Summary of Product Characteristics (SmPC) - DITRALIA 50 000 IU ORODISPERSIBLE FILMS
1 NAME OF THE MEDICINAL PRODUCT
Ditralia 50 000 IU orodispersible films
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film contains 1250 micrograms Colecalciferol (vitamin D3) equivalent to 50 000 IU.
Excipients with known effect: Sunset yellow (E110) and Butylated hydroxyanisol E320.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Orodispersible film
Square, flexible, opaque light orange film (30 mm x 30 mm).
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Initial treatment of vitamin D deficiency (serum levels < 25 nmol/l or < 10 ng/ml)
in adults.
- Prevention of vitamin D deficiency in adults with an identified risk.
- As an adjunct to specific therapy for osteoporosis in adult patients with vitamin D deficiency or at a risk of vitamin D deficiency.
4.2 Posology and method of administration
Posology
The dosage must be determined individually by the treating doctor, depending on the extent of the necessary vitamin D supplementation.
Initial treatment of vitamin D deficiency (serum levels < 25 nmol/l or < 10 ng/ml):
a cumulative dose of 100 000 IU at once in the first month (4x 25 000 IU or 2x 50 000 IU).
After one month, a lower maintenance dose should be considered according to the desirable serum levels of 25-hydroxycolecalciferol (25(OH)D), the severity of the disease and the patient's response to treatment.
Prevention of vitamin D deficiency in adults with an identified risk:
25 000 IU/month – 25 000 IU/2 months
As an adjunct to specific therapy for osteoporosis:
25 000 IU/month
Alternatively, national posology recommendations in the prevention and treatment of vitamin D deficiency can be followed.
Renal impairment
Ditralia should not be used in patients with severe renal impairment (see section 4.3).
Hepatic impairment
No posology adjustment is required in patients with hepatic impairment.
Paediatric patients
Ditralia is not approved for use in children and adolescents under 18 years of age. The strength of 25 000 IU and 50 000 IU orodispersible films is not suitable for the use in paediatric population because studies on the safe use of high doses in paediatric population are too limited. However, products with a strength lower than 25 000 and 50 000 IU are also available.
Method of administration
Ditralia orodispersible films are for oral use and can be taken with or without food.
The orodispersible film should be placed in the mouth, on the tongue, and allowed to dissolve before swallowing. It should be taken immediately upon removal from the sachet.
4.3 Contraindications
- Hypersensitivity to the active substance(s) or to any of the excipients.
- Hypercalcaemia and/or hypercalciuria.
- Nephrolithiasis.
- Severe renal impairment
- Hypervitaminosis D
- Nephrocalcinosis
4.4 Special warnings and precautions for use
Monitoring
During initial and long-term treatment with Ditralia, serum calcium levels should be monitored and the kidney function checked by measurement of serum creatinine. Monitoring is particularly important on elderly patients and in concomitant treatment with cardiac glycosides or diuretics (see section 4.5), and in the case of hyperphosphatemia, as well as for patients with an increased risk of lithiasis. In case of hypercalcaemia or hypercalciuria (exceeding 300 mg (7.5 mmol)/24 hours) treatment has to be discontinued (see section 4.3). In case of impaired renal function, the dose should be reduced or the treatment discontinued.
Renal impairment
Colecalciferol should be used with caution in patients with renal impairment and the effect on the calcium and phosphate metabolism should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal impairment, vitamin D in the form of colecalciferol is contraindicated (see section 4.3).
Pseudohypoparathyroidism
Colecalciferol should not be taken if pseudohypoparathyroidism is present (the need for vitamin D may be reduced by the sometimes normal sensitivity to vitamin D, with a risk of long-term overdose). In such cases, more manageable vitamin D derivatives are available.
Sarcoidosis
Colecalciferol should be prescribed with caution to patients suffering from sarcoidosis, as there is the risk of increased conversion of vitamin D to its active metabolite. Serum and urinary calcium levels should be monitored in these patients.
Concomitant administration of other vitamin D-containing products
If other vitamin D-containing medicines are prescribed, the dose of vitamin D contained in Colecalciferol must be taken into consideration. The additional administration of vitamin D should only be carried out under medical supervision.
Other information
This medicine contains Sunset yellow (E110), which may cause allergic reactions.
This medicine contains Butylated hydroxyanisole (E320), which may cause irritation to the oral mucosa.
4.5 Interaction with other medicinal products and other forms of interaction
Calcium
Medicinal products having effect through the inhibition of bone resorption decrease the calcium amounts derived from bone. In order to avoid this, as well as concomitantly to treatment with medicines enhancing bone development, it is necessary to take vitamin D and ensure proper calcium levels.
Concomitant use with calcium containing products administered in large doses may increase the risk of hypercalcaemia.
Thiazide diuretics
Thiazide diuretics reduce the excretion of calcium with urine. Regular monitoring of the serum calcium level is necessary because of the increased risk of hypercalcaemia.
Anticonvulsants
Anticonvulsants, like phenytoin and barbiturates may reduce the effect of vitamin D.
Systemic corticosteroids
Systemic corticosteroids may increase vitamin D metabolism and elimination. During concomitant use, it may be necessary to increase the dose of vitamin D.
Digitalis and other cardiac glycosides
In cases of treatment with drugs containing digitalis and other cardiac glycosides, the administration of vitamin D may increase the risk of digitalis toxicity (arrhythmias). Strict medical supervision is needed and, if necessary monitoring of ECG and calcium.
Ion exchange resins and laxatives
Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.
Orlistat
Orlistat may potentially impair the absorption of colecalciferol as it is fat-soluble. Vitamin D should not be administered within 2 hours before the administration of orlistat, or within 2 hours thereafter.
Cytotoxic agent actinomycin and imidazole antifungal agents
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.
Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D. Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg/day to 1,200 mg/day ketoconazole for a week to healthy men. However, in vivo drug interaction studies of ketoconazole with vitamin D have not been conducted.
Products containing magnesium
Products containing magnesium (like antacids) may not be taken during vitamin D treatment because of the risk of hypermagnesaemia.
Products containing phosphor
Products containing phosphor used in large doses, given concomitantly may increase the risk of hyperphosphataemia.
Rifampicin
Rifampicin may reduce the effectiveness of colecalciferol due to hepatic enzyme induction.
Isoniazid
Isoniazid may reduce the effectiveness of colecalciferol due to inhibition of the metabolic activation of colecalciferol.
4.6 Fertility, Pregnancy and lactation
During pregnancy and breast-feeding this high dosed product is not recommended and a lower dosed product should be used. During pregnancy and breast-feeding adequate vitamin D intake is necessary.
Pregnancy
There are no or limited amount of data from the use of colecalciferol in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3).
Vitamin D deficiency is harmful for mother and child.
However, overdose of vitamin D must be avoided during pregnancy, as prolonged hypercalcaemia may lead to physical and mental retardation, supravalvular aortic stenosis and retinopathy of the child.
Where there is a vitamin D deficiency the recommended dose is dependent on national guidelines, however, the maximum recommended dose during pregnancy is 4 000 IU/day vitamin D3. <Product name> is not recommended during pregnancy.
Lactation
Vitamin D and its metabolites pass into breast milk. This high-dose vitamin D product should not be used during breastfeeding. If treatment with vitamin D is clinically indicated during breastfeeding this should be considered when giving additional vitamin D to the child.
Fertility
There are no data on the effect of vitamin D on fertility. Normal endogenous levels of vitamin D are not expected to have any adverse effects on fertility.
4.7 Effects on ability to drive and use machines
Ditralia has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The assessment of adverse reactions is based on the following frequency grouping: Very common (≥ 1/10) Common (≥ 1/100, < 1/10) Uncommon (≥ 1/1 000, < 1/100) Rare (≥ 1/10 000, < 1/1 000) Very rare (< 1/10 000) Not known (cannot be estimated from the available data)
Immune system disorders:
Not known (cannot be estimated from the available data): Hypersensitivity reactions such as angio-oedema or laryngeal oedema
Metabolism and nutrition disorders:
Uncommon: Hypercalcaemia and hypercalciuria.
Gastrointestinal disorders:
Not known: Constipation, flatulence, nausea, abdominal pain, diarrhoea.
Skin and subcutaneous disorders:
Rare: Pruritus, rash and urticaria.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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. 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: vitamin D and analogues, colecalciferol
ATC Code: A11CC05
Colecalciferol (vitamin D3) is formed in the skin on exposure to UVB light and converted into its biologically active form, 1,25-dihydroxycolecalciferol, in two hydroxylation steps, first in the liver (position 25) and then in the renal tissue (position 1). Along with parathormone and calcitonin, 1,25- dihydroxycolecalciferol has a considerable impact on the regulation of calcium and phosphate metabolism. In vitamin D deficiency the skeleton does not calcify sufficiently (resulting in rickets) or decalcification of bones occurs (resulting in osteomalacia).
According to production, physiological regulation and mechanism of action, vitaminD3 is to be considered as precursor of a steroid hormone. In addition to physiological production in the skin, colecalciferol can be supplied via the diet or in the form of a drug.
Vitamin D receptors are present in several other tissues besides the skeletal system, therefore vitamin D has diverse effect in several physiological processes. As for its cellular biological effects, study data are available for the autocrine/paracrine realization of growth and differentiation control on hematopoietic and immune cells, skin-, skeletal- and smooth muscle cells, as well as on the cells of the brain, liver and certain endocrine organs.
5.2 Pharmacokinetic properties
Absorption
Vitamin D is fat-soluble and is easily absorbed in the small intestine in the presence of bile acids with the help of micellum and gets into the blood through lymphatic circulation (systemic bioavailability of about 80%). The bile is required for absorption of liposoluble vitamins which may be reduced in patients with hepatic, biliary or gastrointestinal disease, associated with malabsorption syndromes.
Food intake potentially increases the absorption of vitamin D.
Distribution and biotransformation
Colecalciferol and its metabolites circulate in the blood bound to a specific globulin. Colecalciferol is converted in the liver by hydroxylation to 25- hydroxycolecalciferol. It is then further converted in the kidneys to 1,25- dihydroxycolecalciferol. 1,25-dihydroxycolecalciferol is the active metabolite responsible for increasing calcium absorption. Vitamin D, which is not metabolised, is stored in adipose and muscle tissues.
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.
Elimination
Vitamin D is excreted mainly in bile and faeces with a small percentage found in urine.
Special populations
No clinically relevant modifications of Vitamin D pharmacokinetics in special patients populations are to be reported.
5.3 Preclinical safety data
Effects in non-clinical single and repeat-dose toxicity studies have been observed only at exposures of high doses. At doses far higher than the human therapeutic range teratogenicity has been observed in animal studies. Normal endogenous levels of colecalciferol have no potential mutagenic activity (negative in Ames-test) and no carcinogenic activity. No other relevant data is available that has not been mentioned elsewhere in the SmPC (see section 4.6 and 4.9).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Olive oil refined,
Purified water,
Maltodextrin,
Hydroxypropylbetadex,
Copovidone,
Mannitol,
Glycerin, Polysorbate 80,
Glycerol Monolinoleate,
Titanium dioxide,
Sucralose,
Orange flavour*,
Ascorbic acid,
all-rac-α- Tocopherol,
Sunset yellow (E110).
*it contains:
Aromatic Part: Orange essential oil, Terpeneless orange oil, Terpeneless lemon oil, Terpeneless mandarin oil, Ethyl hexanoate, Ethyl 2-methylbutyrate, Ethyl butyrate, Acetaldehyde
Additives: Butylated hydroxyanisol E320, Citric acid E330. Carriers: Maltodextrin, Acacia gum E414
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 30°C. Store in the original package in order to protect from light.
6.5 Nature and contents of container
Each orodispersible film is packed in a PET//Aluminium/PE laminate sachet.
Pack sizes of 2 or 4 orodispersible films of each strength.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
IBSA Farmaceutici Italia S.r.l
Via Martiri di Cefalonia 2
26900 Lodi, Italy
8 MARKETING AUTHORISATION NUMBER(S)
PLGB 21039/0084
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/09/2024