Cadiatev Tablets

CADIATEV is indicated for the short term (up to 13 weeks) treatment of primary insomnia characterised by poor quality of sleep, in patients who are aged 55 years or over.

Posology: The recommended dose in patients 55 years and older is 2 mg once daily, 1 to 2 hours before bedtime and after food. The dosage may be continued for up to 13 weeks. Efficacy in patients younger than 55 years has not been demonstrated.

Special Populations: Renal impairment: The effect of any stage of renal insufficiency 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 use of melatonin as contained in CADIATEV in patients with liver impairment. Data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, CADIATEV is not recommended for use in patients with hepatic impairment. Paediatric population: CADIATEV is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy.

Method of administration: For oral use. Tablets should be swallowed whole.

• Hypersensitivity to the active substance (melatonin), or to any of the excipients listed in section 6.1.
• Safety in pregnancy and lactation has not been established (see section 4.6).

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

Paediatric population: The safety and efficacy of CADIATEV in children aged 0 to 18 years has not been established. CADIATEV contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 medicines.
• Melatonin does not induce CYP1A enzymes in vitro at supra-therapeutic concentrations. Therefore, interactions between melatonin and other active substances as a consequence of melatoninu2019s effect on CYP1A enzymes are not likely to be significant.
• Melatoninu2019s metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes are possible.
• Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum C max) 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 medicines, 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 or vice versa has not been studied.

Pharmacodynamic interactions:

• Alcohol should not be taken with CADIATEV, because it reduces the effectiveness of CADIATEV on sleep.
• CADIATEV 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 CADIATEV and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to zolpidem alone.
• CADIATEV 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, CADIATEV co-administration resulted in increased feelings of tranquillity and difficulty in performing tasks compared to imipramine alone, and increased feelings of u2018muzzy-headednessu2019 compared to thioridazine alone.

Pregnancy: Safety in pregnancy has not been established. There are no clinical data available on use in pregnancy.

Breastfeeding: Safety in lactation has not been established. Endogenous melatonin was measured in breast milk thus exogenous melatonin is probably secreted into human milk.

Fertility: There are no data on fertility.

CADIATEV has moderate influence on the ability to drive and use machines. CADIATEV 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.

System Organ Class MedDRA:

• Infections and infestations: Less frequent Herpes Zoster
• Blood and lymphatic disorders: Less frequent Leukopenia, thrombocytopenia
• Immune system disorders: Frequency unknown Hypersensitivity reaction
• Metabolism and nutrition disorders: Less frequent Hypertriglyceridaemia, hypocalcaemia, hyponatraemia
• Psychiatric disorders: Less frequent Irritability, nervousness, restlessness, insomnia, abnormal dreams, nightmares, anxiety, altered mood, aggression, agitation, crying, early morning awakening, increased libido, disorientation, depressed mood, depression
• Nervous system disorders: Less frequent Migraine, psychomotor hyperactivity, dizziness, lethargy, somnolence, memory impairment, disturbance in attention, poor quality sleep, headache, syncope, memory impairment, paraesthesia, restless legs syndrome
• Eye disorders: Less frequent Reduced visual acuity, blurred vision, increased lacrimation
• Ear and labyrinth disorders: Less frequent Positional vertigo, vertigo
• Cardiac disorders: Less frequent Angina pectoris, palpitations
• Vascular disorders: Less frequent Hot flush, hypertension
• Gastrointestinal disorders: Less frequent Abdominal pain, constipation, abdominal pain upper, dyspepsia, dry mouth, gastrointestinal disorder, gastrointestinal upset, vomiting, abnormal bowel sounds, flatulence, salivary hypersecretion, halitosis, mouth ulceration, nausea, gastro-oesophageal reflux disease, oral mucosal blistering, tongue ulceration, vomiting, abdominal discomfort, gastric disorder, gastritis
• Hepato-biliary disorders: Less frequent Hyperbilirubinaemia, hepatic enzyme increased, liver function test abnormal, laboratory test abnormal
• Skin and subcutaneous tissue disorders: Less frequent Dermatitis, hyperhidrosis, eczema, erythema, pruritic rash, pruritus, dry skin, nail disorder, night sweats, hand dermatitis, psoriasis, rash generalised
• Frequency unknown Angioedema, oedema of mouth, tongue oedema
• Renal and urinary disorders: Less frequent Glycosuria, proteinuria, polyuria, haematuria, nocturia
• Musculoskeletal and connective tissue disorders: Less frequent Pain in extremity, muscle cramp, neck pain, arthritis, night cramps
• Reproductive system and breast disorders: Less frequent Menopausal symptoms, priapism, prostatitis
• Frequency unknown Galactorrhoea
• General disorders and administration site conditions: Less frequent Asthenia, chest pain, fatigue, pain, thirst
• Investigations: Less frequent Increased weight, blood electrolytes abnormal

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the 6.04 Adverse Drug Reactions Reporting Form, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Several cases of overdose have been reported post-marketing. Somnolence was the most reported adverse event. Most were mild to moderate in severity. CADIATEV 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.