1) ADVERSE EFFECTS: COMMON: Somnolence, fatigue, dizziness, nausea and headache have been the most frequently reported events with therapeutic administration. A worsening of insomnia and depression may occur with ramelteon. Some individuals have experienced "sleep driving" (driving while not being fully awake), or other behaviors (eg, preparing and eating food, making phone calls with no memory, or hallucinations. Severe anaphylaxis has been reported after receiving a first dose; patients should not be rechallenged.

1) OVERDOSE: Limited data. Doses up to 400 mg have resulted in mild to moderate effects in adults.
2) MILD TO MODERATE TOXICITY: Events would be anticipated to be an extension of adverse events and include: somnolence, fatigue, dizziness and nausea.
3) SEVERE TOXICITY: Potential adverse events may include drowsiness/lethargy and possibly significant CNS depression, worsening of depression, hallucinations and potential for injury.

1) Treatment is symptomatic and supportive. Significant toxicity is not anticipated; drowsiness is likely to occur.

1) Treatment is symptomatic and supportive. Drowsiness/lethargy is likely to occur; significant CNS depression may develop, especially if coingested with other agents. Monitor mental status; assess airway. Rare reports of cognitive disturbances have developed in some patients with therapy.

1) PREHOSPITAL: Significant toxicity is not expected following overdose. Gastrointestinal decontamination is not routinely indicated.
2) HOSPITAL: Significant toxicity is not expected following overdose. Gastrointestinal decontamination is not routinely indicated. Activated charcoal may be indicated following a recent very large ingestion or if coingestions are suspected, if the patient is awake and alert and can protect the airway.

1) Airway management is unlikely to be necessary unless coingestants are involved.

1) None.

1) Hemodialysis is not effective in reducing exposure to ramelteon, given its high protein binding of 82%.

1) HOME CRITERIA: A minor inadvertent exposure in an asymptomatic child (a single dose) or an extra dose in an adult can likely be monitored at home. In the case of a child, adequate supervision is necessary.
2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion or coingestion of other agents should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with more than a minor ingestion should be observed for possible symptoms.
3) ADMISSION CRITERIA: Any patient who develops significant persistent CNS depression or behavioral changes should be admitted for observation.
4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in cases of severe poisonings or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.

1) Ramelteon is absorbed rapidly from the GI tract following oral administration. The total absorption of ramelteon is at least 84%; however, the oral bioavailability is only 1.8% due to extensive first-pass metabolism. Protein binding of ramelteon is approximately 82%, with the majority of drug bound to albumin (70%). Mean volume of distribution following IV administration is 73.6 L. M-II is the only active metabolite. The elimination half-life of the parent compound is approximately 1 to 2.6 hours; elimination half-life of M-II is 2 to 5 hours and is independent of dose.

1) Coadministration with other agents (eg, alcohol, benzodiazepines) that may potentiate the effects; the potential for abuse of sedative agents.

1) RATS: Administration of ramelteon to pregnant rats at doses of 150 mg/kg/day or greater resulted in fetal teratogenicity including visceral malformations consisting of diaphragmatic hernia and anatomical variations of the skeleton (irregularly-shaped scapula). Reductions in fetal body weights and cysts on the external genitalia were observed following maternal administration of 600 mg/kg/day. The no-effect level (NOEL) of teratogenicity in this study was 40 mg/kg/day (1,892-times and 45-times higher than therapeutic exposure to ramelteon and its active metabolite M-II, respectively, at the maximum recommended human dose based on the AUC) (Prod Info ROZEREM(TM) TABLETS, 2005).
2) RATS: Behavioral changes, developmental delay, and growth retardation were observed when pregnant rats were administered ramelteon doses of at least 100 mg/kg/day orally throughout gestation and lactation, and increased incidences of malformation were observed at doses of 300 mg/kg/day. Increased incidences of fetal structural abnormalities (including malformations and variations) were observed when pregnant rats were administered ramelteon doses of at least 150 mg/kg/day orally during the period of organogenesis (Prod Info ROZEREM oral tablets, 2010).
3) RABBITS: Oral administration of ramelteon to pregnant rabbits at doses of 0, 12, 60, or 300 mg/kg/day during gestation days 6 to 18 did not show any evidence of fetal abnormalities; therefore, the NOEL in this study was 300 mg/kg/day (11,862-times and 99-times higher than the therapeutic exposure to ramelteon and M-II, respectively, at the maximum recommended human dose based on the AUC) (Prod Info ROZEREM(TM) TABLETS, 2005).
4) RABBITS: No embryo-fetal toxicity was observed when pregnant rabbits were administered ramelteon doses of up to 300 mg/kg/day orally (up to 720 times the recommended human dose on a mg/m(2) basis) during the period of organogenesis (Prod Info ROZEREM oral tablets, 2010).

1) The manufacturer has classified ramelteon as FDA pregnancy category C (Prod Info ROZEREM oral tablets, 2010).
2) There are no adequate or well-controlled studies in pregnant women. The manufacturer recommends that ramelteon should be administered during pregnancy only if its potential benefit outweighs the potential risk to the fetus (Prod Info ROZEREM oral tablets, 2010).

1) RATS: An increased incidence of death among offspring were observed when pregnant rats were administered ramelteon doses of 300 mg/kg/day orally throughout gestation and lactation (Prod Info ROZEREM oral tablets, 2010).

1) It is unknown whether ramelteon is excreted in human milk, but it is present in the milk of lactating rats. The manufacturer recommends that caution should be exercised when ramelteon is used in nursing women (Prod Info ROZEREM oral tablets, 2010).

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) MICE - During a two-year carcinogenicity study, mice were orally administered ramelteon at doses of 0, 30, 100, 300, or 1000 mg/kg/day. An increased incidence of hepatic adenomas, hepatic carcinomas, and hepatoblastoma occurred at doses of 100 mg/kg/day or greater. An increased incidence of hepatic adenomas and hepatic carcinomas occurred in female mice at doses of 300 mg/kg/day or greater and at the 1000 mg/kg/day dose level, respectively. The no-effect level (NOEL) for hepatic tumors in male mice was 30 mg/kg/day (103-times and 3-times the therapeutic exposure of ramelteon and M-II, respectively, at the maximum recommended human dose based on the AUC). The NOEL 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 maximum recommended human dose based on the AUC) (Prod Info ROZEREM(TM) TABLETS, 2005).
2) RATS - During a two-year carcinogenicity study, rats were orally administered ramelteon at doses of 0, 15, 60, 250, or 1000 mg/kg/day. An increased incidence of hepatic adenomas and benign Leydig cell tumors of the testis occurred in male rats at doses of 250 mg/kg/day or greater, and an increased incidence of hepatic carcinoma occurred at the 1000 mg/kg/day dose level. In female rats, an increased incidence of hepatic adenomas and hepatic carcinoma occurred at a dose level of 60 mg/kg/day or greater and at the 1000 mg/kg/day dose level, respectively. In male rats, the NOEL for hepatic tumors and benign Leydig cell tumors was 60 mg/kg/day (1,429-times and 12-times the therapeutic exposure to ramelteon and M-II, respectively, at the maximum recommended human dose based on the AUC). In female rats, the NOEL for hepatic tumors was 15 mg/kg/day (472-times and 16-times the therapeutic exposure to ramelteon and M-II, respectively, at the maximum recommended human dose based on the AUC) (Prod Info ROZEREM(TM) TABLETS, 2005).

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

A) Any patient who develops significant persistent CNS depression or behavioral changes should be admitted for observation.

A) A minor inadvertent exposure in an asymptomatic child (a single dose) or an extra dose in an adult can likely be monitored at home. In the case of a child, adequate supervision is necessary.

A) Contact a medical toxicologist or Poison Center for assistance in cases of severe poisonings or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.

A) Patients with a deliberate self-harm ingestion or coingestion of other agents should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with more than a minor ingestion should be observed for possible symptoms.

1) In cases of ramelteon overdose, treatment is symptomatic and supportive.

1) Ramelteon serum levels are not widely available or clinically useful in managing overdose.
2) No routine laboratory tests are needed after overdose unless otherwise clinically indicated.
3) Monitor vital signs and mental status in symptomatic patients.