SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Colecalciferol 1 000 IU Capsules Aviticol 1 000 IU Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains:

1 000 IU Colecalciferol (equivalent to 25 micrograms vitamin D₃)

Excipient with known effect: Azorubine, carmoisine (E122), used as capsule colouring, may cause allergic reactions.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, Hard capsule

Unprinted, hard gelatin red capsule containing clear, slightly yellow oily liquid. Capsule length: 21.7 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The treatment and prevention of vitamin D deficiency.

As an adjunct to specific therapy for osteoporosis in patients with vitamin D deficiency or at risk of vitamin D insufficiency.

Colecalciferol 1 000 IU Capsules is indicated in adolescents and adults.

4.2 Posology and method of administration

One capsule contains 1 000 IU colecalciferol (vitamin D₃).

Adult Posology

- Treatment of vitamin D deficiency: 1-4 capsules (1 000- 4 000 IU) daily for 10 weeks dependent upon the severity of the disease and the patient's response to treatment, followed by maintenance therapy of 1-2 capsules (1 000- 2 000 IU) daily, as directed by your doctor.

Follow-up serum 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 or treatment of vitamin D insufficiency: 1-2 capsules (1 000- 2 000 IU) daily. 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

- As an adjunct to specific therapy for osteoporosis: 1 capsule (1 000 IU) daily.

Adolescent Posology (over 12 years)

Treatment of vitamin D deficiency or insufficiency in children over 12 years: 1 capsule (1 000 IU) daily depending on the severity of the disease and the patient's response to treatment. It should only be given under medical supervision.

Infants and young children (0 -12 years)

Not recommended for children under 12 years.

Pregnancy and breastfeeding

Colecalciferol 1 000 IU Capsules are not recommended during pregnancy unless the clinical condition of the woman requires treatment.

Colecalciferol 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

Colecalciferol 1 000 IU Capsules must not be used in patients with:

•    Hypersensitivity to the active substance (Colecalciferol) 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

Colecalciferol 1000 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 Colecalciferol is not metabolised normally and other forms of vitamin D should be used.

Colecalciferol 1000 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).

Colecalciferol 1000 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

Colecalciferol 1000 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 Colecalciferol 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 Colecalciferol due to hepatic enzyme induction.

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

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

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

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

Colecalciferol 1000 IU Capsules should not be used during pregnancy unless the clinical condition of the woman requires treatment with colecalciferol, 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

Colecalciferol 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. Colecalciferol 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

System Organ Class

Frequency Category
Uncommon	Rare
(affecting less than 1 in 100	(affecting less than 1 in 1000
people)	people)

Metabolism and	Hypercalcaemia
nutrition disorders	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

[UK]: The Yellow Card Scheme www.mhra.gov.uk/yellowcard [MT]: www.medicinesauthority.gov.mt

4.9 Overdose

Acute or chronic overdose of Colecalciferol 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vitamin D and analogues

ATC code: A11CC05

Absorption: Colecalciferol is easily absorbed in the small intestine.

Colecalciferol is produced within the skin under the influence of UV radiation including sunlight. In its biologically active form, Colecalciferol 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 Colecalciferol. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active Colecalciferol.

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

5.2 Pharmacokinetic properties

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

Colecalciferol is metabolised by microsomal hydroxylase to form 25-hydroxycolecalciferol (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-hydroxycolecalciferol (1,25(OH)₂D₃, calcitriol). The metabolites circulate in the blood bound to a specific a-globin.

After a single oral dose of Colecalciferol, 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.

Colecalciferol and its metabolites are excreted mainly in the bile and faeces.

After high doses of Colecalciferol, 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

Colecalciferol is 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.

Colecalciferol 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, Colecalciferol has no teratogenic activity.

Colecalciferol has no potential mutagenic or carcinogenic activity.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule content

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

Colloidal anhydrous silica

Capsule shell:

Gelatin Purified water Polysorbate 80 Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Azorubine, carmoisine (E122)

6.2 Incompatibilities

Not applicable

Shelf life

18 months

6.4 Special precautions for storage

Store below 25°C.

Store in the original package to protect from light and moisture.

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 41344/0013

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

06/04/2016