Shortages of Drugs Threaten Patients

WASHINGTON —  Shortages of drugs commonly used in hospitals are putting patients at risk across the country and forcing doctors and nurses to ration their limited supplies.

Although some shortages stem from temporary manufacturing or distribution problems, many are the result of profound shifts in the economics of the pharmaceutical industry. In response to increasing financial pressures, drug makers are abandoning older, less profitable products used mainly in hospitals in favor of newer, more lucrative medications tailored to the outpatient market.

Government regulators have no authority to prevent drug makers from halting production. Only in rare cases can they even require that manufacturers give notice before dropping products so that doctors have time to find substitutes or make other arrangements.

Aggravating the problem, hospitals have responded to cost-cutting mandates from managed-care insurers and the federal government by keeping increasingly smaller amounts of expensive drugs in their inventories. This management strategy has left hospitals with scant reserves when new supplies were unavailable.

Although there have been no reports of deaths related to drug shortages, doctors, pharmacists and critical-care unit managers in several cities say the problem has threatened patient care.

Among the cases:

* A recent shortage of Fentanyl, a specialized painkiller, contributed to a significant increase in cases of respiratory distress among surgery patients, said Dr. John H. Eichhorn of the University of Mississippi’s medical school. Respiratory distress can be life-threatening, and doctors sometimes must take emergency measures, such as forcing tubes down patients’ throats, to overcome it. The shortage occurred when one manufacturer, ESI Lederle, a division of American Home Products Corp., suspended production. ESI said it wasn’t worth incurring the cost of upgrading manufacturing practices as ordered by the Food and Drug Administration. The drug’s other two makers did not make up the shortfall.

* The disappearance of Wydase, which facilitates the distribution of fluids through surrounding tissues, is causing problems for eye surgery and the care of premature infants. “We don’t have a substitute right now, and that means you could have some of these little preemies who could lose limbs,” said Sharon S. Murphy, manager of pharmacy operations at Northside Hospital in Atlanta. Wyeth-Ayerst, another division of American Home Products, stopped making the drug rather than spend the money to bring its manufacturing plant up to FDA standards.

* Hospitals have been forced to delay some surgeries for months as a result of a shortage of succinylcholine, a drug that helps patients swallow breathing tubes during anesthesia without damage to the esophagus. Pharmaceutical firms have not stepped up production because they view the market as insufficiently profitable.

Hospital pharmacists and doctors say the problem has reached the point that government intervention is needed, if only to give hospitals more warning of impending shortages.

“We’re taking care of patients every day, and the flow of the right pharmaceuticals . . . can’t be a victim of fluctuations in the marketplace,” said Rick Wade, senior vice president for strategic communications at the American Hospital Assn. “This is a time when a regulated marketplace makes sense.”

Drug shortages often crop up without warning because federal law does not require companies to give notice of plans to drop a drug unless it is used to treat a life-threatening condition and is made by only one company.

“Shortages often occur even when there are several companies that manufacture a product,” said Mark Goldberger, a doctor at the FDA’s Center for Drug Evaluation and Research. “In those cases, they don’t have to give notice.”

Pharmaceutical Research and Manufacturers of America, PhRMA, the industry’s trade association, recently convened a meeting to discuss the issue with FDA staffers, doctors, pharmacists and hospital representatives.

“We can’t comment on the shortages,” PhRMA spokeswoman Jackie Cottrell said. “There could be a variety of different reasons for different drugs. We really have no information, and individual companies have to address it for their individual circumstances.”

Seven Key Medications on FDA Shortage List

There is little dispute that the number of drugs that are in short supply is growing, although there is confusion about when short dosages start and when they are resolved

Of the FDA’s roster of hundreds of drugs it categorizes as medical necessities, seven are on its shortage list. They are succinylcholine, Celeston Soluspan, Dexamethasone, Isuprel, Mesantoin, Quinidine Gluconate and Wydase.

The American Society of Health-System Pharmacists, which tracks a more extensive number of drugs, says about 20 are in short supply. The society has become a clearinghouse for reported shortages around the country. Joseph Deffenbaugh, a member of its professional practice and scientific affairs division, said he received reports from hospital pharmacists of about 15 to 20 shortages in February, an additional 15 to 20 in March and at least 20 more in April.

Shortages of Drugs Keep Piling Up

Linda Tyler, a pharmacist and director of drug information for the University of Utah Hospital, said 28 drugs were in short supply at her facility in all of 2000. By March of this year, she had added about 10 more.

“We’re just being creamed now,” Tyler said. She added that doctors at the university’s psychiatric hospital have not administered electroshock therapy to treat severe depression for several months because of the shortage of succinylcholine and similar drugs.

“I’ve been in pharmacy management for 20 years, and I’ve never seen anything like this,” added Elaine Levy, who oversees pharmacy supplies for the seven hospitals operated by Sharp HealthCare in Southern California. “Here we are in an industry that is supposed to be taking care of patients . . . and we are begging, borrowing and rationing drugs.”

Levy said she is tempted to abandon her practice, aimed at cutting costs, of keeping only a few days’ worth of supplies on hand. Now, she says, she is tempted to buy several months ahead.

Ken James, supervisor of Kaiser Permanente’s pharmacy, says that when a drug company quit making a drug to counteract poisonous snakebites, the huge health care provider pooled its remaining stocks at a central location and issued warehouse staffers 24-hour beepers so that they could rush the drug where it was needed.

The FDA eventually persuaded the manufacturer to continue production until another manufacturer could be found.

In most cases, the drugs that are in short supply come in injectable form and are used almost exclusively in hospital treatment or outpatient surgery.

Injectable Drugs Need Sterile Environment

Pharmaceutical companies regard the market for these drugs as limited because far fewer people require hospital treatment than the millions who take pills as outpatients. And unlike most pills, injectable medicines must be manufactured in a sterile, bacteria-free environment.

The most likely companies to step in when drugs are no longer protected by patents are generic pharmaceutical manufacturers. But only a few generic drug companies have the sterile facilities needed to make injectable drugs.

“You need special air-handling units, and the people going in and going out have to gown and glove,” said Carole Ben-Mamion, a physician and chairman of the Generic Pharmaceutical Assn. “You’re limited in what you can make in that kind of facility.”

The effect on patients appears to be growing.

The shortage of the painkiller Fentanyl has doubled or tripled the incidence of respiratory distress among surgical patients nationwide, said Eichhorn, anesthesiology chairman at the University of Mississippi. Other painkillers are available, he said, but many anesthesiologists are less familiar with them and don’t always use them properly.

Fentanyl makers and the FDA recently declared that the drug is no longer in short supply since ESI/Lederle resumed manufacture. However, Eichhorn said doctors are still having problems obtaining the drug in the South. In addition, Tyler, the University of Utah pharmacist, said that the most popular 2-millimeter vials are not to be found.

The Institute for Safe Medication Practices, a nonprofit organization that is working with hospitals and doctors to reduce medical errors, recently surveyed hospital pharmacists about the shortage of Fentanyl. Of the 344 who responded, 10% reported adverse effects, including several instances of respiratory arrest that required cardiopulmonary resuscitation.

Wydase Aids Preemies, Eye Surgery Patients

Wydase, which disperses anesthetic drugs during eye surgery, has disappeared from the market because its only manufacturer, Wyeth-Ayerst, decided to quit making it.

Since it became unavailable, there has been a noticeable increase in the number of post-operative cases of double vision, said Samuel Masket, an ophthalmologist at UCLA’s medical school.

Wydase also disperses drugs that spill out of intravenous tubes into the tissue of premature newborns, thus diluting the drugs and making them less harmful to the tender area around the tubes. When Wydase is not available, the best alternative is to cut two or three small slits in the baby’s flesh and irrigate the area with water to wash out the leaked drugs. It’s a painful procedure for all concerned.

“That’s what people were doing before Wydase existed, but it’s like we’re stepping back in time,” said Ivy Coleman, a pharmacist and drug information specialist at Palmetto Richland Memorial Hospital in Columbia, S.C.

Wyeth-Ayerst quit making Wydase when the FDA ordered the company to upgrade the plant where the drug was manufactured.

“It was a business decision,” said Doug Petkus, a spokesman for the company. “Wydase was one of those products that we decided to discontinue when we evaluated our portfolio over the past six to nine months. Every company has to prioritize its resources, and often you need to make a decision that priorities lie in other areas based on therapeutic need.”

The shortage of succinylcholine has complicated anesthesia that requires the use of breathing tubes. Supplies ran short in part because an alternative drug, Raplon, was withdrawn from the market in March by its manufacturer because it was linked to deaths of five patients and other serious adverse reactions.

About 25% of the succinylcholine market is held by Glaxo Wellcome Inc., which introduced it in 1952. Because the patent has expired, the price is relatively low. When Raplon disappeared, Glaxo had little interest in filling the void by ramping up production of succinylcholine.

“It’s a non-promoted brand. It’s not a big seller for us,” said Nancy Petarek, a spokeswoman for Glaxo. “My guess is that it’s not something we would put a lot of resources into. The resources are going into the newer and bigger products.”

Abbott Laboratories, which also makes succinylcholine, has not yet made a decision about whether to increase production, spokeswoman Tareta Lewis said. “A lot of drugs might be produced on the same production line,” Lewis said. “So then you have to look at the resources and decide where you want to put them.”

Economists say drug shortages reflect a complex set of circumstances.

In the drug industry, a wave of mergers and acquisitions has reduced the number of manufacturers, and those that have survived are focusing on the development and marketing of new products. The hospital market has become less attractive to drug makers than the outpatient drug market, which is much larger and more susceptible to advertising and promotions.

As for the hospitals, which are also under severe financial pressure, they are bargaining hard for lower drug prices, and they are keeping inventories small.

Even globalization has played a role. In some cases, hospital drugs have become scarce because drug makers can’t obtain key ingredients from overseas suppliers.

The American Society of Health-System Pharmacists wants the federal government to consider requiring companies to notify the FDA and health care providers if they anticipate shortages of any drugs.

Princeton University health care economist Uwe Reinhardt is among those who support the notion of tighter government control.

“The pharmaceutical industry is a creature of government,” he said. “It cannot make it through a month without the protection of government through patents . . . and the FDA gives some protection of the industry from liability.

“I think of the drug industry as a little bird that sits in the hands of government. And in return for that protection, the government has a right to have that bird sing tunes it doesn’t always want to sing.”