12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ROZEREM (ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors.

The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle.

Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.

All other known metabolites of ramelteon are inactive.

12.3 Pharmacokinetics

The pharmacokinetic profile of ROZEREM has been evaluated in healthy subjects as well as in subjects with hepatic or renal impairment. When administered orally to humans in doses ranging from 4 to 64 mg, ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear pharmacokinetics. Maximal serum concentration (Cmax) and area under the concentration-time curve (AUC) data show substantial intersubject variability, consistent with the high first-pass effect; the coefficient of variation for these values is approximately 100%. Several metabolites have been identified in human serum and urine.

Absorption

Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism.

Distribution

In vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells.

Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution.

Metabolism

Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.

The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug.

Elimination

Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound. Elimination was essentially complete by 96 hours post-dose.

Repeated once daily dosing with ROZEREM does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1- 2.6 hours).

The half-life of M-II is 2 to 5 hours and independent of dose. Serum concentrations of the parent drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours.

Effect of Food

When administered with a high-fat meal, the AUC0-inf for a single 16 mg dose of ROZEREM was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median Tmax was delayed by approximately 45 minutes when ROZEREM was administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that ROZEREM not be taken with or immediately after a high-fat meal [see Dosage and Administration (2.1)].

12.4****Pharmacokinetics in Special Populations

Age: In a group of 24 elderly subjects aged 63 to 79 years administered a single ROZEREM 16 mg dose, the mean Cmax and AUC0-inf values were 11.6 ng/mL (SD, 13.8) and 18.7 ng·hr/mL (SD, 19.4), respectively. The elimination half- life was 2.6 hours (SD, 1.1). Compared with younger adults, the total exposure (AUC0-inf) and Cmax of ramelteon were 97% and 86% higher, respectively, in elderly subjects. The AUC0-inf and Cmax of M-II were increased by 30% and 13%, respectively, in elderly subjects.

Gender: There are no clinically meaningful gender-related differences in the pharmacokinetics of ROZEREM or its metabolites.

Hepatic Impairment: Exposure to ROZEREM was increased almost 4-fold in subjects with mild hepatic impairment after 7 days of dosing with 16 mg/day; exposure was further increased (more than 10-fold) in subjects with moderate hepatic impairment. Exposure to M-II was only marginally increased in mildly and moderately impaired subjects relative to healthy matched controls. The pharmacokinetics of ROZEREM have not been evaluated in subjects with severe hepatic impairment (Child-Pugh Class C). ROZEREM should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6)].

Renal Impairment: The pharmacokinetic characteristics of ROZEREM were studied after administering a 16 mg dose to subjects with mild, moderate, or severe renal impairment based on pre-dose creatinine clearance (53 to 95, 35 to 49, or 15 to 30 mL/min/1.73 m2, respectively), and in subjects who required chronic hemodialysis. Wide intersubject variability was seen in ROZEREM exposure parameters. However, no effects on Cmax or AUC0-t of parent drug or M-II were seen in any of the treatment groups; the incidence of adverse events was similar across groups. These results are consistent with the negligible renal clearance of ramelteon, which is principally eliminated via hepatic metabolism. No adjustment of ROZEREM dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min/1.73 m2) and patients who require chronic hemodialysis.

12.5Drug-Drug** I****nteractions**

ROZEREM has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in Cmax and AUC). As noted above, CYP1A2 is the major isozyme involved in the metabolism of ROZEREM; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.

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. Other less strong CYP1A2 inhibitors have not been adequately studied. ROZEREM should be administered with caution to patients taking less strong CYP1A2 inhibitors [see Contraindications].

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

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.

MEDICATION GUIDE

ROZEREM®** (**rō-Zair-em)

(ramelteon)

Read the Medication Guide that comes with ROZEREM before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about ROZEREM?

ROZEREM may cause severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking ROZEREM.

After taking ROZEREM, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with ROZEREM. Activities may include:

• driving a car ("sleep-driving")

• making and eating food

• talking on the phone

• having sex

• sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking ROZEREM.

Important:

1. Take ROZEREM exactly as prescribed

• Do not take more ROZEREM than prescribed.

• Take ROZEREM within 30 minutes of going to bed, not sooner.

2. Do not take ROZEREM if you:

• drink alcohol

• take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take ROZEREM with your other medicines.

• cannot get a full night’s sleep

WHAT IS ROZEREM?

ROZEREM is a hypnotic (sleep) medicine. ROZEREM is used in adults for the treatment of the symptom of trouble falling asleep from insomnia.

ROZEREM is not for children.

Who should not take ROZEREM?

Do not take ROZEREM if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in ROZEREM.

Do not take ROZEREM if you are currently taking Luvox (fluvoxamine).

ROZEREM may not be right for you. Before starting ROZEREM, tell your doctor about all of your health conditions, including if you:

• have a history of depression, mental illness, or suicidal thoughts

• have liver disease

• have a lung disease or breathing problems

• are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects.

Do not take ROZEREM with:

*other medicines that can make you sleepy

*Luvox® (fluvoxamine)

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take ROZEREM?

• Take ROZEREM exactly as prescribed. Do not take more ROZEREM than prescribed for you.

• Do not break the tablets. They should be swallowed whole.

*Take ROZEREM within 30 minutes of going to bed. After taking ROZEREM only do activities to get ready for bed.

• Do not take ROZEREM with or right after a meal.

*Do not take ROZEREM unless you are able to get a full night’s sleep before you must be active again.

Call your doctor if your insomnia worsens or is not better within**7-10 days***.** This may mean that there is another condition causing your sleep problems.

• If you take too much ROZEREM or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of ROZEREM?

Possible serious side effects of ROZEREM include:

*severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking ROZEREM.

*getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See “What is the most important information I should know about ROZEREM?”)

*abnormal thoughts and behavior. Symptoms include worsening of depression, suicidal thoughts or actions, nightmares, and hallucinations.

*hormone effects. ROZEREM can decrease testosterone levels and increase prolactin levels in the blood. Symptoms of low testosterone or high prolactin levels are:

odecreased interest in sex

oproblems getting pregnant

oirregular menstrual periods or no menstrual periods

oleakage of milk fromthe nipples**** of a person who is not breastfeeding

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using ROZEREM.** Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.**

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The****most common side effects of ROZEREM are:

• drowsiness

• tiredness

• dizziness

• You may still feel drowsy the next day after taking ROZEREM.Do not drive or do other dangerous activities after taking ROZEREM until you feel fully awake.

These are not all the side effects of ROZEREM. Ask your doctor or pharmacist for more information.

How should I Store ROZEREM?

• Store ROZEREM tablets at room temperature, 59˚ to 86˚ F (15˚ to 30˚C). Keep the container tightly closed and protected from moisture and humidity.

*Keep ROZEREM and all medicines out of reach of children.

General Information about ROZEREM

• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

• Do not use ROZEREM for a condition for which it was not prescribed.

• Do not share ROZEREM with other people, even if you think they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about ROZEREM. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ROZEREM that is written for healthcare professionals. For more information about ROZEREM, please call Takeda Pharmaceuticals America, Inc. at 1**-877-TAKEDA-**7 or visit www.rozerem.com.

What are the ingredients in ROZEREM?

Active Ingredient: ramelteon

Inactive Ingredients: lactose monohydrate, starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, copovidone, titanium dioxide, yellow ferric oxide, polyethylene glycol 8000, and ink containing shellac and synthetic iron oxide black.

Rx Only

This Medication Guide has been approved by the U.S. Food and Drug Administration.

05-1143-MG Revised: 10/2008