Rozerem


Rozerem
SUMMARY:

What Is Rozerem?

Rozerem is a prescription medicine for adults to treat insomnia where the problem is trouble falling asleep.

Rozerem has not been studied in children.  It is not known if Rozerem is safe and effective for children.

Who Should Not Take Rozerem?

You should not take Rozerem if you have any of the following conditions:

What Are The Risks?

The following are the major potential risks and side effects of Rozerem therapy. However, this list is not complete. The following are the major potential risks and side effects of Rozerem therapy:

What Should I Tell My Healthcare Professional?

Before you start taking Rozerem, tell your healthcare professional if you: 

Can Other Medicines or Food Affect Rozerem?

Rozerem and certain other medicines can interact with each other.  Tell your healthcare professional about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.  Some medicines may affect how Rozerem works or Rozerem may affect how your other medicines work. Know the medicines you take. Keep a list of them with you to show your healthcare professional.

Especially, tell your healthcare professional if you take:

Tell your healthcare provider if you drink alcohol.  Alcohol may increase the side effects with Rozerem.

How Should I Take Rozerem?




Effects of Other Drugs on ROZEREM Metabolism Fluvoxamine (strong CYP1A2 inhibitor): When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose co-administration of ROZEREM 16 mg and fluvoxamine, the AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ROZEREM administered alone. ROZEREM should not be used in combination with fluvoxamine (See WARNINGS). Other less potent 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 rifampin 600 mg once daily for 11 days resulted in a mean decrease of approximately 80% (40% to 90%) in total exposure to ramelteon and metabolite M-II, (both AUC0-inf and Cmax) after a single 32 mg dose of ROZEREM. 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%, respectively, when a single 16 mg dose of ROZEREM was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of ROZEREM alone. Similar increases were seen in M-II pharmacokinetic variables. ROZEREM should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole. Fluconazole (strong CYP2C9 inhibitor): The total and peak systemic exposure (AUC0-inf and Cmax) of ramelteon after a single 16 mg dose of ROZEREM was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in M-II exposure. ROZEREM should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. Interaction studies of concomitant administration of ROZEREM with fluoxetine (CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline (CYP1A2 substrate), and dextromethorphan (CYP2D6 substrate) did not produce clinically meaningful changes in either peak or total exposures to ramelteon or the M-II metabolite. Effects of ROZEREM on Metabolism of Other Drugs Concomitant administration of ROZEREM with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), and warfarin (CYP2C9 [S]/CYP1A2 [R] substrate) did not produce clinically meaningful changes in peak and total exposures to these drugs. Effect of Alcohol on Rozerem Alcohol: With single-dose, daytime co-administration of ROZEREM 32 mg and alcohol (0.6 g/kg), there were no clinically meaningful or statistically significant effects on peak or total exposure to ROZEREM. However, an additive effect was seen on some measures of psychomotor performance (i.e., the Digit Symbol Substitution Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of sedation) at some post-dose time points. No additive effect was seen on the Delayed Word Recognition Test. Because alcohol by itself impairs performance, and the intended effect of ROZEREM is to promote sleep, patients should be cautioned not to consume alcohol when using ROZEREM. 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 falsepositive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro. Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a two-year carcinogenicity study, B6C3F1 mice were administered ramelteon at doses of 0, 30, 100, 300, or 1000 mg/kg/day by oral gavage. Male mice exhibited a dose-related increase in the incidence of hepatic tumors at dose levels =100 mg/kg/day including hepatic adenoma, hepatic carcinoma, and hepatoblastoma. Female mice developed a dose-related increase in the incidence of hepatic adenomas at dose levels = 300 mg/kg/day and hepatic carcinoma at the 1000 mg/kg/day dose level. The no-effect level for hepatic tumors in male mice was 30 mg/kg/day (103-times and 3-times the therapeutic exposure to ramelteon and the active metabolite M-II, respectively, at the maximum recommended human dose [MRHD] based on an area-under-the-curve [AUC] comparison). The no-effect level for hepatic tumors in female mice was 100 mg/kg/day (827-times and 12-times the therapeutic exposure to ramelteon and M-II, respectively, at the MRHD based on AUC). In a two-year carcinogenicity study conducted in the Sprague-Dawley rat, male and female rats were administered ramelteon at doses of 0, 15, 60, 250 or 1000 mg/kg/day by oral gavage. Male rats exhibited a dose-related increase in the incidence of hepatic adenoma and benign Leydig cell tumors of the testis at dose levels = 250 mg/kg/day and hepatic carcinoma at the 1000 mg/kg/day dose level. Female rats exhibited a dose-related increase in the incidence of hepatic adenoma at dose levels = 60 mg/kg/day and hepatic carcinoma at the 1000 mg/kg/day dose level. The no-effect level for hepatic tumors and benign Leydig cell tumors in male rats was 60 mg/kg/day (1,429-times and 12-times the therapeutic exposure to ramelteon and M-II, respectively, at the MRHD based on AUC). The noeffect level for hepatic tumors in female rats was 15 mg/kg/day (472-times and 16-times the therapeutic exposure to ramelteon and M-II, respectively, at the MRHD based on AUC). The development of hepatic tumors in rodents following chronic treatment with non-genotoxic compounds may be secondary to microsomal enzyme induction, a mechanism for tumor generation not thought to occur in humans. Leydig cell tumor development following treatment with non-genotoxic compounds in rodents has been linked to reductions in circulating testosterone levels with compensatory increases in luteinizing hormone release, which is a known proliferative stimulus to Leydig cells in the rat testis. Rat Leydig cells are more sensitive to the stimulatory effects of luteinizing hormone than human Leydig cells. In mechanistic studies conducted in the rat, daily ramelteon administration at 250 and 1000 mg/kg/day for 4 weeks was associated with a reduction in plasma testosterone levels. In the same study, luteinizing hormone levels were elevated over a 24 hour period after the last ramelteon treatment; however, the durability of this luteinizing hormone finding and its support for the proposed mechanistic explanation was not clearly established. Although the rodent tumors observed following ramelteon treatment occurred at plasma levels of ramelteon and M-II in excess of mean clinical plasma concentrations at the MRHD, the relevance of both rodent hepatic tumors and benign rat Leydig cell tumors to humans is not known. Mutagenesis Ramelteon was not genotoxic in the following: in vitro bacterial reverse mutation (Ames) assay; in vitro mammalian cell gene mutation assay using 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 in Phase 1-3 Studies Ramelteon MedDRA Placebo 8 mg Preferred Term (n=1370) (n=1250) Headache NOS 7% 7% Somnolence 3% 5% Fatigue 2% 4% Dizziness 3% 5% Nausea 2% 3% Insomnia 2% 3% exacerbated Upper respiratory 2% 3% tract infection NOS Diarrhea NOS 2% 2% Myalgia 1% 2% Depression 1% 2% Dysgeusia 1% 2% Arthralgia 1% 2% Influenza 0 1% Blood Cortisol Decreased 0 1% DRUG ABUSE AND DEPENDENCE ROZEREM is not a controlled substance. Human Data. See the CLINICAL TRIALS section, Studies Pertinent to Safety Concerns for Sleep-Promoting Agents, for the results of human laboratory abuse potential trials 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. Discontinuation of ramelteon in animals or in humans after chronic administration did not produce withdrawal signs. Ramelteon does not appear to produce physical dependence. OVERDOSAGE Signs and Symptoms No cases of ROZEREM overdose have been reported during clinical development. ROZEREM was administered in single doses up to 160 mg in an abuse liability trial. No safety or tolerability concerns were seen. Recommended Treatment General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed. Hemodialysis does not effectively reduce exposure to ROZEREM. Therefore, the use of dialysis in the treatment of overdosage is not appropriate. Poison Control Center As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may contact a poison control center for current information on the management of overdosage. DOSAGE AND ADMINISTRATION The recommended dose of ROZEREM is 8 mg taken within 30 minutes of going to bed. It is recommended that ROZEREM not be taken with or immediately after a high fat meal. ROZEREM should not be used in subjects with severe hepatic impairment. ROZEREM should be used with caution in patients with moderate hepatic impairment. ROZEREM should not be used in combination with fluvoxamine. ROZEREM should be used with caution in patients taking other CYP1A2 inhibiting drugs (see PRECAUTIONS: Drug Interactions). HOW SUPPLIED ROZEREM is available as round, pale orange-yellow, film-coated, 8 mg tablets, with “TAK” and “RAM-8” printed on one side, in the following quantities: NDC 64764-805-30 Bottles of 30 NDC 64764-805-10 Bottles of 100 NDC 64764-805-50 Bottles of 500 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Keep container tightly closed and protected from moisture and humidity. Rx only.
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