Side Effects of Rozerem (ramelteon)

Rozerem (ramelteon) is a hypnotic type of sedative that promotes falling asleep used to treat insomnia. It acts by stimulating receptors for melatonin in the brain.

Melatonin and its receptors control the circadian rhythm of the body which controls the sleep/wake cycle. Unlike many drugs used for treating insomnia, Rozerem is not addictive, and it is not a controlled substance. Rozerem also does not cause withdrawal symptoms or rebound insomnia when it is stopped. 

Common side effects of Rozerem include

• headache,
• drowsiness,
• fatigue,
• dizziness,
• nausea,
• worsening of insomnia, and
• diarrhea.

Serious side effects of Rozerem include

• abnormal thinking,
• behavior changes,
• depression,
• suicidal thoughts,
• manic episodes,
• sleep-driving, and
• rare severe allergic reactions involving swelling of the tongue and closure of the throat.

Drug interactions of Rozerem include doxepin, donepezil, fluvoxamine, ketoconazole, and fluconazole, which increase blood levels of Rozerem, possibly increasing side effects of Rozerem.

Rifampin may decrease blood levels of Rozerem, possibly reducing the effect of Rozerem.

Alcohol increases the sedative effects Rozerem.

Rozerem has not been evaluated in pregnant women. Rozerem should not be used in pregnant women unless it is absolutely necessary. Rozerem has not been evaluated in nursing mothers. Consult your doctor before breastfeeding.

Side effects associated with ramelteon include:

• headache,
• drowsiness,
• fatigue,
• dizziness,
• nausea,
• worsening of insomnia, and
• diarrhea.

Rare cases of severe allergic reactions involving swelling of the tongue and closure of the throat have been reported.

Other important side effects include:

• Abnormal thinking,
• behavior changes,
• depression,
• suicidal thoughts,
• manic episodes, and
• sleep driving.

The following serious adverse reactions are discussed in greater detail in other sections:

• Severe anaphylactic and anaphylactoid reactions
• Abnormal thinking, behavior changes, and complex behaviors
• CNS effects

Clinical Trials Experience

Adverse Reactions Resulting In Discontinuation Of Treatment

The data described in this section reflect exposure to Rozerem in 5373 subjects, including 722 exposed for six months or longer, and 448 subjects for one year.

Six percent of the 5373 individual subjects exposed to Rozerem in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo.

The most frequent adverse events leading to discontinuation in subjects receiving Rozerem were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less.

Rozerem Most Commonly Observed Adverse Events

Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of Rozerem.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice.

The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Table 1. Incidence (% of subjects) of Treatment-Emergent Adverse Events

Effects Of Other Drugs On Rozerem

Fluvoxamine (Strong CYP1A2 Inhibitor)

AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70- fold upon coadministration of fluvoxamine and Rozerem, compared to Rozerem administered alone. Rozerem should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. Rozerem should be administered with caution to patients taking less strong CYP1A2 inhibitors.

Rifampin (Strong CYP Enzyme Inducer)

Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total exposure to ramelteon and metabolite M-II. Efficacy may be reduced when Rozerem is used in combination with strong CYP enzyme inducers such as rifampin.

Ketoconazole (Strong CYP3A4 Inhibitor)

The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with Rozerem. Rozerem should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole.

Fluconazole (Strong CYP2C9 Inhibitor)

The AUC0-inf and Cmax of ramelteon was increased by approximately 150% when Rozerem was coadministered with fluconazole. Rozerem should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole.

Donepezil

The AUC0-inf and Cmax of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with Rozerem. Patients should be closely monitored when Rozerem is coadministered with donepezil.

Doxepin

The AUC0-inf and Cmax of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with Rozerem. Patients should be closely monitored when Rozerem is coadministered with doxepin.

Effect Of Alcohol On Rozerem

Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of Rozerem is to promote sleep, patients should be cautioned not to consume alcohol when using Rozerem. Use of the products in combination may have an additive effect.

Drug/Laboratory Test Interactions

Rozerem is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro.

Drug Abuse And Dependence

Rozerem is not a controlled substance.

Discontinuation of ramelteon in animals or in humans after chronic administration did not produce withdrawal signs. Ramelteon does not appear to produce physical dependence.

Human Data

A laboratory abuse potential study was performed with Rozerem.

Animal Data

Ramelteon did not produce any signals from animal behavioral studies indicating that the drug produces rewarding effects. Monkeys did not self-administer ramelteon and the drug did not induce a conditioned place preference in rats.

There was no generalization between ramelteon and midazolam. Ramelteon did not affect rotorod performance, an indicator of disruption of motor function, and it did not potentiate the ability of diazepam to interfere with rotorod performance.