4.1. Therapeutic indications

Melatonin Mylan is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.

4.2. Posology and method of administration

Posology

The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks.

Paediatric population

The safety and efficacy of Melatonin Mylan in children aged 0 to 18 years has not yet been established. No data are available.

Renal impairment

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to such patients.

Hepatic impairment

There is no experience of the use of Melatonin Mylan in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, Melatonin Mylan is not recommended for use in patients with hepatic impairment.

Method of Administration

Oral use. Tablets should be swallowed whole to maintain prolonged release properties. Crushing or chewing should not be used to facilitate swallowing.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Melatonin Mylan may cause drowsiness. Therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety.

No clinical data exist concerning the use of Melatonin Mylan in individuals with autoimmune diseases. Therefore, Melatonin Mylan is not recommended for use in patients with autoimmune diseases.

Melatonin Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Pharmacokinetic interactions

• Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations. The clinical relevance of the finding is unknown. If induction occurs, this can give rise to reduced plasma concentrations of concomitantly administered medicinal products.

• Melatonin does not induce CYP1A enzymes in vitro at supra-therapeutic concentrations. Therefore, interactions between melatonin and other active substances as a consequence of melatonin's effect on CYP1A enzymes are not likely to be significant.

• Melatonin's metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes is possible.

• Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided.

• Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 and 8-MOP), which increases melatonin levels by inhibiting its metabolism.

• Caution should be exercised in patients on cimetidine a CYP2D inhibitor, which increases plasma melatonin levels, by inhibiting its metabolism.

• Cigarette smoking may decrease melatonin levels due to induction of CYP1A2.

• Caution should be exercised in patients on oestrogens (e.g. contraceptive or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2.

• CYP1A2 inhibitors such as quinolones may give rise to increased melatonin exposure.

• CYP1A2 inducers such as carbamazepine and rifampicin may give rise to reduced plasma concentrations of melatonin.

• There is a large amount of data in the literature regarding the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with the dynamic or kinetic effects of Melatonin Mylan or vice versa has not been studied.

Pharmacodynamic interactions

• Alcohol should not be taken with Melatonin, because it reduces the effectiveness of Melatonin Mylan on sleep.

• Melatonin Mylan may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Melatonin Mylan and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone.

• Melatonin Mylan has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, Melatonin Mylan co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy- headedness” compared to thioridazine alone.

4.6. Fertility, pregnancy and lactation

Pregnancy

For melatonin, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). In view of the lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended.

Breastfeeding

Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably secreted into human milk. There are data in animal models including rodents, sheep, bovine and primates that indicate maternal transfer of melatonin to the foetus via the placenta or in the milk. Therefore, breast-feeding is not recommended in women under treatment with melatonin.

4.7. Effects on ability to drive and use machines

Melatonin Mylan has moderate influence on the ability to drive and use machines. Melatonin Mylan may cause drowsiness, therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety.

4.8. Undesirable effects

Summary of the safety profile

In clinical trials (in which a total of 1,931 patients were taking Melatonin Mylan and 1,642 patients were taking placebo), 48.8% of patients receiving Melatonin Mylan reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Melatonin Mylan (5.743– placebo vs. 3.013– Melatonin Mylan). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the Melatonin Mylan and placebo treated groups.

Tabulated list of adverse reactions

The following adverse reactions were reported in clinical trials and from post-marketing spontaneous reporting.

In clinical trials a total of 9.5% of patients receiving Melatonin Mylan reported an adverse reaction compared with 7.4% of patients taking placebo. Only those adverse reactions reported during clinical trials occurring in patients at an equivalent or greater rate than placebo have been included below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100);

Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be established from the available data).

System Organ Class

Very Common

Common

Uncommon

Rare

Not known: (Cannot be established from the available data)

Infections and infestations

Herpes zoster

Blood and lymphatic system disorders

Leukopenia, thrombocytopenia

Immune system disorders

Hyper- sensitivity reaction

Metabolism and nutrition disorders

Hypertriglyceridaemia, hypocalcaemia, hyponatraemia

Psychiatric disorders

Irritability, nervousness, restlessness, insomnia, abnormal dreams, nightmares, anxiety

Mood altered, aggression, agitation, crying, stress symptoms, disorientation, early morning awakening, libido increased, depressed mood, depression

Nervous system disorders

Migraine, headache, lethargy, psychomotor hyperactivity, dizziness, somnolence

Syncope, memory impairment, disturbance in attention, dreamy state, restless legs syndrome, poor quality sleep, paraesthesia

Eye disorders

Visual acuity reduced, vision blurred, lacrimation increased

Ear and labyrinth disorders

Vertigo positional, vertigo

Cardiac disorders

Angina pectoris, palpitations

Vascular disorders

Hypertension

Hot flush

Gastrointestinal disorders

Abdominal pain, abdominal pain upper, dyspepsia, mouth ulceration, dry mouth, nausea

Gastro-oesophageal reflux disease, gastrointestinal disorder, oral mucosal blistering, tongue ulceration, gastrointestinal upset, vomiting, bowel sounds abnormal, flatulence, salivary hypersecretion, halitosis, abdominal discomfort, gastric disorder, gastritis

Hepatobiliary disorders

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Dermatitis, night sweats, pruritus, rash, pruritus generalised, dry skin

Eczema, erythema, hand dermatitis, psoriasis, rash generalised, rash pruritic, nail disorder

Angioedema, oedema of mouth, tongue oedema

Musculoskeletal and connective tissue disorders

Pain in extremity

Arthritis, muscle spasms, neck pain, night cramps

Renal and urinary disorders

Glycosuria, proteinuria

Polyuria, haematuria, nocturia

Reproductive system and breast disorders

Menopausal symptoms

Priapism, prostatitis

Galactorrhoea

General disorders and administration site conditions

Asthenia, chest pain

Fatigue, pain, thirst

Investigations

Liver function test abnormal, weight increased

Hepatic enzyme increased, blood electrolyes abnormal, laboratory test abnormal

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Several cases of overdose have been reported post-marketing. Somnolence was the most reported adverse event. Most were mild to moderate in severity. Melatonin Mylan has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported.

Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature.

If overdose occurs, drowsiness is to be expected. Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required.