Melatonin Receptor Agonist

Rozerem

Approved 22 Jul 2005OralTablet

Indications

ROZEREM ® is indicated for the treatment of insomnia characterized by difficulty with sleep onset. The clinical trials performed in support of efficacy were up to six months in duration. The final formal assessments of sleep latency were performed after two days of treatment during the crossover study (elderly only), at five weeks in the six week studies (adults and elderly), and at the end of the six month study (adults and elderly) [see Clinical Studies (14) ] .

ROZEREM is indicated for the treatment of insomnia characterized by difficulty with sleep onset. ( 1 )

Contraindications

Patients who develop angioedema after treatment with ROZEREM should not be rechallenged with the drug. Patients should not take ROZEREM in conjunction with fluvoxamine [see Drug Interactions (7) ] . History of angioedema while taking ROZEREM. ( 4 ) Fluvoxamine (strong CYP1A2 inhibitor): Increases AUC for ramelteon and should not be used in combination. ( 7.1 )

Warnings and precautions

Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ( 5.1 ) Need to evaluate for comorbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment. ( 5.2 ) Abnormal thinking, behavioral changes, complex behaviors: May include "sleep-driving" and hallucinations. Immediately evaluate any new onset behavioral changes. ( 5.3 ) Depression: Worsening of depression or suicidal thinking may occur.

( 5.3 ) CNS effects: Potential impairment of activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, after ingesting the drug. ( 5.4 ) Reproductive effects: Include decreased testosterone and increased prolactin levels. Effect on reproductive axis in developing humans is unknown. ( 5.5 ) Patients with severe sleep apnea: ROZEREM is not recommended for use in this population.

( 5.6 )

5.1Severe Anaphylactic and Anaphylactoid Reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of ROZEREM. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.

At a glance

Brand name: Rozerem
Active substance: ramelteon
Pharmacologic class: Melatonin Receptor Agonist
Route: Oral
Dosage form: Tablet
Applicant: Takeda Pharms USA
Status: Prescription
FDA approval: 22 Jul 2005
Application: NDA021782-001

Indications

ROZEREM is indicated for the treatment of insomnia characterized by difficulty with sleep onset. ( 1 )

Contraindications

Warnings and precautions

( 5.6 )

5.1Severe Anaphylactic and Anaphylactoid Reactions

Interactions

Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon. ( 7.1 ) Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. ( 7.1 ) Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. ( 7.1 ) Donepezil: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with donepezil.

( 7.1 ) Doxepin: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with doxepin. ( 7.1 ) Alcohol: Causes additive psychomotor impairment; should not be used in combination. ( 7.2 )

7.1Effects of Other Drugs on

ROZEREM Fluvoxamine (strong CYP1A2 inhibitor) AUC 0-inf for ramelteon increased approximately 190-fold, and the C max increased approximately 70-fold upon coadministration of fluvoxamine and ROZEREM, compared to ROZEREM administered alone. ROZEREM should not be used in combination with fluvoxamine [see Contraindications (4) , Clinical Pharmacology (12.5) ] . 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 [see Clinical Pharmacology (12.5) ] .

Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max 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 [see Clinical Pharmacology (12.5) ] . Fluconazole (strong CYP2C9 inhibitor) The AUC 0-inf and C max 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 [see Clinical Pharmacology (12.5) ] . Donepezil The AUC 0-inf and C max 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 [see Clinical Pharmacology (12.5) ] . Doxepin The AUC 0-inf and C max 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 [see Clinical Pharmacology (12.5) ] .

7.2Effect 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 [see Clinical Pharmacology (12.5) ] . Use of the products in combination may have an additive effect.

7.3Drug/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 .

Adverse reactions

The following serious adverse reactions are discussed in greater detail in other sections: Severe anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.1) ] Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3) ] CNS effects [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥3% and more common than with placebo) are: somnolence, dizziness, fatigue, nausea, and exacerbated insomnia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 MedDRA Preferred Term Placebo (n=1456) Ramelteon 8 mg (n=1405) Somnolence 2% 3% Fatigue 2% 3% Dizziness 3% 4% Nausea 2% 3% Insomnia exacerbated 2% 3%

Rozerem

Indications

Contraindications

Warnings and precautions

5.1Severe Anaphylactic and Anaphylactoid Reactions

At a glance

Two medicines in one question?

Rozerem

Indications

Contraindications

Warnings and precautions

5.1Severe Anaphylactic and Anaphylactoid Reactions

At a glance

Two medicines in one question?

5.2Need to Evaluate for Comorbid Diagnoses

5.3Abnormal Thinking and Behavioral Changes

5.4CNS Effects

5.5Reproductive Effects

5.6Use in Patients with Concomitant Illness

5.7Laboratory Tests Monitoring

Interactions

7.1Effects of Other Drugs on

7.2Effect of Alcohol on

7.3Drug/Laboratory Test Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment

Composition

Official product information