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
|
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) |
|
|
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. |
|
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 |
|
|
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.
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