August 2005 • www.clinicalneurologynews.com Sleep Disorders 9 FDA Approves Melatonin Agonist for Insomnia

BY ELIZABETH MECHCATIE zyme inducer. Cautious use with strong with fertility. Dr. Richardson, an investi- been shown to be an effective hypnotic Senior Writer CYP3A4 inhibitors, such as ketoconazole, gator in trials and a consultant to Takeda, when taken to promote sleep. This may be and strong CYP2C9 inhibitors, such as said that although the increases in pro- related to a metabolite of melatonin, he Food and Drug Administration fluconazole, are among the other recom- lactin levels in women were self-limited which increases with increasing doses and has approved an insomnia drug mendations. and below what an endocrinologist would prevents it from being effective, he said. Twith a unique mechanism of action Increases in serum prolactin have been consider pathological, this finding should Ramelteon is not scheduled as a con- and several features unique among hyp- documented in some women and men on be kept in mind, particularly because some trolled substance. In a study evaluating its notics approved for insomnia: It is not a ramelteon, with no clinical effects. But the women may have unrecognized mild to abuse potential in 14 people with a histo- controlled substance and does not produce label advises that prolactin and testos- moderate hyperprolactinemia at baseline ry of sedative/hypnotic abuse or anxi- some CNS side effects associated with terone levels should be considered in pa- and may be more susceptible to this po- olytic abuse, there were no differences be- other hypnotics approved for insomnia, ac- tients with unexplained amenorrhea, tential effect. tween a placebo and increasing doses of cording to one of the drug’s investigators. galactorrhea, reduced libido, or problems As a supplement, melatonin has never ramelteon. ■ The drug, ramelteon, a melatonin re- ceptor agonist, was approved last month for treating insomnia characterized by diffi- culty with sleep onset. Ramelteon binds to melatonin MT1 Ramelteon does and MT2 recep- not produce the tors, two of the three known NEWATION CNS sedation, melatonin re- memory ceptors. This ac- tion may poten- INDIC impairment, or tiate sleep, since imbalance seen the receptors “acted upon by with hypnotics endogenous approved for melatonin, are thought to be treatment of involved in the insomnia. maintenance of the circadian rhythm underlying the normal sleep-wake RESTLESS LEGS SYNDROME (RLS)—AN IRRESISTIBLE URGE TO MOVETM cycle,” according to the drug’s label. Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insom- nia—one in people aged 18-64 and anoth- er in those aged 65 and older—those tak- ing ramelteon fell asleep faster and slept longer than those on placebo. The rec- ommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal, which delays absorption. In an interview with CLINICAL NEUROL- OGY NEWS, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbal- ance that are side effects of the other hyp- notic drugs approved for insomnia, the benzodiazepines and the newer non-ben- zodiazepines—a particular advantage in el- Now Provide Requip derly patients. Because the action of the drugs is specific to the MT1 and MT2 re- ceptors, which are located only in the suprachiasmatic nuclei (SCN), the activi- THE FIRST AND ONLY ty of the drug is specific. There are precautions and potential FDA-approved treatment for drug interactions to consider, however: Ramelteon should not be used in people moderate-to-severe primary RLS with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is Important Safety Information the major isoenzyme involved in metabo- lizing ramelteon, so it cannot be taken Requip has been associated with sedating effects, including somnolence, with fluvoxamine, a strong CYP1A2 in- and the possibility of falling asleep while engaged in activities of daily hibitor, and should be administered with living, including operation of a motor vehicle. Syncope or symptomatic caution with drugs that are weaker hypotension may occur, particularly during initial treatment or dose titration. CYP1A2 inhibitors, according to the drug’s label. Other drugs on a list of drugs that For more information about Requip, visit www.requip.com. www.requip.com may have effects on ramelteon metabo- lism include rifampin, a strong CYP en- Please consult brief summary of Prescribing Information on next page.