A Review of Sleeping Pill Ramelteon (ROZEREM)

Ramelteon (ROZEREM) was approved by the Food and Drug Administration (FDA) in July 2005 for the treatment of insomnia characterized by a difficulty in falling asleep. This sleeping pill, called a melatonin receptor agonist (activator), works in a new way. Drugs that work in new ways also have the possibility of inflicting harm in new ways. When they are minimally effective, like ramelteon, we invoke our Seven-Year Rule because little is known about the safety of new drugs.  

Ramelteon is sold by Takeda Pharmaceuticals North America, Inc., headquartered in Lincolnshire, Ill.

The fact that this drug is called a melatonin receptor activator evokes the image that it is similar to melatonin, a popular, unregulated dietary supplement that is promoted as a natural sleep aid. The advocacy of melatonin itself as a sleep aid is done without the evidence that is required for a manufacturer to promote an FDA-regulated product as being safe and effective.  

Unlike other FDA approved sleeping pills, ramelteon is not a controlled substance. That is, it does not seem to have a potential for abuse.

This review is based primary on the reviews of FDA scientists of the studies and data submitted by Takeda to support the approval of ramelteon. These reviews can be found on the FDA’s Web site at: http://www.fda.gov/cder/foi/nda/2005/021782s000_RozeremTOC.htm.  

Examining the FDA reviews of new drugs is now an essential part of performing an independent evaluation of the therapeutic value of a new drug. It is no longer possible to rely solely on the published medical literature to evaluate a new drug because the line between science and promotion has been blurred, even in the medical journals with the best reputations. In addition, some of the studies submitted to the FDA by manufacturers may not be published in a timely manner, or at all. This leaves patients and health professionals without some important information that is needed to make informed decisions about using new drugs. Thus the FDA reviews, which include detailed information from all the submitted clinical trials, are much more complete and are less likely to contain pharmaceutical company distortions.

Seven “gold standard” randomized controlled clinical trials were submitted to the FDA by Takeda Pharmaceuticals in support of ramelteon’s approval. At the time this article was written, not a single randomized controlled clinical trial involving ramelteon had been published as a full length report in a medical journal. Since sales of drugs largely depend on advertising, it is much easier to sell new drugs when patients and health professionals know as little as possible about the drugs.

Several of the FDA scientists who reviewed the ramelteon data and studies commented that the effect of the drug on sleep was statistically significant but of “marginal clinical significance.” Statistically significant results are not necessarily meaningful — they may not result in an appreciable benefit to patients. Unfortunately, the rules for new drug approvals under which the the FDA operates do not require that new drugs be more effective or safer than drugs that are already on the market.  

Five of the seven studies submitted to the FDA used instrumentation, called polysomnography, to measure the time that it took patients to fall asleep. This time is known technically as latency to persistent sleep. Patients who were given ramelteon in a dose of eight milligrams fell asleep, on average, from between 7.6 minutes to 13.4 minutes more quickly than patients given a placebo. In the fifth study, patients taking eight milligrams of ramelteon, on average, took 2.8 minutes longer to fall asleep than those patients receiving a placebo.

Six of the seven studies submitted by Takeda measured how much longer a patient taking ramelteon would sleep compared to a placebo. This is called total sleep time. The average amount of total sleep time ranged from 11 minutes longer to 14 minutes longer in the patients given ramelteon. These results were statistically significant in five of the six studies. In one of the six studies, no statistical difference was found between ramelteon and the placebo. Again, one must question the clinical importance of such a short amount of increased sleep time, even in the studies where the difference was statistically significant.

Some of the FDA scientists reviewing ramelteon were concerned that the drug can cause an increase in the blood levels of a hormone called prolactin. An increase in prolactin levels was seen in one six-month clinical trial in which the patients received 16 milligrams of ramelteon, twice the approved dose. Thirty-two percent of the patients in this study exhibited an increase in prolactin levels. This effect was most pronounced in women.

Prolactin induces and maintains lactation in women who have just given birth. Even mild, persistent elevations of prolactin, called hyperprolactinemia, can result in a condition known as hypogonadism in which the ovaries in females and testes in men do not function properly. Hypogonadism may result in amenorrhea (absence or suppression of menstruation) in women, and infertility and decreased libido (sex drive) in both males and females.

The professional product labeling for ramelteon recommends that patients taking the drug who experience unexplained loss of menstruation (amenorrhea), who have spontaneous flow of milk from the nipple (galactorrhea), or who encounter problems with fertility should have their prolactin and testosterone levels measured by their physician.  

The editors of The Medical Letter on Drugs and Therapeutics, an independent source of drug information written for health professionals, concluded their Nov. 7, 2005 review of ramelteon with the following statement:

Ramelteon (Rozerem), a melatonin receptor agonist, is not a controlled substance and apparently has no potential for abuse, but its hypnotic effect is not impressive. In clinical trials, it produced small, statistically significant improvements in sleep latency, but had little effect on sleep maintenance. Comparative clinical studies with other hypnotics, including melatonin itself, are lacking. The long-term safety of ramelteon, which has been reported to increase serum prolactin concentrations, is unknown.

A number of drugs can cause sleeping problems. Before considering taking ramelteon, or any other sleeping pill, consult the new fourth edition of Worst Pills, Best Pills or read this list of the drugs that can cause insomnia. If you are taking one of these drugs, ask your doctor if the dosage of the drug can be reduced or if another drug can be used that does not cause insomnia. Both the book and the Web site contain additional information on good sleep hygiene. These non-drug measures may be sufficient to keep you from needing a sleeping pill such as Ramelteon.    

What You Can Do

You should not use ramelteon until July 2012. This drug is minimally effective and the long term safety effects of the increased prolactin levels caused by ramelteon are unknown.