Ramelteon (Rozerem): ADVERSE DRUG EFFECTS

2 Mar
2010

The adverse drug events (ADEs) associated with ramelteon appear to be minor and similar to those of placebo. Of the 3,594 subjects evaluated in the phase 1 to phase 3 studies of ramelteon, the most frequent ADEs leading to discontinuation were somnolence (0.8%), dizziness (0.5%), nausea (0.3%), fatigue (0.3%), headache (0.3%), and insomnia (0.3%). Of those patients receiving ramelteon 8 mg in studies, only 3.8% discontinued therapy because of ADEs.

No significant changes in laboratory values, electrocardiograms (ECG), or blood and urine analyses have been reported in clinical trials. The drug has been associated with effects on the reproductive system in adults. Patients experiencing unexplained amenorrhea, galact-orrhea, decreased libido, or problems with fertility should be assessed for alterations in testosterone levels or increased prolactin.

ABUSE POTENTIAL

When compared with triazolam (Hal-cion) and placebo in a small sample of 14 subjects who were evaluated for abuse liability, ramelteon demonstrated no abuse potential. No evidence of abuse was demonstrated even at doses up to 20 times the usual treatment dose. These results were vastly different from the abuse potential demonstrated by triazo-lam at treatment doses and doses up to three times higher than usual. canadian cialis online

DRUG INTERACTIONS

The cytochrome CYP 1A2 isoenzyme is the major enzyme involved in the metabolism of ramelteon. The use of ramelteon is contraindicated with fluvox-amine (Luvox), which is a strong inhibitor of the CYP 1A2 isoenzyme. Ramel-teon should be administered with caution to patients taking other CYP 1A2 inhibitors. The CYP 2C9 and CYP 3A4 iso-enzymes are also involved with the drug’s metabolism to a minor degree. Health care providers should use caution when prescribing ramelteon in conjunction with strong inhibitors of these isoenzymes as well.

CLINICAL EFFICACY

Studies in animals have consistently shown that ramelteon has a sleep-promoting action; it does not appear to cause learning, memory, or motor function impairment or to provide “reward” properties. Thus far, ramelteon does not tend to be associated with benzo-diazepine-like abuse or dependence in long-term studies lasting over one year of administration in human and animal models. Erman et al.

Erman and colleagues conducted a multicenter, double-blind, randomized, placebo-controlled crossover study to evaluate the dose-related efficacy, safety, and dose response of ramelteon. They enrolled 107 patients, 18 to 64 years of age, with chronic primary insomnia, according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).

Patients had presented with insomnia complaints for at least three months, as confirmed with a polysomnograph. The inclusion criteria consisted of a mean latency to persistent sleep of more than 20 minutes, and mean wake-up time of more than 60 minutes in a sleep laboratory on two consecutive nights. Latency can be defined as the amount of time it takes for an awake person to fall asleep.

Each patient was randomly assigned to a dosing sequence that included 4, 8, 16, and 32 mg of ramelteon and placebo. Patients served as their own controls and received all five treatments with washout periods of five to 12 days between treatments.

The medication was administered 30 minutes before the patient’s habitual bedtime, followed by eight hours of poly-somnographic monitoring.

To determine the patients’ alertness and ability to concentrate, the investigators assessed residual effects using next day Visual Analogue Scale (VAS) scores to measure mood and feeling as well as a post-sleep questionnaire. They also measured a Digit Symbol Substitution Test (DSST) and a word list memory test involving immediate and delayed recall. In the DSST, the patient is given a key and must fill in a symbol corresponding to a number within 90 or 120 seconds. The score is the number of correctly completed symbols.

Polysomnographic assessment demonstrated statistically significant reductions in latency to persistent sleep and increases in total sleep time for all tested doses of ramelteon, compared with placebo (P < 0.001). Total sleep time and sleep efficiency improved with each increase in ramelteon dosage in comparison with placebo:

•  With the 8-mg group of patients, the reduced latency to persistent sleep was 24.3 minutes; with placebo, it was 37.7 minutes (P< 0.001).

•  With the 8-mg group, the total sleep time was 412.9 minutes; with placebo, it was 400.2 minutes (P < 0.01). buy cialis soft tabs

The researchers observed a decrease of approximately 1.3% to 2.1% in slow-wave sleep (stages 3 and 4 of the sleep cycle) in the treated patients. Patients receiving placebo did not demonstrate any changes in sleep stages. No differences were apparent in the ramelteon or placebo groups among the dosage sequences administered in awake time after the onset of persistent sleep, subjective total sleep time, quality of sleep, VAS scores, DSST scores, memory test scores, or in post-sleep levels of alertness or concentration.

There were no next-day residual effects or differences in the number or type of ADEs seen at any dose, compared with placebo. The most commonly reported ADEs were mild and included headache, somnolence, and sore throat.

Overall, the drug was well tolerated and demonstrated statistically significant reductions in latency to persistent sleep and increases in total sleep time in patients with chronic primary insomnia.

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