Rozerem Insert pdf/2008 - American Pharmacists Association

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WHAT PHARMACISTS SHOULD KNOW ABOUT ROZEREM ® (ramelteon) ROZEREM is a melatonin receptor agonist that was approved by the U.S. Food and Drug Administration (FDA) in July 2005 for the treatment of insomnia characterized by difficulty with sleep onset. It is the first and only prescription insomnia medication that has not been designated as a controlled substance (i.e., it is “nonscheduled”) 14 and has shown no evidence of abuse potential, 12 withdrawal, 14 middle-of-thenight balance impairment, 15 or rebound insomnia in clinical studies. 14 It also does not work by depressing the general central nervous system (CNS), 14,16 but instead works with the brain’s normal sleep-wake cycle. 14 Melatonin plays an important role in working with the sleep-wake cycle by helping to regulate the suprachiasmatic nucleus (SCN), 17 a region of the hypothalamus involved in circadian rhythms. 18 Melatonin acts at melatonin receptors in the SCN called MT 1 and MT 2 . 19 The MT 1 receptors in the SCN are associated with normal sleep induction, while the MT 2 receptors are associated with maintaining circadian rhythm. 18,20 Melatonin is secreted from the pineal gland and helps control the function of the SCN. The synthesis and secretion of melatonin is affected by exposure of the eyes to light and follows a circadian pattern—low during the day (in daylight) and high during the night (in darkness). It is believed that melatonin inhibits activity in the SCN that produces wakefulness. Therefore, high melatonin concentrations contribute to the creation of a state that allows sleep. 17 ROZEREM targets the MT 1 and MT 2 receptors in the brain. The activity at these receptors in the SCN is believed to promote sleep. 14,21 Efficacy The efficacy of ROZEREM in decreasing the mean latency to persistent sleep (LPS) has been demonstrated in clinical trials using dosages ranging Table 3. Clinical Studies Demonstrating the Efficacy of ROZEREM from 4 mg to 64 mg in both younger (18 to 64 years of age) and older (at least 65 years of age) adults. 14,22 Several studies also have demonstrated efficacy and increased total sleep time. 14,23 Efficacy has been demonstrated in the treatment of both acute insomnia and chronic insomnia, for up to five weeks of treatment in adults (Table 3). 14,24,25,26 No evidence of rebound insomnia (worsening of insomnia after stopping use of a sleep aid) or withdrawal effects were seen in any of these clinical studies. 14 Special Populations Additional clinical trials have been conducted to assess the safety of ROZEREM with sleep-related breathing disorders. In one study, the safety of a single bedtime dose of ROZEREM 16 mg compared with placebo was studied in 26 patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) in a double-blind, randomized, crossover trial. ROZEREM had no statistically sig- Patient Population and Study Intervention 375 healthy adults 35–60 years of age in a novel sleep environment Single dose of ROZEREM 16 mg, 64 mg, or placebo 107 patients with chronic insomnia, 18–64 years of age Two days of treatment with each of the following in a randomized dosing sequence: ROZEREM 4 mg, 8 mg, 16 mg, 32 mg, and placebo 405 adults with chronic insomnia Five weeks’ treatment with ROZEREM 8 mg, 16 mg, or placebo 829 older adults with chronic insomnia, ≥65 years of age Five weeks’ treatment with ROZEREM 4 mg, 8 mg, or placebo 100 older adults with chronic insomnia 65–83 years of age (crossover) Two days of treatment with ROZEREM 4 mg, 8 mg, or placebo in a randomized dosing sequence (crossover) Objective To evaluate the efficacy of ROZEREM for the treatment of transient insomnia in healthy adults To evaluate the efficacy, safety, and dose response of ROZEREM in patients with chronic primary insomnia To evaluate safety and efficacy of ROZEREM in subjects with chronic primary insomnia To assess the safety and efficacy of ROZEREM for chronic insomnia treatment in older adults To assess the efficacy and safety of ROZEREM for insomnia treatment in older adults (crossover) Results Both dosages of ROZEREM significantly reduced objective LPS and increased objective TST. Only the 16 mg dose significantly reduced subjective sleep latency and increased subjective TST, using a postsleep questionnaire. 22 All dosages of ROZEREM significantly reduced objective LPS and increased objective TST. Subjective sleep latency was significantly reduced only at the 16 mg dose, based on a post-sleep questionnaire. Several assessments revealed no next-day residual effects at any dose. 23 Both dosages of ROZEREM significantly reduced objective LPS throughout the five weeks of treatment. Objective TST was increased for both dosages at week 1, and continued to be significantly longer than placebo at week 3 for the 16 mg dose. Further, based on a post-sleep questionnaire, both dosages of ROZEREM significantly reduced subjective sleep onset and increased subjective TST throughout the five weeks of treatment with the 8 mg dose. The 16 mg dose showed significant reduction in subjective sleep onset at weeks 1 and 3 and increased TST at week 1. No evidence seen of next-day residual effects, withdrawal symptoms, or rebound insomnia after completion of treatment. 25 Patient-reported data were collected using sleep diaries. Both dosages of ROZEREM significantly reduced subjective sleep latency throughout the five weeks of treatment, except for the 4 mg dose at week 3. Subjective TST was increased at week 1 and week 3 (4 mg). No differences were seen across 5 weeks for 8 mg. No evidence of rebound insomnia or withdrawal symptoms. 24 Both dosages of ROZEREM significantly reduced LPS and improved TST (objective only). For subjective sleep latency, using a post-sleep questionnaire, only the 4 mg dose showed significant reductions. No evidence seen of adverse next-day psychomotor or cognitive effects. 32 LPS = latency to persistent sleep; TST = total sleep time. 4 TODAY IN PHARMACY DRUG THERAPY
nificant effect on any measure of arterial oxygen percent saturation (SaO 2 ). The mean percent SaO 2 for the entire night was 92.9% in both treatment groups. The mean apnea-hypopnea index was also similar in both treatment groups. 27,28 ROZEREM has also been studied in patients with severe COPD 29 ; however, the FDA has not yet evaluated these studies and ROZEREM is not currently recommended for this patient population. 14 A similar study was conducted to assess the safety of ROZEREM in patients with mild-to-moderate obstructive sleep apnea. Twenty-six adults received a single bedtime dose of ROZEREM 16 mg in a double-blind, randomized, crossover trial. The apnea-hypopnea index was similar in both treatment groups. ROZEREM had no effect on the number of central, obstructive, or mixed apnea episodes, nor was there any significant effect on mean SaO 2 . 30 Although ROZEREM did not exacerbate sleep apnea, it has not been studied in patients with severe sleep apnea and is not recommended for this patient population. 14 Safety and Precautions ROZEREM is well tolerated, with rates of adverse events reported in clinical trials similar to those seen with placebo. The most common adverse events seen with ROZEREM that had at least a 2% incidence difference from placebo were somnolence, dizziness, and fatigue (Table 4). Further, in clinical studies, ROZEREM has been shown to promote sleep without the risks of abuse potential, withdrawal, middle-of-the-night balance impairment, or rebound insomnia. 14,15 Two studies have assessed the effects of ROZEREM on endocrine function. In the first study, no differences were found between ROZEREM 16 mg and placebo after 28 days of treatment in 99 healthy volunteers. Hormone levels assessed included adrenocorticotropic hormone, cortisol, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, thyroid-stimulating hormone, thyroxine, and tri-iodothyronine. 31 In the second study, 6 months of treatment with ROZEREM 16 mg or placebo were compared in 122 patients with chronic insomnia. In this study, prolactin levels were significantly increased in women who received ROZEREM. The mechanism for this effect remains unclear. 31 ROZEREM was found to decrease circulating testosterone levels in the rat. 14 It is not known how the effects Table 4. Treatment-Emergent Adverse Events in Phase 1–3 Clinical Trials of ROZEREM 14 Adverse Event noted on reproductive hormones (decreased testosterone and increased prolactin) might affect the reproductive axis in adolescents and children. The safety and efficacy of ROZEREM has not been studied in these patients. Patients should consult a health care provider if they experience amenorrhea, galactorrhea, decreased libido, or problems with fertility. In addition, patients should consult a health care provider if they have worsening insomnia or experience any new symptoms of concern. 14 ROZEREM has a “Pregnancy Category C” labeling. There are no adequate and well-controlled studies of ROZEREM in pregnant women. ROZEREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 14 As ROZEREM is metabolized by the liver, it should not be used in patients with severe hepatic impairment, and should be used with caution in patients with moderate hepatic impairment. 14 Placebo (%) n=1,370 ROZEREM 8 mg (%) n=1,250 Headache NOS 7 7 Somnolence 3 5 Fatigue 2 4 Dizziness 3 5 Nausea 2 3 Insomnia exacerbated 2 3 Upper respiratory tract infection NOS 2 3 Diarrhea NOS 2 2 Myalgia 1 2 Depression 1 2 Dysgeusia 1 2 Arthralgia 1 2 Influenza 0 1 Blood cortisol decreased 0 1 Potential for Abuse Available evidence indicates that ROZEREM is unlikely to be abused. A clinical trial in subjects with a history of poly-drug abuse found no indication of abuse potential for subjects receiving ROZEREM, even at doses up to 20 times the recommended therapeutic dose. 12 Binding affinity of ROZEREM to receptors associated with abuse and impairment (e.g., dopamine receptors, opiate receptors) is minimal. 21 (Preclinical studies in monkeys found no signs of a reinforcing effect.) No signs of physical dependence or withdrawal symptoms have been noted in clinical studies lasting up to 5 weeks. Likewise, no signs of memory or psychomotor impairment have been noted. 12 Dosage and Administration The recommended dose of ROZEREM is 8 mg taken within 30 minutes of going to bed. After taking ROZEREM, patients should limit their activities to those required to get ready for bed and avoid potentially hazardous situations. A high-fat meal may delay the onset of effect of ROZEREM, and increase total exposure to the drug. Therefore, it is recommended that ROZEREM not be taken with or immediately after a high-fat meal. 14 ROZEREM is primarily metabolized by CYP1A2. Fluvoxamine, which is a strong CYP1A2 inhibitor, should not be used in combination with ROZEREM. Caution should be used if ROZEREM is combined with other CYP1A2 inhibitors. 14 Alcohol has not been shown to alter the pharmacokinetics of ROZEREM, but may have an additive effect on measures of alcohol performance. Because of these additive effects, patients should be cautioned not to consume alcohol when using ROZEREM. 14 <strong>Rozerem</strong> ® (ramelteon) 5
Page 1 and 2: For a brief summary of prescribing
Page 3 and 4: UNDERSTANDING INSOMNIA (ramelteon)
Page 5: the pharmacist’s guide to assessi
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Page 11 and 12: Brief Summary of Prescribing Inform

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