Summary of medicine characteristics - COLECALCIFEROL 10000IU/ML ORAL SOLUTION
1 NAME OF THE MEDICINAL PRODUCT
Colecalciferol 10000IU/ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Colecalciferol oral solution contains the active substance, colecalciferol.
Each ml of oral solution contains 10000IU colecalciferol.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral solution
A clear, yellow coloured solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Prevention and treatment of vitamin D deficiency in adults, adolescents and children with an identified risk.
As an adjunct to specific therapy for osteoporosis in patients with vitamin D deficiency or at risk of vitamin D insufficiency.
4.2 Posology and method of administration
Posology
Adults:
Prevention of vitamin D deficiency and osteoporosis:
Recommended dose is 600 – 800 IU per day (0.06–0.08ml).
Treatment of vitamin D deficiency:
800 IU (0.08ml) per day. Higher doses should be adjusted dependent upon desirable serum levels of 25-hydroxycolecalciferol (25(OH)D), the severity of the disease and the patient’s response to treatment.
The daily dose should not exceed 4,000 IU (0.4ml per day).
Paediatric population
Prevention:
For prevention in children (0 years to 11 years old) with an identified risk, the recommended dose is 400 IU (0.04ml) per day.
For prevention in adolescents (12 years to 18 years old) with an identified risk, the recommended dose is 600–800 IU (0.06–0.08ml) per day.
Treatment of deficiency in children and adolescents:
The dose should be adjusted dependent upon desirable serum levels of 25-hydroxycolecalciferol (25(OH)D), the severity of the disease and the patient’s response to treatment.
The daily dose should not exceed 1000 IU (0.1ml) per day for infants <1 year, 2000 IU (0.2ml) per day for children 1–10 years and 4000 IU (0.4ml) per day for adolescents >11 years.
Alternatively, national posology recommendations in prevention and treatment of vitamin D deficiency can be followed.
Special Populations
Dosage in hepatic impairment
No dose adjustment is required.
Dosage in renal impairment
Patients with mild or moderate renal impairment: no specific adjustment is required.
Colecalciferol must not be used in patients with severe renal impairment.
Dosage in pregnancy
The recommended daily intake for pregnant women is 400 IU (0.04ml), however, in women who are considered to be vitamin D3 deficient a higher dose may be required (up to 2000 IU per day – 0.2ml).
Other conditions: such as obese patients, patients with malabsorption syndromes, and patients on medications affecting vitamin D3 metabolism, higher doses are required for the treatment and prevention of vitamin D3 deficiency.
Method of administration
Patients should be advised to take Colecalciferol preferably with a meal (see section 5.2).
The product should be shaken before use.
Colecalciferol Oral solution has a taste of sunflower oil. Colecalciferol Oral Solution can be taken as is or to facilitate the intake it can also be mixed with a spoonful or a small amount of cold or lukewarm food immediately prior to use. The patient should be sure to take the entire dose.
In children, Colecalciferol Oral solution can be mixed with a small amount of children’s foods, yogurt, milk, cheese or other dairy products. The parents should be warned not to mix Colecalciferol Oral solution into a bottle of milk or container of soft foods in case the child does not consume the whole portion, and does not receive the full dose. The parents should ensure that their child takes the entire dose. In children who are not breast-fed, the prescribed dose should be administered with a meal (see section 6.6).
4.3 Contraindications
Hypersensitivity to the colecalciferol (vitamin D3) or to any of the excipients listed in section 6.1.
Hypercalcaemia or hypercalciuria
Hypervitaminosis D
Kidney stones (nephrolithiasis, nephrocalcinosis) in patients with current chronic hypercalcaemia
Severe renal impairment
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).
Colecalciferol should be prescribed with caution to patients suffering from sarcoidosis, due to a possible increase in the metabolism of vitamin D3 in its active form. These patients should be monitored with regard to the calcium content in serum and urine.
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.
During long-term treatment with a daily dose exceeding 1,000 IU vitamin D3 the serum calcium values must be monitored.
For patients with elevated levels of parathyroid hormone (PTH) or clinical evidence of rickets, calcium should be supplemented along with vitamin D. This is because vitamin D replacement and a normalisation of PTH levels can precipitate hypocalcaemia by suppressing bone resorption and from increased bone mineralisation, also referred to as the „hungry bone“ syndrome.
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-dihydroxyvitamin D3 by the kidney enzyme, 25-hydroxyvitamin D-1-hydroxylase.
Atorvastatin (colecalciferol lowers its plasma concentration); calcium channel blockers, cimetidine, gabapentin, heparin, hydroxychloroquine, indapamide, isoniazid, neomycin, or valproic acid (lowers colecalciferol levels).
4.6 Fertility, pregnancy and lactation
Fertility
There are no data on the effect of colecalciferol on fertility. However, normal endogenous levels of vitamin D are not expected to have any adverse effects on fertility.
Pregnancy
There are no or limited amount of data from the use of colecalciferol (vitamin D3) 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 lU/day – 0.2ml). 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.
Overdose in infants induced by nursing mothers has not been observed, however, when prescribing additional vitamin D3 to a breast-fed child the practitioner should consider the dose of any additional vitamin D3 given to the mother.
4.7 Effects on ability to drive and use machines
There are no data on the effect of Colecalciferol on the ability to drive or use machines. 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 to <1/100) or rare (>1/10,000 to <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 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 Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseDiscontinue Colecalciferol 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. An overdose manifests as hypercalcaemia and hypercalciuria, the symptoms of which include the following: nausea, vomiting, thirst, constipation, polyuria, polydipsia and dehydration.
Due to vitamin D overdose, calcium phosphate crystals may be deposited in soft tissues throughout the body. Acute hypercalcaemia due to vitamin D toxicity directly shortens the myocardial action potential, which is reflected in a shortened QT interval.
Chronic overdosage may lead to vascular and organ calcification, as a result of hypercalcaemia.
Treatment in cases 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 supplements (vitamin D3 and analogues)
ATC code: A11C C05
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 parathyroids 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 D 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-colecalciferol and then undergoes further hydroxylation in the kidney to form the active metabolite 1,25-dihydroxy-colecalciferol (calcitriol).
Elimination:
The metabolites circulate in the blood bound to a specific a – 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
5.3 Preclinical safety dataPre-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 (vitamin D3) has been shown to be teratogenic at high doses in animals.
At doses equivalent to those used therapeutically, colecalciferol (vitamin D3) has no teratogenic activity.
Colecalciferol (vitamin D3) has no potential mutagenic or carcinogenic activity.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Refined almond oil
Refined sunflower oil
6.2 Incompatibilities
In absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
15 months
Discard 30 days after first opening.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package.
Keep the bottle in the outer carton in order to protect from light.
For storage condition after first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Bottle: Amber (Type III) glass
Closure: Tamper evident, child resistant plastic cap consists of polypropylene inner, polyethylene outer, expanded polyethylene (EPE) liner
Dosing device: 1ml oral syringe with 0.01ml graduation mark and an LDPE adaptor
Pack size: 15ml
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Colecalciferol Oral Solution should only be mixed with food (including yogurts, milk, cheese or other dairy products immediately before being consumed.
Colecalciferol should not be stored mixed with food.
Method of administration
Use the measuring syringe provided in the pack to deliver the required dose.
Instructions for the use of syringe:
a) Open the bottle, press the cap and turn it anticlockwise (figure 1)
b) Separate the adaptor from the syringe (figure 2). Insert the adaptor into the bottle neck (figure 3). Ensure it is properly fixed. Take the syringe and put it in the adaptor opening (figure 4).
c) Turn the bottle upside down. Fill the syringe with a small amount of solution by pulling the piston down (figure 5A), then push the piston upwards in order to remove any possible bubble (figure 5B). Pull the piston down to the graduation mark corresponding to the quantity in millilitres (ml) prescribed by your doctor (figure 5C, this pictogram represents an example for measuring a dose of 0.08ml).
The total volume delivered from the syringe is 1ml with each numbered increment of 0.1ml, which is equivalent to 1000 IU colecalciferol. Each of the 0.1ml increment is further divided into ten divisions and each of these divisions represent 0.01ml, equivalent to 100 IU colecalciferol (see figure below).
d) Turn the bottle the right way up (figure 6A). Remove the syringe from the adaptor (figure 6B).
e) Empty the contents of the syringe into the patient’s mouth by pushing the piston to the bottom of the syringe (figure 7). The contents of the syringe should be emptied into the side cheek of the patient’s mouth to avoid a choking hazard. Close the bottle with the plastic screw cap. Wash the syringe with water (figure 8).