Summary of Product Characteristics (SmPC) - Choli-D3 50 000 IU capsules, soft
1 NAME OF THE MEDICINAL PRODUCT
Choli-D3 50,000 IU Capsules, soft
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 50,000 IU Colecalciferol (equivalent to 1250 micrograms Vitamin D3)
Excipient(s) with known effect
Each capsule contains 5.28 mg of sorbitol.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule, soft (capsule)
Natural transparent, oval shaped soft gelatin capsule containing clear transparent liquid. Capsule size is about 11 mm in length.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
The treatment of vitamin D3 deficiency.
4.2 Posology and method of administration
Posology
Paediatric population
Due to lack of clinical data, Choli-D3 50,000 IU Capsules is not recommended.
Pregnancy and breastfeeding
Due to lack of clinical data, Choli-D3 50,000 IU Capsules is not recommended.
Adults
Higher doses may be required in certain situations, see below.
⎯ Treatment of vitamin D3 deficiency (<25 nmol/l) 50,000 IU/week (1 capsule) for 6-8 weeks, followed by maintenance therapy (1400-2000 IU/day may be required, such as 1 capsule per month; 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).
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
⎯ Obese individuals
⎯ Patients being evaluated for osteoporosis
⎯ Use of certain concomitant medications (e.g., anticonvulsant medications,
glucocorticoids)
⎯ Patients with malabsorption, including inflammatory bowel disease and coeliac disease ⎯ Those recently treated for vitamin D deficiency, and requiring maintenance therapy.
Special Populations
Hepatic impairment: no dose adjustment is necessary for patients with hepatic impairment. Renal impairment: Choli-D3 50,000 IU Capsules should not be used in combination with calcium in patients with severe renal impairment.
Method of administration
Oral
The capsules should be swallowed whole (not chewed) with water. It should be taken with food.
4.3 Contraindications
⎯ Hypersensitivity to the active substance(s) or to any of the excipients. ⎯ Hypercalcaemia and/or hypercalciuria.
⎯ Nephrolithiasis and/or nephrocalcinosis
⎯ Severe renal impairment.
⎯ Hypervitaminosis D
⎯ Pseudohypoparathyroidismas the vitamin D requirement may be reduced due to phases of normal vitamin D sensitivity, involving the risk of prolonged overdose. Better-regulatable vitamin D derivatives are available for this
⎯ Pregnancy
⎯ Children and adolescents (under 18 years of age)
4.4 Special warnings and precautions for use
Vitamin D3 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
Caution is required in patients receiving treatment for cardiovascular disease (see section 4.5 Interaction with other medicinal products and other forms of interaction - cardiac glycosides including digitalis).
Vitamin D3 should be prescribed with caution in patients with sarcoidosis, due to a possible increase in the metabolism of Vitamin D3 in its active form. In these patients the serum and urinary calcium levels should be monitored.
Allowances should be made for the total dose of Vitamin D3 in cases associated with treatments already containing Vitamin D3, foods enriched with Vitamin D3, cases using milk enriched with Vitamin D3, and the patient’s level of sun exposure.
There is no clear evidence for causation between Vitamin D3 supplementation and renal stones, but the risk is plausible, especially in the context of concomitant calcium supplementation. The need for additional calcium supplementation should be considered for individual patients. Calcium supplements should be given under close medical supervision.
Oral administration of high-dose Vitamin D3 (500,000 IU by single annual bolus) was reported to result in an increased risk of fractures in elderly subjects, with the greatest increase occurring during the first 3 months after dosing.
This medicinal product contains sorbitol which may cause gastrointestinal discomfort and mild laxative effect.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use of anticonvulsants (such as phenytoin) or barbiturates (and possibly other drugs that induce hepatic enzymes) may reduce the effect of Vitamin D3 by metabolic inactivation.
In cases of treatment with thiazide diuretics, which decrease urinary elimination of calcium, monitoring of serum calcium concentration is recommended.
Concomitant use of glucocorticoids can decrease the effect of Vitamin D3.
In cases of treatment with drugs containing digitalis and other cardiac glycosides, the administration of Vitamin D3 may increase the risk of digitalis toxicity (arrhythmia). Strict medical supervision is needed, together with serum calcium concentration and electrocardiographic monitoring if necessary
Simultaneous treatment with ion exchange resin such as cholestyramine, colestipol hydrochloride, orlistat or laxative such as paraffin oil may reduce the gastrointestinal absorption of Vitamin D3.
The cytotoxic agent actinomycin and imidazole antifungal agents interfere with Vitamin D3 activity by inhibiting the conversion of 25-hydroxyVitamin D3 to 1,25- dihydroxy Vitamin D3 by the kidney enzyme, 25-hydroxyVitamin D3-1-hydroxylase.
4.6 Fertility, pregnancy and lactation
In pregnancy and lactation, the high strength formulation is not recommended and a low strength formulation should be used.
Pregnancy
There are no or limited amount of data from the use of colecalciferol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3 Preclinical safety data). The recommended daily intake for pregnant women is 400 IU, however, in women who are considered to be Vitamin D3 deficient a higher dose may be required (up to 2000 IU/day- 10 drops with the oral drops presentation).
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 Vitamin D3 and its metabolites are excreted in breast milk.
Breast-feeding
Vitamin D3 can be prescribed while the patient is breast-feeding if necessary. This supplementation does not replace the administration of Vitamin D3 in the neonate
Fertility
There is no data regarding treatment with vitaminD3 and its effects on fertility.
4.7 Effects on ability to drive and use machines
There are no data on the effects of Vitamin D3 on the ability to drive. However, an effect on this ability is unlikely.
4.8 Undesirable effects
Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: uncommon (>1/1,000, <1/100) or rare (>1/10,000, <1/1,000).
Metabolism and nutrition disorders:
Uncommon: Hypercalcaemia and hypercalciuria.
Skin and subcutaneous disorders:
Rare: pruritus, rash, and urticaria.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continues 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 Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Ergocalciferol (vitamin D2) and colecalciferol (vitamin D3) have a relatively low therapeutic index. The threshold for vitamin D intoxication is between 40,000 and 100,000 IU daily for 1 to 2 months in adults with normal parathyroid function. Infants and small children may react sensitively to far lower concentrations. Therefore, it is warned against intake of vitamin D without medical supervision.
Overdose leads to increased serum and urinary phosphorus levels, as well as hypercalcaemic syndrome and consequently calcium deposits in the tissues and above all in the kidneys (nephrolithiasis, nephrocalcinosis) and the vessels.
Discontinue Vitamin D3 when calcaemia exceeds 10.6 mg/dl (2.65 mmol/l) or if the calciuria exceeds 300 mg/24 hours in adults or 4-6 mg/kg/day in children. Chronic overdosage may lead to vascular and organ calcification, as a result of hypercalcaemia.
The symptoms of intoxication are little characteristic and manifest as nausea, vomiting, initially also diarrhoea, later constipation, loss of appetite, weariness, headache, muscle pain, joint pain, muscle weakness, persistent sleepiness, azotaemia, polydipsia and polyuria and, in the final stage, dehydration. Typical biochemical findings include hypercalcaemia, hypercalciuria, as well as increased serum 25 hydroxy colecalciferol concentrations.
Treatment of overdose
Symptoms of chronic vitamin D overdosage may require forced diuresis as well as administration of glucocorticoids or calcitonin.
Overdosage requires measures for treating the - often persisting and under certain circumstances life- threatening - hypercalcaemia.
The first measure is to discontinue the vitamin D preparation; it takes several weeks to normalise hypercalcaemia caused by vitamin D intoxication.
Depending on the degree of hypercalcaemia, measures include a diet that is low in calcium or free of calcium, abundant liquid intake, increase of urinary excretion by means of the drug furosemide, as well as the administration of glucocorticoids and calcitonin.
If kidney function is adequate, calcium levels can be reliably lowered by infusions of isotonic sodium chloride solution (3–6 litres in 24 hours) with addition of furosemide and, in some circumstances, also 15 mg/kg body weight/hour sodium edetate accompanied by continuous calcium and ECG monitoring. In oligoanuria, in contrast, haemodialysis (calcium-free dialysate) is necessary.
No special antidote exists.
It is recommended to point out the symptoms of potential overdose to patients under chronic therapy with higher doses of vitamin D (nausea, vomiting, initially also diarrhoea, later constipation, anorexia, weariness, headache, muscle pain, joint pain, muscle weakness, persistent sleepiness, azotaemia, polydipsia and polyuria).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Vitamin D and analogues, ATC code: A11CC05
In its biologically active form Vitamin D3 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 parathyroid is inhibited directly by the biologically active form of vitamin D3. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active Vitamin D3.
5.2 Pharmacokinetic properties
The pharmacokinetics of Vitamin D3 is well known.
Absorption
Vitamin D3 is well absorbed from the gastro-intestinal tract in the presence of bile, so the administration with the major meal of the day might therefore facilitate the absorption of Vitamin D3.
Distribution and Biotransformation
It is hydroxylated in the liver to form 25-hydroxy-cholecalciferol and then undergoes further hydroxylation in the kidney to form the active metabolite 1, 25-dihydroxycholecalciferol (calcitriol).
Elimination
The metabolites circulate in the blood bound to a specific α – globin, Vitamin D3 and its metabolites are excreted mainly in the bile and faeces.
Characteristics in Specific Groups of Subjects or Patients
A 57% lower metabolic clearance rate is reported in subjects with renal impairment as compared with that of healthy volunteers.
Decreased absorption and increased elimination of Vitamin D3 occurs in subjects with malabsorption.
Obese subjects are less able to maintain Vitamin D3 levels with sun exposure, and are likely to require larger oral doses of Vitamin D3 to replace deficits.
5.3 Preclinical safety data
Pre-clinical studies conducted in various animal species have demonstrated that toxic effects occur in animals at doses much higher than those required for therapeutic use in humans.
In toxicity studies at repeated doses, the effects most commonly reported were increased calciuria and decreased phosphaturia and proteinuria. Hypercalcaemia has been reported in high doses. In a state of prolonged hypercalcaemia, histological alterations (calcification) were more frequently borne by the kidneys, heart, aorta, testes, thymus and intestinal mucosa.
Colecalciferol has been shown to be teratogenic at high doses in animals.
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 fill:
Medium chain triglycerides
all-rac-α-Tocopheryl acetate (Vitamin E acetate)
Capsule shell:
Gelatin
Glycerol
Sorbitol liquid, partially dehydrated
Purified water
6.2 Incompatibilities
Not applicable
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store the capsules in the original container in order to protect from light.
6.5 Nature and contents of container
PVC/PVdC/Aluminium foil blister packs Pack sizes: 3, 4, 6, 8, 10, 20 and 30 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
OSGEN PHARMACEUTICALS LIMITED Unit 2 Cleveland Way, Hemel Hempstead Industrial Estate, Hemel Hempstead, HP2 7DL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 48836/0013
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/12/2022
10 DATE OF REVISION OF THE TEXT
22/12/2022