4.1. Therapeutic indications

Magnesium Kora Healthcare is indicated for the treatment and prevention of magnesium deficiency in adults, adolescents and children aged from 12 years.

4.2. Posology and method of administration

The duration of magnesium treatment required will depend on the clinical circumstances of each patient

It is recommended that serum magnesium levels should be monitored at regular intervals e.g. every 3-6 months, particularly in children and in patients with renal impairment.

Posology

Adults (> 18 years)

The recommended daily dose for an adult (> 18 years) is 12-24 mmol magnesium, e.g. 1 – 2 tablets administered 3 times a day (equivalent to 291.6– 583.2 mg magnesium or 12-24 mmol magnesium daily).

Children and adolescents (12 to 18 years)

The recommended daily dose for children (12 to 18 years) and adolescents is 12 mmol magnesium, e.g. 1 tablet administered 3 times a day (equivalent to 291.6 mg magnesium or 12 mmol magnesium daily).

Special populations

Children less than 12 years:

Magnesium Kora Healthcare is not recommended for children less than 12 years as the safety and efficacy of Magnesium Kora Healthcare in children less than 12 years has not yet been established.

Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

Elderly:

As older patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal impairment below).

Patients who experience difficulties swallowing tablets should preferably be treated with a magnesium powder for oral solution.

Patients with renal impairment:

Magnesium Kora Healthcare is contraindicated in patients with severe renal impairment (see section 4.3).

There is no dose adjustment necessary in patients with mild to moderate renal impairment.

Method of administration

For oral use.

The tablet may be broken in half using the score line. The score line is present only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.3. Contraindications

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

Severe renal impairment (glomerular filtration rate < 30 ml/min).

4.4. Special warnings and precautions for use

If an undesirable effect occurs, such as diarrhoea, the therapy should be temporarily interrupted and can be restarted after improvement and /or elimination of the symptoms with a reduced dosage.

In the case of confirmed magnesium deficiency, concomitant hypocalcaemia and hypokalaemia should be suspected and corrected if confirmed since magnesium deficiency is frequently secondary to those conditions.

Exercise caution when prescribing Magnesium Kora Healthcare for patients with disorders of cardiac conduction.

Magnesium Kora Healthcare is not intended as first-line treatment for patients with severe symptomatic hypomagnesemia or serum levels <0.4mmol/L for whom intravenous magnesium is indicated. Subject to local treatment protocols, oral magnesium treatment may begin when serum magnesium rises above 0.4 mmol/L or when acute symptoms of hypomagnesemia have resolved.

The bioavailability of magnesium preparations can vary, therefore caution should be exercised when switching between magnesium preparations to ensure tolerability and equivalent therapeutic effect.

Diabetes mellitus is commonly associated with magnesium depletion. Other associated endocrine conditions that may be linked to hypomagnesaemia, include hyperthyroidism and hyperaldosteronism, these conditions should be considered, and excluded.

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

As magnesium and other medicinal products may mutually influence each other's absorption, a time interval of 2 to 3 hours should generally be respected if possible.

This specifically applies to:

• Cellulose sodium phosphate; edetate disodium: concurrent use with magnesium supplements may result in binding of magnesium; patients should be advised not to take magnesium supplements within 1 hour of cellulose sodium phosphate or edentate disodium.

• Fluorides and tetracycline: if they must be used, the doses must be separated by 2 to 3 hours or more to prevent their admixture in the gut.

• Aminoquinolines, quinidine and quinidine derivatives, nitrofurantoin, penicillamine, iron, bisphosphonates, eltrombopag, nitroxoline: to avoid impairment of absorption, magnesium preparations should be taken 3 to 4 hours before or after the administration of those drugs.

Magnesium homeostasis influenced by medication

Because of increased magnesium losses, a dose adjustment of magnesium may be necessary when taking the following substances:

Diuretics (e.g. thiazide, furosemide) are widely used in the treatment of hypertension, heart failure and kidney diseases. They increase urinary output with hypermagnesuria probably leading to hypomagnesaemia and magnesium depletion.

EGF-receptor antagonist (e.g. cetuximab, erlotinib, panitumumab). Since EGF is a magnesiotropic hormone, treatment with EGF-receptor antagonists can result in severe hypomagnesaemia.

VEGF-blockers Bevacizumab is a humanised IgG1 antibody that binds and inhibits VEGF activity. Hypomagnesaemia is recognised as a very common adverse reaction associated with bevacizumab therapy.

PD-1 inhibitors Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody that works as a checkpoint inhibitor that allows the immune system to kill cancer cells. Treatment with nivolumab can result in dysregulation of magnesium metabolism.

Long-term treatment with proton pump inhibitors (e.g. omeprazole, esomeprazole, lansoprazole and pantoprazole) has been related to severe hypomagnesaemia, probably due to disturbances in absorption.

Aminoglycoside antibiotics (e.g. gentamycin, tobramycin and amikacin) are widely used in the treatment of severe bacterial infections. Studies showed that in 25 % of the patients, hypomagnesaemia occurs due to renal magnesium loss.

Foscarnet is a pyrophosphate analogue that inhibits many viral DNA polymerases.

Hypomagnesaemia is among others a side effect of foscarnet treatment as foscarnet is a potent chelator of divalent cations. Other viral DNA polymerase inhibitors include Pentamidine, Rapamycin and Amphotericin B.

Immunosuppressive agents (e.g. Ciclosporin A and Tacrolimus) increase the loss of magnesium via the kidneys.

Chemotherapy agents (e.g. Cisplatin and Carboplatin) can result in hypomagnesemia - a widely recognised toxic side effect of chemotherapy and occurs due to renal tubular toxicity.

Magnesium homeostasis influenced by medical conditions

Excessive excretion of magnesium into the urine is a cause of magnesium depletion. Osmotic diuresis due to glucosuria can result in magnesium depletion, therefore, those with diabetes mellitus have an increased requirement for magnesium.

4.6. fertility, Pregnancy and lactation

Pregnancy

A large amount of data on pregnant women over 16 weeks' gestation (more than 1,000 pregnancy outcomes) do not indicate malformative toxicity or feto/neonatal toxicity of magnesium.

Magnesium Kora Healthcare can be used during pregnancy if clinically needed.

Administration of aminoglycoside antibiotics should be avoided during this period, as there are indications of interactions (see 4.5).

Lactation

Magnesium Kora Healthcare can be used during breast-feeding. Magnesium citrate / metabolites are excreted in human milk, but at therapeutic doses of Magnesium Kora Healthcare no effects on the breastfed newborns/infants are anticipated.

Fertility

Based on long-term experience, no effects of magnesium on male and female fertility are anticipated.

4.7. Effects on ability to drive and use machines

Magnesium Kora Healthcare has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

At high dosage diarrhoea or gastrointestinal irritation may occur. If diarrhoea occurs, the daily dose should be reduced and gradually increased later if needed.

In cases of high doses and long-term use fatigue may be experienced. This may be an indication that an elevated magnesium level has been achieved. Hypermagnesemia is rare after oral administration of magnesium salts, unless there is renal dysfunction.

The evaluation of undesirable effects is based on the following frequencies:

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 estimated from the available data).

Safety information is based on pooled data from clinical trials on magnesium supplementation.

MedDRA System Organ Class

Frequency

Undesirable Effects

Gastrointestinal disorders

Common

Soft stools or diarrhoea following high dosage

General disorders and administration site conditions

Very rare

Fatigue if used long-term

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 United Kingdom

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

In the case of intact renal function, magnesium intoxication due to oral overdose of magnesium is not expected. Only in the case of severe renal insufficiency accumulation of magnesium may arise in combination with a manifested intoxication.

In general, plasma concentrations up to 2 mmol/l magnesium are well tolerated.

Intoxication symptoms:

Blood pressure fall, nausea, vomiting, hyporeflexia, somnolence, changes in the electrocardiogram, respiratory depression and cardiac arrest.

Intoxication therapy:

Intravenous administration of calcium and slow intravenous administration of neostigmine methylsulfate;

Intravenous and per-oral administration of isotonic sodium chloride solution; ventilatory and circulatory support;

When patients have renal insufficiency haemodialysis may be used to lower the serum magnesium concentration.