SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Aviticol 20 000 IU Capsules Cholecalciferol 20 000 IU Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains:

20 000 IU cholecalciferol (equivalent to 500 pg vitamin D₃)

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, Hard

Ivory opaque, unprinted, hard gelatin capsule containing a clear, slightly yellow oily liquid.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment and prevention of vitamin D deficiency.

Aviticol is indicated in adolescents and adults

4.2 Posology and method of administration

One capsule contains 20 000 IU Cholecalciferol (vitamin D₃).

Adult Posology

Treatment of vitamin D deficiency: 40 000 IU every week (2 capsules) for 7 weeks, followed by maintenance therapy (equivalent to 1 400 - 2 000 IU/day, such as 2-3 capsules per month, as directed by your doctor.

Follow-up 25(OH)D measurements should be made approximately three to four months after initiating maintenance therapy to confirm that the target level has been achieved)

- Prevention of vitamin D deficiency: 20 000 IU every 4 weeks (1 capsule), higher doses may be required in certain populations, see below.

Certain populations are at high risk of vitamin D deficiency, and may require higher doses and monitoring of serum 25(OH)D:

•    Institutionalised or hospitalised individuals

•    Dark skinned individuals

•    Individuals with limited effective sun exposure due to protective clothing or consistent use of sun screens

•    Patients being evaluated for osteoporosis

•    Obese individuals

•    Use of certain concomitant medications (e.g. anticonvulsant medications glucocorticoids, anti-retrovirals)

•    Those recently treated for vitamin D deficiency, and requiring maintenance therapy

•    Patients with liver or renal disease

•    Patients with malabsorption, including inflammatory bowel disease and coeliac disease.

• Paediatric Posology

- Treatment of vitamin D deficiency 12-18 years: 20 000 IU (1 capsule) once every 2 weeks for 6 weeks.

- Prevention of vitamin D deficiency 12-18 years: 20 000 IU (1 capsule) every 6 weeks.

Infants and young children (0 -12 years)

Not recommended for children under 12 years.

Pregnancy and breastfeeding

Aviticol 20 000 IU capsules are not recommended during pregnancy unless the clinical condition of the woman requires treatment.

Cholecalciferol and its metabolites are excreted in breast milk. Overdose in infants induced by nursing mothers has not been observed but allowance for any maternal dose should be made when prescribing vitamin D products to a breast-fed child.

Method of administration

This medicine is taken orally.

The capsule should be swallowed whole with water, preferably with the main meal of the day.

4.3 Contraindications

Aviticol 20 000 IU Capsules must not be used in patients with:

•    Hypersensitivity to the active substance (cholecalciferol) or to any of the excipients listed in section 6.1

•    Hypercalcaemia and/or hypercalciuria

•    Nephrolithiasis (Renal calculi)

•    Hypervitaminosis

•    Severe renal impairment

4.4 Special warnings and precautions for use

Aviticol 20 000 IU Capsules should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of cholecalciferol is not metabolised normally and other forms of vitamin D should be used.

Aviticol 20 000 IU Capsules should not be taken by patients with a tendency to form calcium-containing renal calculi.

Caution is required in patients receiving treatment for cardiovascular disease (see section 4.5 - cardiac glycosides including digitalis).

Aviticol 20 000 IU Capsules should be prescribed with caution to patients suffering from sarcoidosis because of the risk of increased metabolism of vitamin D to its active form. These patients should be monitored with regard to the calcium content in serum and urine.

Allowances should be made for vitamin D supplements, other vitamin D containing medicines or from other sources.

The need for additional calcium supplementation should be considered for individual patients. Calcium supplements should be given under close medical supervision.

Medical supervision is required whilst on treatment to prevent hypercalcaemia.

Paediatric population

Aviticol 20 000 IU Capsules should not be given to infants and children under the age of 12.

4.5 Interaction with other medicinal products and other forms of interaction

Phosphate infusions should not be administered to lower hypercalcaemia of hypervitaminosis D because of the dangers of metastatic calcification.

Patients treated with cardiac glycosides may be susceptible to high calcium levels and should have ECG parameters and calcium levels monitored. It is recommended to reduce the dose or interrupt treatment if the calcium content in the urine exceeds 7.5 mmol/24 hours (300 mg/24 hours).

Simultaneous administration of benzothiadiazine derivatives (thiazide diuretics) increases the risk of hypercalcaemia because they decrease the calcium excretion in the urine. The calcium levels in plasma and urine should therefore be monitored for patients undergoing long-term treatment.

If cholecalciferol is combined with metabolites or analogues of vitamin D careful monitoring of serum calcium levels is recommended.

Anti-convulsants e.g. phenytoin, phenobarbital, primidone may diminish the effect of cholecalciferol due to hepatic enzyme induction.

Rifampicin may reduce the effectiveness of cholecalciferol due to hepatic enzyme induction.

Isoniazid may reduce the effectiveness of cholecalciferol due to inhibition of the metabolic activation of cholecalciferol.

Drugs leading to fat malabsorption, e.g. orlistat, liquid paraffin, cholestyramine, may impair the absorption of cholecalciferol.

The cytotoxic agent actinomycin and imidazole antifungal agents interfere with vitamin D activity by inhibiting the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the kidney enzyme, 25-hydroxyvitamin D-1-hydroxylase.

Concomitant use of glucocorticoids can decrease the effect of vitamin D.

4.6 Fertility, pregnancy and lactation

Pregnancy

Aviticol 20 000 IU Capsules should not be used during pregnancy unless the clinical condition of the woman requires treatment with cholecalciferol, at a dose necessary to overcome the deficiency.

During pregnancy women should follow the advice of their medical practitioner as their requirements may vary depending on the severity of their disease and their response to treatment.

Based on human experience and animal studies, vitamin D overdose causes physical and mental disability and congenital heart and eye conditions, due to hypercalcaemia, when administered during pregnancy.

Breast-feeding

Aviticol and its metabolites are excreted in breast milk. Overdose in infants induced by nursing mothers has not been observed. However, when prescribing additional vitamin D to a breast-fed child the practitioner should consider the dose of any additional vitamin D given to the mother.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive or use machines have been performed. Aviticol has no known side effects that are likely to affect the ability to drive and use or operate machines.

4.8 Undesirable effects

Adverse reactions are listed below, by system organ class and frequency.

MedDRA	Frequency Category
System Organ Class	Uncommon (affecting les than 1 in 100 people)	Rare (affecting less than 1 in 1000 people)
Metabolism and nutrition disorders	Hypercalcaemia Hypercalciuria
Skin and		Pruritus
Subcutaneous disorders		Rash Urticaria

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

The Yellow Card Scheme (www.mhra. gov.uk/yellowcard).

4.9 Overdose

Acute or chronic overdose of Aviticol can cause hypercalcaemia, an increase in the serum and urinary concentrations of calcium. The symptoms of hypercalcaemia are not very specific and consist of nausea, vomiting, diarrhoea often in the early stages and later constipation, anorexia, fatigue, headache, muscle and joint pain, muscle weakness, polydipsia, polyuria formation of renal calculi, nephrocalcinosis, kidney failure, calcification of soft tissues, changes in ECG measurements, arrhythmias and pancreatitis. In rare and isolated cases there are reports that hypercalcaemia is fatal.

Treatment of overdose

A normalisation of hypercalcaemia due to vitamin D intoxication lasts several weeks. The recommendation for the treatment of hypercalcaemia is the avoidance of any further administration of vitamin D, including supplements, dietary intakes and the avoidance of sunlight. A low calcium or calcium-free diet can also be considered.

Rehydration and the treatment with diuretics e.g. furosemide to ensure adequate diuresis should be considered. Additional treatment with calcitonin or corticosteroids can also be considered.

Phosphate infusions should not be administered to lower hypercalcaemia of hypervitaminosis D because of the dangers of metastatic calcification.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vitamin D and analogues ATC code: A11CC05

Absorption: Cholecalciferol is easily absorbed in the small intestine.

Cholecalciferol is produced within the skin under the influence of UV radiation including sunlight. In its biologically active form, cholecalciferol stimulates intestinal calcium absorption, incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed

calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of calcium and phosphate by promoting tubular resorption. The production of parathyroid hormone (PTH) in the parathyroids is inhibited directly by the biologically active form of cholecalciferol. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active cholecalciferol.

Elimination: Cholecalciferol and other forms of vitamin D are excreted in faeces and urine.

5.2 Pharmacokinetic properties

The pharmacokinetics of cholecalciferol have been widely studied and are well-known. Cholecalciferol from nutritional sources is almost completely absorbed from within the gastro-intestinal tract in the presence of dietary lipids and bile acids. Cholecalciferol is stored in fat cells and its biological half-life is approximately 50 days.

Cholecalciferol is metabolised by microsomal hydroxylase to form 25-hydroxycholecalciferol (25(OH)D₃, calcidiol), the primary storage form of vitamin D₃. 25(OH)D₃ undergoes a secondary hydroxylation within the kidney to form the predominant active metabolite 1,25-hydroxycholecalciferol (1,25(OH)₂D₃, calcitriol). The metabolites circulate in the blood bound to a specific a-globin.

After a single oral dose of cholecalciferol, the maximum serum concentrations of the primary storage form are reached after approximately 7 days. 25(OH)D₃ is then slowly eliminated with an apparent half-life in serum of about 50 days. Cholecalciferol and its metabolites are excreted mainly in the bile and faeces.

After high doses of cholecalciferol, serum concentrations of 25(OH)D₃ may be increased for months. Overdose-induced hypercalcaemia may persist for weeks (see

4.9 "Overdose”).

5.3 Preclinical safety data

Cholecalciferol is a well-known and established product and has been used in clinical practice for many years. No further specific toxicological hazard for humans is expected other than in chronic overdosage where hypercalcaemia could be seen.

Cholecalciferol overdosage in animals has been shown to induce malformations in rats, mice and rabbits at doses significantly higher than the human dose. The malformations included skeletal defects, microcephaly and cardiac malformations.

At doses equivalent to those used therapeutically, cholecalciferol has no teratogenic activity.

Cholecalciferol has no potential mutagenic or carcinogenic activity.

6.1    List of excipients

Capsule content

Medium-chain Triglycerides (from vegetable sources) Butylated Hydroxytoluene (BHT)

Colloidal silicon dioxide

Capsule shell:

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

18 months

6.5 Nature and contents of container

Opaque, white PVC/PVdC blister packs with aluminium foil.

Pack sizes: 10, 14, 20, 28, 30, 56, 60, 84 and 100

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal. Any unused product should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Colonis Pharma Limited Hanover Place 8 Church Road Royal Tunbridge Wells Kent TN1 1JP United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 41344/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/12/2014

10    DATE OF REVISION OF THE TEXT

09/07/2015