Drug Review Rozerem (ramelteon)

Transcription

1 Drug Review Rozerem (ramelteon) Introduction 1 Ramelteon is a melatonin receptor agonist with affinity for MT 1 and MT 2 and selectivity over the MT 3 receptor. The activity at the MT 1 and MT 2 receptors is believed to contribute to its sleep promoting properties, as these receptors are thought to be involved in the maintenance of circadian rhythm. Indication 1 Insomnia presents as difficulty falling asleep (sleep latency), difficulty maintaining sleep (frequent awakenings), or as nonrestorative sleep. Ramelteon is indicated only for the treatment of insomnia characterized by difficulty with sleep onset. Dosing 1 8mg taken within 30 minutes of going to bed. Not to be taken with a high fat meal. Pharmacokinetic Considerations 1 There is substantial intersubject variability in C max and AUC, consistent with a high first pass metabolism. The absolute bioavailability is 1.8% due to extensive first pass metabolism. The half life of ramelteon is approximately hours. Repeated dosing does not result in significant accumulation. Ramelteon is metabolized primarily through CYP1A2 and CYP3A4 and CYP2C9 to a lesser degree. It has one known active metabolite, M-II, which has a lower binding affinity for the MT 1 and MT 2 receptors. Dosage adjustments are not necessary in the following populations: Mild to moderate hepatic impairment Renal impairment Patients who require hemodialysis Adults greater than 64 years of age Warnings 1 Ramelteon should not be used by patients with severe hepatic impairment. Sleep disturbances may be a manifestation of physical or psychiatric disorder, and symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. A variety of cognitive and behavioral changes have been reported to occur in association with the use of hypnotics. In primarily depressed patients, worsening of depression, including suicidal ideation has been reported in association with the use of hypnotics. After taking ramelteon, patients should confine their activities to those necessary to prepare for bed. 1

2 Precautions 1 Ramelteon has not been studied in subjects with severe sleep apnea or severe COPD and is not recommended for use in these populations. Patients should be advised to exercise caution if they consume alcohol in combination with ramelteon. Ramelteon has been associated with an effect on reproductive hormones in adults, eg, decreased testosterone levels and increased prolactin levels. It is not known what effect chronic or chronic intermittent use of ramelteon may have on the reproductive axis in developing humans. Table 1. Drug-Drug interactions 1 Drug Effect Action Rifampin (CYP inducer) Mean decrease of ~80% in total exposure to ramelteon and its M-II metabolite Efficacy may be reduced with enzyme inducers Ketoconazole (CYP 3A4 inhibitor) AUC and Cmax of ramelteon by ~ 84% and 36% respectively. Administer with caution with 3A4 inhibitors Fluconazole (CYP 2C9 inhibitor) Ramelteon and M-II metabolite total and peak systemic exposure by ~150% when administered with fluconazole Administer with caution with 2C9 inhibitors Fluoxetine No clinically meaningful changes in peak or total ramelteon None listed (CYP 2D6) inhibitor exposure Omeprazole No clinically meaningful changes in peak or total ramelteon None listed (CYP 1A2 inducer/ 2C19 inhibitor) exposure or object drug exposure Theophylline No clinically meaningful changes in peak or total ramelteon None listed (CYP 1A2 substrate) exposure or object drug exposure Dextromethorphan No clinically meaningful changes in peak or total ramelteon None listed (CYP 2D6 substrate) exposure or object drug exposure Warfarin No clinically meaningful changes in peak or total object drug None listed (CYP 2C9/1A2 substrate) exposure Alcohol Additive effects on some measures of psychomotor Caution: do not consume Fluvoxamine CYP 1A2 inhibitor performance ramelteon AUC 190 fold; Cmax 70 fold alcohol with ramelteon Do not use in combination Pregnancy Category C Nursing mothers Pediatrics Geriatrics Abuse potential Animal teratogen when given at 197 times a human dose. Use of ramelteon in nursing mothers is not recommended. Safety and effectiveness in pediatrics has not been established. No overall differences in safety and efficacy were observed between elderly and younger patients. Data from animal and human studies suggest that ramelteon at doses up to 20 times therapeutic dose is not likely to cause abuse or physical dependence. 2

3 Treatment emergent adverse effects See Table 2. Clinical Trials Results See Table 3. Table 2 Incidence (% of subjects) of treatment emergent adverse effects (Phase 1-3 Studies) 1,2 Placebo (n=1370) Headache 7% 7% Somnolence 3% 5% Fatigue 2% 4% Dizziness 3% 5% Nausea 2% 3% Insomnia exacerbated 2% 3% Upper respiratory tract infection 2% 3% Diarrhea 2% 2% Myalgia 1% 2% Depression 1% 2% Dysguesia 1% 2% Arthralgia 1% 2% Influenza 0 1% Blood Cortisol Decreased 0 1% Ramelteon 8mg (n=1250) Clinical Considerations Ramelteon is a melatonin receptor agonist with specificity for the MT 1 and MT 2 receptors. It is the only indicated sleep promoter that is not scheduled. Study results are published mainly in abstract form making a thorough clinical analysis difficult. The only fully published trial reported results for transient insomnia in healthy adults at doses that are not commercially available. 3 Two abstracts presented data from studies in adult subjects with primary chronic insomnia. 4,5 Two other abstracts presented data from studies evaluating ramelteon in elderly patients with chronic insomnia. 6,7 Ramelteon demonstrates a flat dose response curve. No benefit was seen for doses greater than 8 mg. Compared to placebo, ramelteon has been shown to offer statistically significant differences in sleep onset and total sleep time. The actual difference from placebo for latency to persistent sleep ranged from 8 to 15 minutes, and the actual difference from placebo for total sleep time ranged from 7 to 20 minutes. Considering that the results were pooled from the study population, it is possible that ramelteon may be beneficial for certain patients, but provide little or no benefit for others. The method in which the trials were reported does not allow a clear understanding of this hypothesis. Another study, also published as an abstract, presented results of the abuse potential of ramelteon in 14 adults with a known history of sedative drug abuse. 8 Ramelteon was not associated with abuse potential or behavioral impairment at doses up to 20 times the therapeutic dose. Therefore, it may have some value in a patient population with past or current drug abuse who have insomnia. There dose not appear to be potential for withdrawal after multiple doses of ramelteon. 3

4 The AE profile of ramelteon is somewhat non-specific and comparable to placebo. Headache, somnolence, fatigue, and dizziness are the most commonly reported AE. However, ramelteon may be associated with other, subtle, adverse effects with a low incidence, but potentially serious consequences. A greater proportion of elderly trial patients who received ramelteon had reports of decreased appetite, depression and myalgia compared to the placebo group of the same age group, relative to the same comparison made for subjects <65 years of age. 2 There are also indications that ramelteon may affect certain hormone levels, although no consistent effects were seen. There is one long-term, unpublished, open-label study of 6 or 12 months duration which evaluated the incidence rates of AE. 2 Headache, somnolence, nasopharyngitis, upper respiratory tract infection and fatigue were the most commonly reported AE in this trial. There were also 2 patients with abnormal morning cortisol levels with subsequent abnormal ACTH stimulation tests; 1 patient was diagnosed with prolactinoma, and in a subgroup of elderly males, a reduction in testosterone levels was observed. 2 In summary, ramelteon may offer the benefit of sleep onset for some patients; however, it appears to have minimal actual benefit (number of minutes) for sleep related measures in pooled results, and it appears to pose subtle AE risks that may not be first recognized as drug-induced effects. 4

5 Table 3. Summary of short term clinical efficacy trials Study and treatment groups Roth Stubbs Walsh To evaluate the efficacy of ramelteon for transient insomnia in healthy adults Treatment groups 16 mg n= mg n=126 Placebo n=123 Erman Abstract 0748.L To study dose-related safety and efficacy in adult subjects with primary chronic insomnia Treatment groups N=107 4 mg 8 mg 16 mg 32 mg Placebo / Inclusion Criteria Methods Results Single administration randomized double-blind placebo-controlled, transient insomnia related to sleeping in a novel environment model Inclusion criteria Healthy volunteers (35-60 years), who reported a usual total sleep duration of hours a usual sleep latency of 30 minutes or less, and a habitual bedtime between 8:30-midnight. Patients were within 20% of ideal body weight. 2 consecutive night dosing double-blind placebo-controlled crossover 5 treatment period Inclusion criteria Insomnia complaints for >3 months PSG-defined mean latency to persistent sleep >20 minutes Mean wake time >60 minutes on 2 consecutive screenings PSG= polysomnography Subjects were stratified into 2 groups depending on usual nightly sleep duration (6.5- <7.5 hr or hr). Then subjects were randomly assigned to one of the three treatment groups. Dosing Single administration of ramelteon 16mg or 64 mg or placebo 30 minutes before bedtime Each subject was randomized into a dosing schedule that included 4, 8, 16, and 32 mg of ramelteon and placebo. Subjects underwent 5 treatment periods, with a 5 or 12 day washout period between treatments. Medication was administered 30 minutes before habitual bedtime on 2 consecutive nights. PSG monitoring was performed for 8 hours. Post sleep assessments were administered. Primary endpoint: Latency to persistent sleep 16mg 64mg plb overall p LPS (minutes) 14.1± ± ±21.9 <0.001 TST (minutes) 425.4± ± ± Secondary Endpoints Subjective sleep latency (p= Significant for 16 mg only) Subjective sleep quality (overall p= difference between groups does not appear to be clinically significant) No difference on the following secondary endpoint measures: Wake time after sleep onset Mean number of awakenings Subjective total sleep time Subjective number of awakenings Subjective ease of falling back to sleep Adverse events 16mg 64mg plb Headache 9 (7.1) 8 (6.3) 2 (1.6) Fatigue 3 (2.4) 5 (4.0) 0 Somnolence 6 (4.8) 3 (2.4) 3 (2.4) Nausea 3 (2.4) 2 (1.6) 0 Dizziness 3 (2.4) 1 (0.8) 1 (0.8) Primary endpoint not identified Results reported as least square means 4mg 8mg 16mg 32mg plb LPS (minutes) TST (minutes) SE 85.7% 86.0% 85.7% 87.1% 83.5% P< for all active treatments compared to placebo No statistically significant differences among the 5 active treatment groups for awake time after persistent sleep, subjective TST and sleep quality No statistically significant differences among active treatment groups or between ralmelteon and placebo on post-sleep assessments. Most common AE: headache (19.6%), somnolence (7.5%), pharyngolarngeal pain (7.5%) [% not separated by group] AE reported to be similar between placebo and ramelteon groups 5

6 Zammit, Roth, Erman Abstract 0680 To evaluate the efficacy of ramelteon in adult patients with chronic insomnia Treatment groups N=405 8 mg n= mg n=135 Placebo n=131 Some information retained from Dossier Roth, Seiden, Weigand et al 6 Abstract 87, no date To determine efficacy of ramelteon in elderly patients with chronic insomnia Treatment groups N=100 4 mg 8 mg Placebo [n/group not provided] Roth Seiden Zee 2005, 7 Abstract A21 To evaluate ramelteon in elderly patients with chronic insomnia Treatment groups N=829 Ramelteon 4mg n=287 8mg n=273 Placebo n= night double-blind randomized multi-center placebo-controlled Inclusion criteria Insomnia complaints for >3 months PSG-defined mean latency to persistent sleep >20 minutes Mean wake time >60 minutes on 2 consecutive screenings PSG= polysomnography 2 consecutive night dosing Three-way crossover Population Elderly patients (mean age 70.7 years; 63 women, 37 men) with chronic primary insomnia Randomized Double blind 35 days Inclusion Criteria Elderly patients ages 64-93, with chronic primary insomnia, daytime complaints associated with disturbed sleep, sleep latency 45min, <6.5 hrs/night sleep during lead in period Mean age 72.4 yr Patients took ramelteon 8 or 16 mg or placebo every night for 35 nights. Evaluation in the sleep laboratory occurred on nights 1, 15, 29 and 36. using PSG and post sleep questionnaire. Placebo was given on night 36 to evaluate rebound and withdrawal. Each subject was randomized to ramelteon 4mg, 8 mg or placebo for 2 nights with 5- to 12- day washout periods between treatments Medication was administered 30 minutes before habitual bedtime. PSG monitoring was performed overnight. Following a 7 day placebo lead-in period, patients were randomized to receive ramelteon 4 mg, 8mg, or placebo each night for 5 weeks followed by a 7 day placebo wash out period to evaluate rebound insomnia and withdrawal effects Patients completed a sleep diary and benzodiazepine withdrawal questionnaire. Primary endpoint mean LPS 8mg 16mg Placebo p (16 & 8 mg vs plb) LPS (minutes) Night p< p< p=0.003 Other efficacy variables showed some statistical difference from placebo after pos-hoc analysis and only at certain time points. No rebound insomnia or withdrawal effects were observed AE rates were reported to be similar in all groups. Primary efficacy variable: LPS- latency to persistent sleep Results reported as least square means 4mg 8mg plb p (vs 8mg) LPS (min) p=0.005 TST (min) p=0.007 SL not significant AE 14% 7% 9% No next day residual effect with ramelteon compared to placebo LPS- latency to persistent sleep TST- total sleep time SL Patient reported sleep latency Primary endpoint=patient reported sleep latency (SL)* at week 1 Results reported as least square means 4mg 8mg placebo p (vs 8mg) SL* (minutes) p=0.008 (wk 1) TST (minutes) p=0.05 (wk 1) Adverse events Rebound insomnia did not occur No withdrawal effects were observed Most AE were mild or moderate Incidence of severe or serious AEs was low with occurrence similar between treatment groups [no specific AE information provided] 6

7 LPS- latency to persistent sleep (minutes) TST- total sleep time SE sleep efficiency Reference List 1. Rozerem product information. Takeda Pharmaceutical America, Inc. August Rozerem Dossier. Takeda Pharmaceutical America, Inc. 3. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005;28(3): Erman M, Seiden D, Zammit G. Phase II study of the selective ML-1 receptor agonist TAK-375 in subjects with primary chronic insomnia. Sleep, 2003; Vol 26 (Abstract Supplement) Abstract 0748.L pa Zammit, Roth, Erman, et al. Double-blind, placebo-controlled polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with chronic insomnia. Sleep. 2005; Vol 28 (Abstract Supplement) Abstract pa Roth, Seiden, Weigand et al. Phase III study to determine the efficacy of ramelteon in elderly patients with chronic insomnia. Poster Abstract. Abstract 87, no date. 7. Roth T, Seiden P, Zee P. Phase III outpatient trial of ramelteon for the treatment of chronic insomnia in elderly patients. 2005, AGS 2005 Annual Meeting, Abstract A21. ps Griffiths R, Suess P, Johnson M. Ramelteon and triazolam in humans: behavioral effects and abuse potential. Sleep Vol 28 (Abstract Supplement) Abstract pa44. 7