.”

Transparency in the available supply chain data could help prevent drug shortages in the future. Pharmaceutical companies, wholesalers and suppliers typically know where the raw materials for drugs are sourced and which countries manufacture which parts of a drug, as well as which factories could take over if production needs to be scaled up. But each company keeps this data confidential, and even the F.D.A. does not have a systematic way to look across drug production and supply chain capabilities.

“We need to make this at least somewhat more transparent and begin to look for ways to plan for and identify where we have vulnerabilities and where we should be changing policy,” Mr. Schondelmeyer said. “Right now, we’re trying to build that bridge as we’re walking across it.”