Circadin

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Circadin on Prescriptsy

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Circadin is a prolonged-release melatonin tablet containing 2 mg of melatonin, manufactured by RAD Neurim Pharmaceuticals and licensed in the United Kingdom for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients aged 55 years and over.

It is the only prolonged-release melatonin product with a UK marketing authorisation specifically for insomnia management.

Unlike conventional sedative-hypnotic medications such as benzodiazepines and Z-drugs, Circadin works by supplementing the body's declining natural melatonin production, helping to restore the normal circadian sleep-wake rhythm without producing pharmacological sedation, dependence, or rebound insomnia.

Insomnia is one of the most common health complaints in the UK, with an estimated prevalence of 30 to 40% among adults.

In people aged 55 and over, sleep quality frequently deteriorates due to age-related reductions in endogenous melatonin secretion by the pineal gland.

This decline results in difficulty falling asleep, frequent nocturnal awakenings, reduced deep (slow-wave) sleep, and earlier morning waking.

NICE recommends cognitive behavioural therapy for insomnia (CBT-I) as first-line treatment, with pharmacological options reserved for cases that do not respond adequately to non-drug measures.

Circadin offers a pharmacological option with a significantly more favourable safety and dependency profile than traditional hypnotics.

This page provides a comprehensive clinical overview of how Circadin works, correct dosing, clinical evidence, side effects, important safety information, and how to obtain a prescription in the UK.

Important safety information about Circadin

Before reading further, note the following key safety points. Circadin is a prescription-only medicine (POM) in the United Kingdom.

• Circadin is for short-term use only (up to 13 weeks). Review with your GP after 3 weeks to assess benefit.
• Swallow the tablet whole. Do not crush, chew, or break it, as this destroys the prolonged-release coating.
• Do not take Circadin with fluvoxamine, which can increase melatonin levels dramatically.
• Avoid alcohol during treatment, as it disrupts sleep architecture and reduces the benefit of melatonin.
• Exercise caution when driving or operating machinery until you know how Circadin affects you individually.

Understanding insomnia in older adults

Insomnia is defined as difficulty initiating or maintaining sleep, or non-restorative sleep, associated with impaired daytime function, occurring at least three nights per week for at least one month.

In adults aged 55 and over, insomnia is particularly common and is often multifactorial, involving age-related changes in circadian rhythm regulation, reduced melatonin secretion, medical comorbidities (pain, nocturia, respiratory conditions), psychiatric conditions (depression, anxiety), medication effects, and environmental factors.

The impact of chronic insomnia extends beyond tiredness.

Poor sleep is associated with increased risk of falls, cognitive decline, depression, cardiovascular disease, reduced immune function, and overall reduced quality of life.

Despite its prevalence, insomnia in older adults is often undertreated or managed with sedative-hypnotic medications that carry significant risks of dependence, falls, cognitive impairment, and next-day residual sedation in this age group.

How Circadin works: mechanism of action

Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring hormone synthesised from serotonin in the pineal gland.

Its production is tightly regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives direct light input from the retina via the retinohypothalamic tract.

Light suppresses melatonin synthesis, while darkness triggers its release.

The resulting circadian pattern of melatonin secretion is the primary endogenous signal for the biological night, synchronising the sleep-wake cycle with the environmental light-dark cycle.

In younger adults, plasma melatonin levels begin to rise approximately 2 hours before habitual bedtime (a period known as the dim light melatonin onset, or DLMO), peak between 2 a.m.

and 4 a.m., and decline to near-undetectable levels by morning. This profile promotes sleep onset, consolidation, and appropriate sleep architecture.

With advancing age, the amplitude of this melatonin rhythm decreases, the peak concentration is reduced (often by 50% or more compared with young adults), and the timing may shift earlier, contributing to advanced sleep phase and early morning awakening.

Circadin delivers exogenous melatonin in a prolonged-release formulation designed to replicate the natural nocturnal melatonin curve.

The tablet matrix releases melatonin gradually over 8 to 10 hours, providing a plasma profile that closely mirrors healthy endogenous secretion.

This sustained release distinguishes Circadin from immediate-release melatonin preparations, which produce a sharp spike followed by rapid elimination and do not maintain melatonin levels through the night.

Melatonin acts primarily through two G-protein-coupled receptors, MT1 and MT2, located in the suprachiasmatic nucleus. MT1 activation suppresses neuronal firing in the SCN, promoting sleep onset.

MT2 activation influences the timing of the circadian clock, facilitating circadian phase shifting.

Together, these receptor-mediated effects promote earlier sleep onset, improve sleep quality and continuity, and help entrain the circadian rhythm to the desired sleep schedule.

Clinical evidence for Circadin

Pivotal clinical trials

The efficacy of Circadin was established in three randomised, double-blind, placebo-controlled clinical trials involving over 900 patients aged 55 and over with primary insomnia.

The primary endpoints were subjective sleep quality and morning alertness, assessed using validated patient-reported outcome measures including the Leeds Sleep Evaluation Questionnaire (LSEQ) and the Clinical Global Impression of Improvement (CGI-I) scale.

In the main pivotal study (Lemoine et al., 2007), Circadin 2 mg taken for 3 weeks significantly improved sleep quality, ease of getting to sleep, and morning alertness compared with placebo.

In a subgroup analysis of patients with the poorest baseline sleep quality, the improvements were clinically meaningful and consistent across endpoints.

Polysomnographic data from a subset of patients showed preservation of normal sleep architecture, including maintained slow-wave sleep and REM sleep proportions, unlike benzodiazepines and Z-drugs which typically suppress slow-wave and REM sleep.

Long-term extension studies

An extension study (Wade et al., 2010) evaluated Circadin over 6 months of continuous use in a subset of patients.

Sleep quality benefits were maintained without evidence of tolerance, dose escalation, or withdrawal effects upon discontinuation.

No rebound insomnia was observed when treatment was stopped, and next-morning function remained unimpaired throughout the treatment period.

These findings are clinically important because they demonstrate that melatonin does not produce the same dependency pattern seen with benzodiazepines and Z-drugs.

NICE Evidence Summary

NICE Evidence Summary ES2 (Melatonin for primary insomnia in people aged 55 and over) acknowledges the evidence base for Circadin and notes its favourable safety profile compared with benzodiazepines and Z-drugs, particularly regarding absence of dependence, rebound, and next-morning impairment.

The NICE Clinical Knowledge Summary on insomnia notes that melatonin may be considered when non-pharmacological measures have been tried and where sedative-hypnotics are inappropriate, particularly in older adults at risk of falls.

Circadin versus benzodiazepines and Z-drugs

The key advantages of Circadin over benzodiazepines (temazepam, nitrazepam, diazepam) and Z-drugs (zopiclone, zolpidem) in older adults include no evidence of physical dependence or tolerance at recommended doses, no rebound insomnia upon discontinuation, no withdrawal syndrome, preservation of normal sleep architecture (including slow-wave and REM sleep), minimal next-morning residual sedation, no significant impairment of balance or psychomotor function (reduced falls risk), and no evidence of cognitive impairment with short-term use.

The principal limitation of Circadin compared with sedative-hypnotics is that its sleep-promoting effect is more modest in magnitude.

It works by restoring a natural physiological process rather than inducing pharmacological sedation.

Patients should understand that Circadin is not intended to produce immediate "knockout" sedation but to gradually improve sleep quality over several days to weeks.

Dosage and administration

Take one Circadin 2 mg tablet orally, 1 to 2 hours before bedtime, after food (food increases absorption). Swallow the tablet whole with water.

Do not crush, chew, or break the tablet, as this will destroy the prolonged-release mechanism and release the full melatonin dose at once.

Treatment should continue for up to 13 weeks. A clinical review at 3 weeks is recommended to assess whether a meaningful improvement in sleep quality has occurred.

If no benefit is evident, treatment should be discontinued. If benefit has been achieved, treatment may continue for the full 13-week course.

There is no need to taper the dose when stopping, as no rebound or withdrawal effects occur.

Consistent timing is important. Taking Circadin at the same time each evening, approximately 1 to 2 hours before the intended sleep time, aligns the exogenous melatonin release with the natural circadian window and optimises the therapeutic effect.

Side effects of Circadin

Common side effects

The most commonly reported adverse effects in clinical trials were headache, nasopharyngitis (symptoms of a common cold), back pain, and arthralgia (joint pain). These occurred at rates comparable to placebo in most studies, indicating a favourable tolerability profile.

Uncommon side effects

Uncommon side effects include irritability, restlessness, insomnia (paradoxical worsening), abnormal dreams, dizziness, drowsiness, lethargy, abdominal pain, constipation, dry mouth, nausea, weight increase, pruritus, rash, dry skin, pain in extremities, and elevated liver enzymes.

Rare side effects

Rarely reported effects include palpitations, chest pain, visual disturbances, mood changes (including depressed mood and aggression), disorientation, and blood abnormalities. The clinical significance of these rare reports is uncertain given the comparable rates observed in placebo groups.

When to seek medical advice

Contact your GP or call NHS 111 if you experience excessive daytime drowsiness, persistent mood changes, worsening insomnia, or any symptom that concerns you.

Seek emergency care (call 999 or attend A&E) if you develop signs of a severe allergic reaction (swelling of the face, lips, tongue, or throat, or difficulty breathing).

Report any suspected adverse reactions via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk .

Warnings and precautions

Contraindications

Circadin is contraindicated in patients with known hypersensitivity to melatonin or any of the excipients (the tablet contains lactose monohydrate, which is relevant for patients with galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption).

It should not be used by patients with severe hepatic impairment, as melatonin is metabolised primarily by CYP1A2 in the liver and impaired metabolism may lead to excessive melatonin levels.

Drug interactions

Fluvoxamine, a potent CYP1A2 inhibitor, is contraindicated with Circadin due to the risk of dramatically increased melatonin levels (up to 17-fold).

Other CYP1A2 inhibitors including ciprofloxacin, oestrogen-containing medications (HRT, combined oral contraceptives), and cimetidine may also increase melatonin exposure and should be used with caution.

CYP1A2 inducers such as carbamazepine, rifampicin, and smoking may reduce melatonin levels and efficacy.

Concurrent use with benzodiazepines or Z-drugs is not recommended due to additive sedative effects.

Melatonin may have a mild blood pressure lowering effect; caution is advised with antihypertensive medications, and blood pressure should be monitored.

Alcohol should be avoided as it disrupts sleep and may interact with melatonin.

Special populations

Circadin is not recommended during pregnancy or breastfeeding due to insufficient safety data. Women of childbearing potential should use appropriate contraception.

Caution is advised in patients with autoimmune diseases, as melatonin has immunomodulatory properties and its effect in autoimmune conditions is not established.

Patients with renal impairment should be monitored, as experience in this group is limited.

Non-pharmacological approaches to insomnia

NICE recommends cognitive behavioural therapy for insomnia (CBT-I) as the first-line treatment for chronic insomnia in adults.

CBT-I includes sleep restriction therapy, stimulus control, cognitive restructuring, relaxation techniques, and sleep hygiene education.

Evidence from multiple randomised trials demonstrates that CBT-I is at least as effective as pharmacotherapy in the short term and superior in the long term, with benefits maintained for months to years after treatment.

Circadin is most effective when used alongside good sleep hygiene practices and, where available, CBT-I.

Practical sleep hygiene measures include maintaining a consistent wake time and bedtime, keeping the bedroom cool (16 to 18 degrees Celsius), dark, and quiet, avoiding screens (phones, tablets, computers, television) for at least 30 minutes before bed, limiting caffeine intake after midday, exercising regularly but not within 3 hours of bedtime, avoiding large meals late in the evening, and using the bed only for sleep and intimacy.

If you cannot sleep after 20 minutes, get up and do a quiet activity in another room until you feel sleepy, then return to bed.

How to get Circadin in the UK

Circadin is a prescription-only medicine (POM) in the UK. It can be prescribed by your GP or by an authorised online prescriber following a clinical assessment.

Your GP will typically take a sleep history, exclude secondary causes of insomnia (such as sleep apnoea, depression, pain, medication effects, or substance use), and discuss non-pharmacological options before considering Circadin.

Melatonin 2 mg immediate-release tablets have been reclassified as a pharmacy (P) medicine for the short-term relief of jet lag in adults, available without prescription from pharmacies.

This reclassification does not apply to Circadin or to the indication of primary insomnia. A prescription remains necessary for the prolonged-release formulation used to treat insomnia.

The standard NHS prescription charge in England is currently 9.90 pounds per item; prescriptions are free in Scotland, Wales, and Northern Ireland.

Sources

• Circadin 2 mg Prolonged-release Tablets, Summary of Product Characteristics (EMC)
• Melatonin, British National Formulary (BNF)
• NICE CKS: Insomnia
• Insomnia, NHS
• MHRA Yellow Card Scheme