Ramelteon reduces latency to persistent sleep.


Company: Takeda

Pharmacologic class: Hypnotic (melatonin agonist)

Active ingredient: Ramelteon 8 mg; tabs.

Indication: Insomnia with difficulty in sleep onset.

Pharmacology: Melatonin is an endogenous hormone that is involved in the maintenance of circadian rhythm. The melatonin receptors MT1 and MT2 have been identified as playing a role in sleep patterns. Ramelteon is a melatonin receptor agonist with high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. It is theorized that the activity of ramelteon at the MT1 and MT2 receptors contributes to its sleep-promoting properties.

Clinical trials: The efficacy of ramelteon in treating chronic insomnia was evaluated in two randomized double-blind trials. In the first study, patients 18-64 years of age were given one nightly dose of ramelteon 8 mg, 16 mg, or placebo for 35 days. Polysomnography (PSG) was done on the first two nights in each of weeks 1, 3, and 5. Both doses of ramelteon reduced the average latency to persistent sleep at each of the time points vs. placebo.

In the second study, patients >65 years old were given ramelteon 4 mg, 8 mg, or placebo and had PSG assessment in a sleep lab for two consecutive nights in each of the three study periods. Both ramelteon doses reduced the latency to persistent sleep compared to placebo.

In a study conducted in outpatients >65 years old with chronic insomnia, sleep diaries were used to evaluate the efficacy of ramelteon. Subjects were given ramelteon 4 mg, 8 mg, or placebo for 35 nights. Both doses of ramelteon reduced patient-reported sleep latency vs. placebo. A similar study in patients 18-64 years of age who were given ramelteon 8 mg or 16 mg did not replicate this finding.

In a randomized, double-blind, parallel-group trial using a first-night-effect model, subjects received either placebo or ramelteon 8 mg or 16 mg before spending one night in a sleep lab and being evaluated with PSG. The 8-mg dose resulted in a decrease in mean latency to persistent sleep as compared to placebo.

Studies indicated that there was no evidence of next-day residual effect (after two nights of dosing) or rebound insomnia.

Adults: Take 8 mg within 30 min of bedtime. Do not take with high-fat/heavy meals (delays effect).

Children: Not recommended.

Contraindications: Severe hepatic impairment. Concomitant fluvoxamine.

Precautions: Severe chronic obstructive pulmonary disease, severe obstructive sleep apnea: not recommended. Moderate hepatic impairment. Depression. Suicidal ideation. Behavioral abnormalities. Monitor prolactin and testosterone levels if unexplained amenorrhea, galactorrhea, decreased libido, or fertility problems occur. Labor & delivery. Pregnancy (Cat. C). Nursing mothers: not recommended.

Interactions: See Contraindications. Avoid alcohol. Potentiated by potent inhibitors of CYP1A2, CYP3A4 (e.g., ketoconazole), CYP2C9 (e.g., fluconazole). Antagonized by potent CYP450 inducers (e.g., rifampin).

Adverse reactions: Somnolence, dizziness, fatigue; reduced testosterone or cortisol levels, increased prolactin levels (monitor if occurs); others (see literature).

How supplied: Tabs — 30, 100, 500