Melatonin

Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Ammu Susheela, M.D. [2]

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## Overview

Melatonin is a hormone that is FDA approved for the treatment of sleep cycle support. Common adverse reactions include hypothermia, somnolence, fatigue.

## Adult Indications and Dosage

### FDA-Labeled Indications and Dosage (Adult)

* Sleep cycle support.

### Off-Label Use and Dosage (Adult)

#### Guideline-Supported Use

* Cancer: 20 mg ORALLY once daily has been used in clinical trials[1]
* Cancer: up to 40 years, immediate-release, 1.5 mg ORALLY daily
* Cancer: 40 to 60 years, immediate-release, 1.5 to 3 mg ORALLY daily
* Cancer: older than 60 years, immediate-release, 3 to 6 mg ORALLY daily
* Jet lag: 1.5 to 3 mg ORALLY at 11 PM (local time in the destination country) on day 1, 10:30 PM on day 2, and 10 PM on day 3
* Sleep disorder: immediate-release, 5 mg ORALLY 30 minutes prior to time of sleep[2][3] ; up to 10 mg ORALLY daily
* Sleep disorder: extended-release, 2 mg ORALLY 1 to 2 hours before bedtime [4]

#### Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Melatonin in adult patients.

## Pediatric Indications and Dosage

### FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Melatonin in pediatric patients.

### Off-Label Use and Dosage (Pediatric)

#### Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Melatonin in pediatric patients.

#### Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Melatonin in pediatric patients.

## Contraindications

* Specific contraindications have not been determined.

## Warnings

Stop use and seek medical attention if symptoms worsen or persist more than 5 days

## Adverse Reactions

### Clinical Trials Experience

* Erythema
* Fixed drug eruption

* Fixed-drug eruptions on the glans was described as burning, itching, and sharply marginated, erythematous, vesicular plaques and well-demarcated erosions on the shaft in 2 adult males, occurring within 6 to 8 hours after taking melatonin for jet lag. Lesions dissipated within 10 days.

* Flushing

* Occasional vasodilation has been reported in patients with Parkinson disease treated with a maximum of melatonin 1000 mg/day.

* Pruritus

* Pruritus was reported in 1 of 12 elderly subjects with insomnia during therapy with sustained-release melatonin in one study.

* Gynaecomastia
* Hypothermia

### Postmarketing Experience

There is limited information regarding Postmarketing Experience of Melatonin in the drug label.

## Drug Interactions

Drug interactions have been reported with the following drugs.

##### Fluvoxamine

Concomitant use can cause central nervous depression.

##### Nifedipine

Concomitant use can cause increased blood pressure.

##### Warfarin

Increased risk of bleeding has been noted with concomitant use of warfarin.

## Use in Specific Populations

#### Pregnancy

Pregnancy Category (FDA):

* Pregnancy Category

Pregnancy Category (AUS):

* Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Melatonin in women who are pregnant.

#### Labor and Delivery

There is no FDA guidance on use of Melatonin during labor and delivery.

#### Nursing Mothers

There is no FDA guidance on the use of Melatonin with respect to nursing mothers.

#### Pediatric Use

There is no FDA guidance on the use of Melatonin with respect to pediatric patients.

#### Geriatic Use

There is no FDA guidance on the use of Melatonin with respect to geriatric patients.

#### Gender

There is no FDA guidance on the use of Melatonin with respect to specific gender populations.

#### Race

There is no FDA guidance on the use of Melatonin with respect to specific racial populations.

#### Renal Impairment

There is no FDA guidance on the use of Melatonin in patients with renal impairment.

#### Hepatic Impairment

There is no FDA guidance on the use of Melatonin in patients with hepatic impairment.

#### Females of Reproductive Potential and Males

There is no FDA guidance on the use of Melatonin in women of reproductive potentials and males.

#### Immunocompromised Patients

There is no FDA guidance one the use of Melatonin in patients who are immunocompromised.

## Administration and Monitoring

#### Administration

* Oral

#### Monitoring

##### Physical Findings

* Improvement of sleep in insomnia (eg, reduced sleep latency, longer sleep duration, improved quality of sleep) may indicate efficacy.
* Alleviation of symptoms in jet lag (eg, correction of disturbed sleep, reduced daytime tiredness) may indicate efficacy.

## IV Compatibility

There is limited information regarding IV Compatibility of Melatonin in the drug label.

## Overdosage

There is limited information regarding Chronic Overdose of Melatonin in the drug label.

## Pharmacology

Melatonin

Systematic (IUPAC) name
N-[2-(5-methoxy-1H-indol-3-yl)ethyl]
acetamide
Identifiers
CAS number | 73-31-4
ATC code | N05CH01
PubChem | 896
DrugBank | DB01065
Chemical data
Formula | Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass | 232.278 g/mol
SMILES | eMolecules & PubChem
Pharmacokinetic data
Bioavailability | 30 – 50%
Metabolism | Hepatic via CYP1A2 mediated 6-hydroxylation
Half life | 35 to 50 minutes
Excretion | Renal
Therapeutic considerations
Pregnancy cat. |

Legal status |

Prescription Only (S4)(AU) POM(UK) OTC(US)

Routes | In humans: orally, as capsules, tablets, or liquid, sublingually, or as transdermal patches. In lab animals: also injection.

### Mechanism of Action

* The binding of melatonin to melatonin receptors activates a few signaling pathways.[5]
* MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorylation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB.[4] MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell.[5][6][7]The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[7]
* As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.[7]
* When melatonin receptor agonists activate their receptors it causes numerous physiological processes.[7][8]
* MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. The SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions.[9]
* Melatonin receptors have been identified in the cardiovascular system. Evidence from animal studies points to a dual role of melatonin in the vasculature.
* Activation of MT1 receptors mediates vasoconstriction and the activation of MT2 receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT1 and MT2 receptors.
* MT1 and MT2 receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma, and in phototransduction. This is not a complete list since many of the possible processes need further confirmation

### Structure

There is limited information regarding Melatonin Structure in the drug label.

### Pharmacodynamics

There is limited information regarding Pharmacodynamics of Melatonin in the drug label.

### Pharmacokinetics

There is limited information regarding Pharmacokinetics of Melatonin in the drug label.

### Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Melatonin in the drug label.

## Clinical Studies

There is limited information regarding Clinical Studies of Melatonin in the drug label.

## How Supplied

There is limited information regarding Melatonin How Supplied in the drug label.

### Storage

There is limited information regarding Melatonin Storage in the drug label.

## Images

### Drug Images

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### Package and Label Display Panel

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## Patient Counseling Information

Take 15 minutes before meals.

* Adults and children 12 years and older 20 drops twice a day in a little water. Hold in the mouth for about 30 seconds then swallow.
* Children between 12 years and 6 years of age 10 drops twice a day in a little water. Hold in the mouth for about 30 seconds then swallow.
* Children under 6 years

## Precautions with Alcohol

* Alcohol-Melatonin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

## Brand Names

* GUNA-MELATONIN ®[10]

## Look-Alike Drug Names

There is limited information regarding Melatonin Look-Alike Drug Names in the drug label.

## Drug Shortage Status

## Price

## References

The contents of this FDA label are provided by the National Library of Medicine.

1. ↑ Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF; et al. (2012). "The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials". Cancer Chemother Pharmacol. 69 (5): 1213–20. doi:10.1007/s00280-012-1828-8. PMID 22271210.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
2. ↑ Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes JD (1991). "Delayed sleep phase syndrome response to melatonin". Lancet. 337 (8750): 1121–4. PMID 1674014.CS1 maint: Multiple names: authors list (link)
3. ↑ Warman GR, Pawley MD, Bolton C, Cheeseman JF, Fernando AT, Arendt J; et al. (2011). "Circadian-related sleep disorders and sleep medication use in the New Zealand blind population: an observational prevalence survey". PLoS One. 6 (7): e22073. doi:10.1371/journal.pone.0022073. PMC 3138759. PMID 21789214.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
4. ↑ Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M; et al. (2010). "Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety". BMC Med. 8: 51. doi:10.1186/1741-7015-8-51. PMC 2933606. PMID 20712869 PMID: 20712869 Check `|pmid=` value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
5. ↑ 5.0 5.1 Rivara S, Mor M, Bedini A, Spadoni G, Tarzia G (2008). "Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders". Curr Top Med Chem. 8 (11): 954–68. PMID 18673165.CS1 maint: Multiple names: authors list (link)
6. ↑ Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N; et al. (2008). "Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways". Prog Neurobiol. 85 (3): 335–53. doi:10.1016/j.pneurobio.2008.04.001. PMID 18571301 PMID 18571301 Check `|pmid=` value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ 7.0 7.1 7.2 7.3 Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J (2010). "International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors". Pharmacol Rev. 62 (3): 343–80. doi:10.1124/pr.110.002832. PMC 2964901. PMID 20605968 PMID 20605968 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
8. ↑ Witt-Enderby PA, Bennett J, Jarzynka MJ, Firestine S, Melan MA (2003). "Melatonin receptors and their regulation: biochemical and structural mechanisms". Life Sci. 72 (20): 2183–98. PMID 12628439 PMID 12628439 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)
9. ↑ Dubocovich ML (2007). "Melatonin receptors: role on sleep and circadian rhythm regulation". Sleep Med. 8 Suppl 3: 34–42. doi:10.1016/j.sleep.2007.10.007. PMID 18032103 PMID 18032103 Check `|pmid=` value (help).
10. ↑ ": GUNA-MELATONIN - melatonin solution/ drops".

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