RxPG News : Ramelteon

Ramelteon shows less potential to foster abuse and dependence

Mon, 05 Jun 2006 16:18:37 PST

( from http://www.rxpgnews.com ) As part of the effort to develop effective behavioral and medical sleep therapies, scientists consider the potential for dependence and abuse associated with prescription sleep drugs. This line of research has produced findings showing that a recently approved prescription sleep drug may spare users the potential for dependence and abuse found with other sleep aids. Laboratory studies of the effects of ramelteon suggest that the drug's targeting of the brain's melatonin receptors rather than its benzodiazepine receptors make its subjective side effects different from those of old and new sedative hypnotics.

At the University of Texas Health Science Center in San Antonio, pharmacology researchers led by Charles P. France, PhD, assessed whether ramelteon instigated the same kinds of broad cognitive effects as other, more commonly prescribed sleep aids. That other group includes traditional hypnotics and newer drugs such as zaleplon (Sonata) and zolpidem (Ambien), all of which bind to the brain's benzodiazepine receptors and may result in impaired thinking, hangover, withdrawal symptoms and rebound insomnia.

Laboratory tests and clinical studies also show that even low-dose benzodiazepines, especially in long-term use, create the potential for dependence and abuse. Says Dr. France, "Although medication might not always be indicated for insomnia, when they are prescribed, it is essential to limit the adverse side effects as much as possible."

The U.S. Food and Drug Administration (FDA) approved the use of ramelteon (brand name Rozerem) in July of 2005. Prior to FDA approval, Dr. France and his colleagues researched drug side effects, capitalizing on the fact that monkeys just like humans -- can be trained to recognize the specific effects of a drug class, presumably by how they feel. Says Dr. France, "Those experienced with the 'feeling' of a particular drug can easily recognize when they have received that drug and can reliably detect when they have been given a drug from a different pharmacologic class."

In one experiment, the researchers trained monkeys to press a lever only when given a benzodiazepine called midazolam (Versed). Then the team gave the monkeys ramelteon. The animals did not press the lever associated with midazolam, their lack of response indicating that they felt different after receiving ramelteon than they did after receiving midazolam.

In a second experiment, the researchers determined that ramelteon and the benzodiazepines have different pharmacologic mechanisms. The team gave monkeys diazepam (Valium) for at least a year. Then they administered flumazenil (Romazicon), which reverses the effects of benzodiazepines. The subsequent administration of ramelteon did not change the effects of flumazenil, further evidence that ramelteon works altogether differently. Says Dr. France, that difference makes ramelteon unlikely to promote a benzodiazepine type of dependence.

In a third experiment, the team carefully watched how monkeys who'd been given ramelteon for a year behaved when the drug was withdrawn. To assess whether the monkeys had come to depend on the drug, Dr. France and his colleagues measured clinical behavior, operant (learned) behavior, and blood levels of the drug. The first type of measure was the most revealing: Of the 33 usual withdrawal-related signs of dependence, such as teeth grinding, rubbing lips on bars, nose rubbing, scratching, biting fingernails, shakes and tremors, 10 were never seen; all but one of the other behaviors didn't change in frequency.

The authors say that together, the findings highlight significant differences between ramelteon and the prototypical benzodiazepines studied. They say their results, "suggest that ramelteon does not likely share subjective effects with benzodiazepines in humans and, thus, should not be expected to share abuse liability with BZRAs [benzodiazepine receptor agonists]." The findings also indicate that ramelteon will not produce benzodiazepine-like physical dependence in humans. Thus the authors say these findings are potentially important for the treatment of sleep problems.

Ramelteon showed significant reduction in time to fall asleep

Mon, 03 Apr 2006 23:34:37 PST

( from http://www.rxpgnews.com ) Results of a sub-analysis from a Phase III clinical study showed that ROZEREMTM (ramelteon) significantly reduced time to fall asleep in adults with chronic insomnia and showed no evidence of rebound insomnia or withdrawal effects.

In this placebo-controlled analysis, approximately two-thirds of patients who received 8 mg of ROZEREM experienced at least a 50 percent reduction in the time it took them to fall asleep. Study participants also experienced no rebound insomnia or withdrawal effects following discontinuation of treatment with ROZEREM. Rebound insomnia is the worsening of insomnia symptoms after a person stops taking their insomnia medications.

"These data show that ROZEREM can be effective in helping patients fall asleep faster without rebound insomnia and other withdrawal effects," said Thomas Roth, PhD, director of the Sleep Disorders and Research Center, Detroit, Mich. "This may represent another option for patients who are looking for a sleeping medication that is right for them."

About the Study
In this sub-analysis of a large, double-blind, placebo-controlled study, a total of 269 adults received 8 mg of ROZEREMTM (n=138) or placebo (n=131) nightly for five weeks (35 nights). Sleep parameters were evaluated at weeks 1, 3, and 5 by using a polysomnograph. ROZEREM was replaced with placebo for the two nights following the study (nights 36 and 37) to evaluate rebound insomnia and withdrawal effects.

The primary endpoint was the percentage of patients who achieved at least 50 percent improvement in the time it took to fall asleep (latency to persistent sleep, or LPS).

Results showed that a statistically significantly greater percentage of adults with chronic insomnia treated with ROZEREM 8 mg demonstrated at least 50 percent LPS reduction compared to those who received placebo at week 1 (63 percent vs. 40 percent (P less than 0.001)).

Those results were sustained throughout the study (63 percent vs. 41 percent at week 3 (P less than 0.001); 66 percent vs. 48 percent at week 5 (P leass than 0.005)).

The analysis revealed no evidence of rebound insomnia or withdrawal for patients taking ROZEREM as measured by the BWSQ. Adverse events were similar in both groups, with somnolence, fatigue and headache being the only events reported in 5 percent or more of patients in either group. This incidence was similar to that seen in other clinical studies.

"It is estimated that about 60 million people in the U.S. struggle with symptoms of insomnia, and this is even more significant as we learn more about the relationship between sleep disorders and other medical conditions, and the consequences of poor sleep. In this analysis of chronic insomnia patients, it was shown that approximately two-thirds had their sleep onset time cut in half or better with the use of ROZEREM 8 mg. This effect continued through all five weeks of the study," said Louis Mini, MD, medical director, Neuroscience at Takeda Pharmaceuticals North America, Lincolnshire, Ill. "These results represent another measure of the effectiveness of ROZEREM, and can help patients and physicians better understand this unique option for the treatment of insomnia."

ROZEREM is the first and only prescription sleep medication that has shown no evidence of abuse and dependence in clinical studies,* and as a result, has not been designated as a controlled substance. With the exception of ROZEREM, all other prescription medications indicated for insomnia are classified as Schedule IV controlled substances by the U.S. Drug Enforcement Administration. ROZEREM has a unique therapeutic mechanism of action that selectively targets two receptors located in the brain's suprachiasmatic nucleus (SCN). The SCN is known as the body's "master clock" because it regulates 24-hour, or circadian rhythms, including the sleep-wake cycle.

The FDA approved ROZEREM in July 2005 for the treatment of insomnia, characterized by difficulty with sleep onset. It is approved for long-term use in adults.

*ROZEREM is not a controlled substance. A clinical abuse liability study showed no differences indicative of abuse potential between ROZEREM and placebo at doses up to 20 times the recommended dose (N=14). Three 35-day insomnia studies showed no evidence of rebound insomnia or withdrawal symptoms with ROZEREM compared to placebo (N=2082).

FDA Approves Ramelteon, the First 'No Abuse' Drug for Insomnia

Sat, 23 Jul 2005 23:55:38 PST

( from http://www.rxpgnews.com ) Takeda Pharmaceuticals North America, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for ROZEREM(TM) (ramelteon) 8-mg tablets for the treatment of insomnia characterized by difficulty with sleep onset. The FDA approval allows physicians to prescribe ROZEREM for long-term use in adults.

ROZEREM is the first and only prescription sleep medication that has shown no evidence of abuse and dependence and, as a result, has not been designated as a controlled substance by the U.S. Drug Enforcement Administration (DEA). With the exception of ROZEREM, all other prescription medications indicated for insomnia are classified as Schedule IV controlled substances by the DEA. Additionally, ROZEREM is the first prescription insomnia medication with a new therapeutic mechanism of action in 35 years, and will be available for patients by late September.

"People with insomnia are not only affected by their sleeplessness at night; insomnia's impact is also in how they feel and function the next day," said Thomas Roth, Ph.D., director of the Sleep Disorders and Research Center, Detroit, Mich. "Current therapies often used for insomnia work by broadly inhibiting the activity of neurons in the brain. Ramelteon treats insomnia by specifically affecting the activity of neurons in an area of the brain involved in the sleep-wake process, and has been shown to carry no risks of abuse, withdrawal, or dependency, and negligible risk for next-day 'hangover' effects."

"ROZEREM represents an exciting new option in sleep medicine that we anticipate can help millions of people who live with sleepless nights and sluggish days," said Yasuchika Hasegawa, president and chief operating officer of Takeda. "The approval of ROZEREM marks a major milestone for Takeda as we seek to bring innovative therapies to patients in a variety of therapeutic areas."

ROZEREM has a unique therapeutic mechanism of action that selectively targets two receptors located in the brain's suprachiasmatic nucleus (SCN). The SCN is known as the body's "master clock" because it regulates 24-hour, or circadian, rhythms including the sleep-wake cycle.

The ROZEREM NDA, submitted in September 2004 by Takeda Global Research & Development Center, Inc., was based on data collected from an extensive clinical research program, including recently completed clinical studies with more than 4,200 patients ages 18 to 93. In one study, 472 patients received single daily doses of ROZEREM for up to one year. Also, based on recently presented clinical trials, ROZEREM has been shown to be safe for older adults, as well as those who have mild-to-moderate chronic obstructive pulmonary disease (COPD) and mild-to-moderate sleep apnea.

About Insomnia

Approximately 60 million people in the United States suffer from insomnia, yet the vast majority remains undiagnosed and untreated. Insomnia is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, leading to impairment of next-day functioning.

Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease and depression. According to the U.S. Surgeon General, nearly $15 billion annually is spent on healthcare related to insomnia, while $50 billion is lost in productivity.

About ROZEREM

ROZEREM is indicated for the treatment of insomnia characterized by difficulty with sleep onset. ROZEREM should not be used in patients with hypersensitivity to ramelteon or any components of the formulation. ROZEREM can be prescribed for long-term use. However, failure of insomnia to remit after a reasonable period of time, worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities after taking ROZEREM should be evaluated, as such symptoms may be the result of an unrecognized underlying medical disorder. In primarily depressed patients, worsening of depression, including suicidal ideation, has been reported in association with the use of hypnotics.

ROZEREM should not be used by patients with severe hepatic impairment, or in patients in combination with fluvoxamine.

ROZEREM has not been studied in subjects with severe sleep apnea or severe COPD and is not recommended for use in those populations. Patients should be advised to exercise caution if they consume alcohol in combination with ROZEREM.

ROZEREM has been associated with decreased testosterone levels and increased prolactin levels. As a result, healthcare professionals should be mindful of any unexplained symptoms possibly associated with such changes in these hormone levels. ROZEREM has not been studied in children or adolescents, and the effects in these populations are unknown.

ROZEREM should be taken within 30 minutes before going to bed and activities should be confined to those necessary to prepare for bed. ROZEREM should not be taken with or immediately after a high-fat meal. Engaging in hazardous activities that require concentration (such as operating a motor vehicle or heavy machinery) after taking ROZEREM should be avoided.

The most common adverse events seen with ROZEREM that had greater than 2% incidence difference from placebo were somnolence, dizziness, and fatigue.

FDA approved Ramelteon

Sat, 23 Jul 2005 18:11:38 PST