A federal advisory panel voted 20-2 to recommend that the FDA not grant approval for an expanded indication for sodium oxybate (Xyrem) — also known as GHB — to treat fibromyalgia.
A number of members on the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committees felt the potential for widespread abuse of the “date rape” drug was too great to warrant expanding the indication to a condition that affects an estimated 2% of the U.S. population.
Sodium oxybate, currently approved at a 500 mg/ml dose for narcolepsy-associated cataplexy and excessive daytime sleepiness, is a central nervous system depressant and carries a boxed warning against its use in combination with other similar drugs.
The label information also warns that sodium oxybate is a drug known to be abused. Sodium oxibate is a sodium salt of y-hydroxybutyrate, or GHB.
“Right now it’s viewed as a drug for a very rare condition, and that is not fibromyalgia,” said panelist Thomas Kosten, MD, professor of psychiatry and addiction at Baylor College of Medicine in Houston. “We’ve gone from a micro, tiny population, to something that’s going to affect a huge population.
“Should we be giving LSD to people because it improves their psychotherapy? Should we give marijuana to people because it improves their well-being?” Kostan said. “What are we thinking?!”
Other panelists weren’t as worried — or as agitated — as Kostan over the potential for abuse, but they noted that the drug’s maker, Jazz Pharmaceuticals, failed to convincingly prove the drug worked. Others were concerned about the odd dosing mechanism of the drug.
The vote came at the end of an unusually tense joint advisory board meeting during which one panelist sparred with an FDA official; fibromyalgia patients pleaded with the panel to give them access to a drug they said helped save them from lives filled with pain; and drug abuse prevention advocates urged the FDA not to add another indication to sodium oxybate out of fear it will increase the amount of GHB on the streets.
Panelists Question Effectiveness Data
Although narcolepsy is a rare disorder, fibromyalgia effects about five million people, or 2% of the U.S. population, according to FDA staff reviewers in briefing documents prepared for the panel. However, if approved, the sodium oxybate would be used in far fewer patients, Jazz Pharmaceuticals argued, largely because many patients would be scared off by all the safety warnings and by horror stories they’ve heard about GHB.
The committee examined the company’s two randomized, double-blind, phase III trials testing sodium oxybate versus placebo.
In one of the trials, involving 548 patients randomized to placebo or to 4.5 g or 6 g per night of the drug, researchers reported the following improvements relative to baseline:
•Pain visual analogue scale (VAS) score: placebo, -18 points; low drug dose, -29 points; high drug dose, -32 points (P<0.001 for both doses) •Fatigue VAS score: placebo, -17 points; low drug dose, -28 points; high drug dose, -30 points (P<0.001 for both doses) •Jenkins Sleep Scale score: placebo, -2.9 points; low drug dose, -6.1 points; high drug dose, -6.2 points (P<0.001 for both doses) At Friday's meeting, FDA staff said there was no question that the drug was effective, but panelists weren't so sure. For starters, several panelists rejected the idea that a true placebo could exist in Jazz's trials -- or in any trial testing a "hypnotic sedative." One patient who was enrolled in the Jazz trial told the panel she knew she received the test drug from the onset. "From the very first dose, I knew this was no placebo," patient Barbara Gehr told the panel. She was bedridden for eight months with pain from fibromyalgia before enrolling in a Jazz sodium oxybate trial. Patients taking the drug pass out almost immediately, with no time to even "send an e-mail" as another patient put it. Dosing Raises Red Flags Panelists were also concerned with the unusual dosing mechanism. The drug has an extremely short half-life, so patients must take one dose at bedtime, and set their alarm clocks to wake up and take a second dose four hours later. The dosing apparatus also has the potential for confusion, panelists pointed out. Patients must empty a solution into a small cup and mix it with water. Several people in the study accidentally took a double dose. A pediatrician on the panel said she was concerned that children could accidentally ingest the drug, even though the dosing devices are "childproof." Patients might prepare their second dose and set it next to their bed in order to easily take it in the middle of the night, she suggested. Panel chairwoman Kathleen O'Neil, associate professor of pediatrics at the University of Oklahoma College of Medicine in Oklahoma City, said she worries a child might walk in and take the drug, "because mommy's out cold." (Fibromyalgia is more common in women).