Ramelteon (Rozerem) - Uses, Dose, MOA, Side effects, Brands

Ramelteon (Rozerem) is a potent and selective activator of melatonin (MT-1 and MT2) receptors. It is used in the treatment of patients with insomnia and delirium in ICU patients.

Ramelteon Uses:

  • Insomnia:

    • It is prescribed for people who have trouble falling asleep to address their insomnia.
  • Off Label Use of Ramelteon in Adults:

    • For the prevention of ICU-related delirium.

Ramelteon (Rozerem) Dose in Adults

Ramelteon (Rozerem) Dose in the treatment of Insomnia:

  • 8 mg taken orally once daily, 30 minutes before bedtime.
  • The daily dosing capacity is 8 mg.

Ramelteon (Rozerem) Dose in the treatment of ICU-related delirium (off-label):

  • 8 mg once a day at bedtime.

Use in Children:

Not indicated.

Pregnancy Risk Category: C

  • Animal reproduction studies have shown adverse pregnancy outcomes. It can cause hormonal abnormalities, such as a change of libido or menstrual irregularities.

Use while breastfeeding

  • It is unknown if the drug is excreted into breastmilk. It is recommended that breastfeeding mothers use it with caution, weighing both the risks and benefits.
  • If breastfeeding is continued, it should be checked for signs of somnolence or feeding problems.
  • Alternatively, nursing mothers may be asked to breastfeed their infants for as long as possible.

Dose in Kidney Disease:

No dosage adjustment is necessary.

Dose in Liver disease:

  • Mild impairment:
    • The manufacturer's labelling does not mention dosage modifications.
  • Moderate impairment:
    • The manufacturer's labelling does not mention dosage modifications.
    • It should be used with caution.
  • Severe impairment:
    • Avoid using it in severe hepatic impairment.

Side Effects of Ramelteon (Rozerem):

  • Central Nervous System:

    • Dizziness
    • Somnolence
    • Fatigue
    • Insomnia Worsened
    • Depression
  • Endocrine & Metabolic:

    • Serum Cortisol Decreased
  • Gastrointestinal:

    • Nausea
    • Taste Perversion
  • Neuromuscular & Skeletal:

    • Myalgia
    • Arthralgia
  • Respiratory:

    • Upper Respiratory Infection
  • Miscellaneous:

    • Influenza

Contraindications to Ramelteon (Rozerem):

  • Patients who have angioedema from previous ramelteon therapy should not be rechallenged.
  • Concurrent use with fluvoxamine

Warnings and precautions

  • Abnormal thinking and behavior changes:

    • The use of hypnotic or sedative drugs has been linked to abnormal thinking and behavior such as aggression, agitation, decreased inhibition, bizarre behavior and depersonalization.
    • These symptoms may appear suddenly in patients who have not previously been diagnosed with a psychiatric disorder.
  • Depression in the CNS:

    • CNS depression can occur, which may lead to impairments in mental and physical abilities. People who are required to be alert for mental tasks, such as driving or operating heavy machinery, should be cautious.
  • Hyperprolactinemia

    • It can increase serum prolactin levels. Patients undergoing treatment for prolactin should be viewed carefully to avoid unnecessary investigations or treatment.
  • Hypersensitivity reactions

    • Rarely have allergic reactions including angioedema been reported. The drug should be avoided by patients in the future.
  • Activities that are sleep-related:

    • It has been linked to dangerous sleep-related activities. It has been reported that individuals have used it to cook, eat, drive, make phone calls, and have sex.
    • Other neuropsychiatric symptoms include anxiety, amnesia, and even anxiety.
    • The risk of developing these conditions may be increased by the use of sedatives or other CNS depressants drugs, such as alcohol, in combination with sedatives.
    • If the patient reports complex sleep-related problems, it is best to stop treatment.
  • Depression

    • Patients suffering from depression should be cautious when taking the drug. It should not be used in patients with severe depression.
    • Suicidal thoughts have been linked to the use of hypnotics.
  • Hepatic impairment

    • Patients with mild-to-moderate liver disease should use it with caution. It should not be used in severe liver disease.
  • Respiratory disease

    • Patients suffering from chronic respiratory conditions like asthma, COPD or sleep Apnea should be cautious about using the drug. The drug should not be used in patients suffering from severe symptoms, such as severe sleep apnea or impending respiratory failure.

Ramelteon: Drug Interaction

Risk Factor C (Monitor therapy)

Abiraterone Acetate

May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).

Alcohol (Ethyl)

CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).

Alizapride

May enhance the CNS depressant effect of CNS Depressants.

Brimonidine (Topical)

May enhance the CNS depressant effect of CNS Depressants.

Brexanolone

CNS Depressants may enhance the CNS depressant effect of Brexanolone.

Bromopride

May enhance the CNS depressant effect of CNS Depressants.

Cannabidiol

May enhance the CNS depressant effect of CNS Depressants.

Cannabis

May enhance the CNS depressant effect of CNS Depressants.

Chlorphenesin Carbamate

May enhance the adverse/toxic effect of CNS Depressants.

CNS Depressants

May enhance the adverse/toxic effect of other CNS Depressants.

CYP1A2 Inhibitors (Moderate)

May decrease the metabolism of CYP1A2 Substrates (High risk with Inhibitors).

CYP3A4 Inducers (Strong)

May decrease the serum concentration of Ramelteon.

CYP3A4 Inhibitors (Strong)

May increase the serum concentration of Ramelteon.

Deferasirox

May elevate CYP1A2 substrates' serum concentration (High risk with Inhibitors).

Dimethindene (Topical)

CNS depressants may have an enhanced CNS depressant impact.

Doxylamine

CNS depressants may have an enhanced CNS depressant impact. Management: The producer of the pregnancy-safe drug Diclegis (doxylamine/pyridoxine) particularly advises against combining it with other CNS depressants.

Dronabinol

CNS depressants may have an enhanced CNS depressant impact.

Esketamine

CNS depressants may have an enhanced CNS depressant impact.

Fluconazole

CNS depressants may have an enhanced CNS depressant impact.
Ramelteon serum concentration can rise.

HydrOXYzine

May enhance the CNS depressant effect of CNS Depressants.

Kava Kava

May enhance the adverse/toxic effect of CNS Depressants.

Lofexidine

May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

Magnesium Sulfate

May enhance the CNS depressant effect of CNS Depressants.

Melatonin

May enhance the sedative effect of Hypnotics (Nonbenzodiazepine).

MetyroSINE

CNS Depressants may enhance the sedative effect of MetyroSINE.

Minocycline

May enhance the CNS depressant effect of CNS Depressants.

Mirtazapine

CNS Depressants may enhance the CNS depressant effect of Mirtazapine.

Nabilone

May enhance the CNS depressant effect of CNS Depressants.

Obeticholic Acid

May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).

Peginterferon Alfa-2b

May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).

Piribedil

CNS Depressants may enhance the CNS depressant effect of Piribedil.

Pramipexole

CNS Depressants may enhance the sedative effect of Pramipexole.

ROPINIRole

CNS Depressants may enhance the sedative effect of ROPINIRole.

Rotigotine

CNS Depressants may enhance the sedative effect of Rotigotine.

Rufinamide

May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.

Selective Serotonin Reuptake Inhibitors

CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced.

Tetrahydrocannabinol

May enhance the CNS depressant effect of CNS Depressants.

Tetrahydrocannabinol and Cannabidiol

May enhance the CNS depressant effect of CNS Depressants.

Trimeprazine

May enhance the CNS depressant effect of CNS Depressants.

Risk Factor D (Consider therapy modification)

Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin.

Buprenorphine

CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.

Chlormethiazole

May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.

Droperidol

May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

Flunitrazepam

CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.

HYDROcodone

CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Methotrimeprazine

CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.

Opioid Agonists

CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

OxyCODONE

CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Perampanel

May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination.

Suvorexant

CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended.

Tapentadol

May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Vemurafenib

May elevate CYP1A2 substrates' serum concentration (High risk with Inhibitors). Management: If possible, look into alternatives to such combinations, especially if the CYP1A2 substrate has a relatively limited therapeutic index. Medicines marked as exclusions from this document are covered in separate monographs on drug interactions.

Zolpidem

CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.

Risk Factor X (Avoid combination)

Azelastine (Nasal)

CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).

Bromperidol

May enhance the CNS depressant effect of CNS Depressants.

FluvoxaMINE

May increase the serum concentration of Ramelteon.

Orphenadrine

CNS Depressants may enhance the CNS depressant effect of Orphenadrine.

Oxomemazine

May enhance the CNS depressant effect of CNS Depressants.

Paraldehyde

CNS Depressants may enhance the CNS depressant effect of Paraldehyde.

Sodium Oxybate

Hypnotics (Nonbenzodiazepine) may intensify Sodium Oxybate's CNS depressive effects.

Thalidomide

The CNS depressing effect of thalidomide may be enhanced by CNS depressants.

Monitoring Parameters:

None mentioned.

How to administer Ramelteon (Rozerem)?

  • The drug should not be administered with or after high-fat meals as it may delay the time to reach the T-max and increases the AUC.
  • The tablets ought to be consumed whole. Keep the tablets intact.
  • After administering the drug, activities outside of the bedroom should be limited.

Mechanism of action of Ramelteon (Rozerem):

  • It acts as a selective and potent activator of melatonin receptors 1 (MT1) and 2 (MT2 respectively). 
  • It is not a good affinity for MT3 receptors. The suprachiasmic nucleus (hypothalamus) contains melatonin receptors. 
  • This area is responsible for the synchronization and determination of circadian rhythms.
  • MT1 receptor activation induces sleeping while MT2 receptor activation regulates circadian rhythm. 
  • Ramelteon has an 8-fold higher affinity to MT1 receptors that MT2. 
  • Ramelteon has a 6-fold higher affinity for MT1 receptors than melatonin, which accounts for its enhanced sleep-inducing effects.

The onset of action:

  • 30 minutes

Absorption:

  • It is rapidly absorbed. A high-fat meal delays the time to reach T-max and increases the AUC by about 31%.

Protein binding:

  • About 82%

Metabolism:

  • It experiences a significant first-pass effect. To create the active metabolite, M-II, it undergoes oxidative metabolism largely through CYP1A2 and to a lesser extent through CYP2C and CYP3A4.

Bioavailability:

  • Absolute: 1.8%

Half-life elimination:

  • Ramelteon: 1 to 2.6 hours;
  • M-II: 2 to 5 hours

Time to peak plasma concentration:

  • Median: 0.5 to 1.5 hours

Excretion:

  • Primarily as metabolites:
    • Urine (84%);
    • feces (4%)

International Brand Names of Ramelteon:

  • Rozerem

Ramelteon Brand Names in Pakistan:

No Brands Available in Pakistan.