Safety in off-label use of drugs

A revelation that a university hospital in Tokyo has been habitually administering a powerful sedative banned for use on children placed on ventilators has raised safety questions on the reportedly widespread practice of off-label use of drugs. Doctors can and do, at their own discretion, use drugs on patients in ways forbidden by drug manufacturers when it’s deemed a matter of medical necessity. The question is whether priority is given to the benefit and safety of patients or to the convenience of doctors.

A 2-year-old boy who had an operation to remove lymphangioma at Tokyo Women’s Medical University Hospital in February died three days after he was given propofol, an anesthesia-inducing agent while he was on a ventilator at an intensive care unit of the hospital in Shinjuku Ward. Following a complaint from the boy’s parents and a police investigation, the hospital admitted that the boy’s death had been caused by improper use of the sedative. The hospital also disclosed that its doctors had administered propofol to 63 patients aged 14 or younger who had been on ventilators over the past five years and that 12 of the patients died. But it denied any link between their deaths and the use of the drug.

Propofol is reportedly used widely to induce anesthesia during surgeries or other medical procedures, both on adults and children, because it takes effect fast and wears off quickly — a characteristic that also benefits doctors. However, high-dose usage of propofol over a long period carries a risk of causing circulatory failure and other problems. The 2-year-old boy died of acute circulatory failure after he was given the drug intravenously for about 70 hours.

Following reports of deaths overseas, the drug’s manufacturer has prohibited its use for children on ventilators at intensive care units, as indicated on the product label.

Still, what the doctors in question did is not banned under the law. Doctors may at their discretion give their patients drugs in ways different from those listed on the drug label and even use the drugs in ways that the label prohibits.

It is believed that in the treatment of children, off-label use of drugs is sometimes necessary because clinical trials in the development of new drugs in most cases are carried out solely on adult patients and there are not many drugs whose effects or safety for children have been confirmed.

A 1999 survey by a health ministry panel on state-run university hospitals and other institutions showed that the labels of only 23.4 percent of the drugs administered on children at these hospitals mentioned specified appropriate doses and uses for young children. The remaining 76.6 percent of the drugs were used on patients in an off-label manner, including 4.8 percent that were administered in ways prohibited on the labels. Nine out of the 70 hospitals across Japan that answered a recent questionnaire by Kyodo News said they also occasionally use propofol on children in ways prohibited on the label — often without informing the patients or their families.

Such off-label use of drugs should be limited to cases in which no alternative medicines are available or when the drugs in question are deemed absolutely necessary to treat the patients in the most effective manner. Convenience on the part of the doctors and other medical staff, such as the ease of the drugs’ use, should not be given priority.

Tokyo Women’s Medical University Hospital, which appears to have administered propofol in an off-label manner more frequently than other institutions, needs to thoroughly examine how and why the drug was habitually used by the hospital staff, and whether adequate steps were taken to ensure the safety of the patients who received it.