Summary of medicine characteristics - HELIODREI 25.000 IU CAPSULE HARD
1 NAME OF THE MEDICINAL PRODUCT
HELIODREI 25.000 I.U., capsule, hard
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
HELIODREI 25.000 IU:
1 capsule contains 0.625 mg cholecalciferol, equivalent to 25.000 IU vitamin D3.
Excipient(s) with known effect
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Transparent hard gelatine capsule containing clear, slightly yellow oil
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Initial treatment of symptomatic vitamin D deficiency in adults.
4.2 Posology and method of administration
Posology
Recommended dose: One capsule (25. 000 IU) weekly.
After first month, lower doses may be considered, dependent upon desirable serum levels of 25-hydroxycolecalciferol (25(OH)D), the severity of the disease and the patient's response to treatment. Alternatively, national posology recommendations in treatment of vitamin D deficiency can be followed.
Special populations
Paediatric population:
HELIODREI 25.000 IU is not recommended in children and adolescents under 18 years of age.
Patients with renal impairment/hypercalcaemia:
In the event of hypercalcaemia or signs of reduced renal function, the dose must be reduced or the treatment discontinued. If hypercalciuria occurs (more than 7.5 mmol equivalent to 300 mg calcium/24 hours), the dose is to be reduced or treatment discontinued.
In case of serious renal impairment HELIODREI 25.000 IU is contraindicated.
Dosage in hepatic impairment
No dose adjustment is required.
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
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
Hypercalcaemia and/or hypercalciuria.
Nephrolithiasis.
Serious renal impairment
Hypervitaminosis D
Pseudohypoparathyroidism as 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 de rivatives are available for this.
4.4 Special warnings and precautions for use
The highly concentrated vitamin D3 solutions may easily cause vitamin D intoxication when dosing errors are made. As a consequence: severe cases of hypercalcemia following high vitamin D loading dose have been reported.
During treatment with HELIODREI 25.000 IU , the serum and urinary calcium levels should be monitored and the kidney function checked by measurement of serum creatinine. These checks are particularly important in elderly patients and in concomitant treatment with cardiac glycosides or diuretics. In the case of hypercalcaemia or signs of impaired kidney function, the dose must be reduced or treatment interrupted. It is recommended to reduce the dose or to interrupt treatment if the urinary calcium level exceeds 7.5 mmol/24 hours (300 mg/24 hours).
HELIODREI 25.000 IU must be used with particular caution in patients with disturbed urinary excretion of calcium and phosphate, in treatment with benzothiadiazine derivatives and in immobilized patients (risk of hypercalcaemia and hypercalciuria). Plasma and urinary calcium levels should be monitored in these patients.
HELIODREI 25.000 IU 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.
In patients with renal insufficiency who are treated with HELIODREI 25.000 IU , the effect on the calcium and phosphate metabolism should be monitored.
To avoid overdosing of vitamin D, all potential sources of vitamin D, such as other vitamin D containing medicines, food, food enriched in vitamin D, dietary complements, etc. should be taken into account when prescribing HELIODREI 25.000 IU.The additional administration of vitamin D or calcium should only be carried out under medical supervision. In such cases the serum and urinary calcium levels must be monitored. (see above).
Oral administration of high-dose vitamin D (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.
Paediatric population
HELIODREI 25.000 IU is not recommended in children and adolescents under 18 years of age.
4.5 Interaction with other medicinal products and other forms of interaction Phenytoin or barbiturates may impair the effect of vitamin D.
Thiazide diuretics can lead to hypercalcaemia due to reduced calcium excretion via the kidneys. Therefore, plasma and urinary calcium levels should be monitored during long-term treatment.
Simultaneous administration of glucocorticoids can impair the effect of vitamin D.
The toxicity of cardiac glycosides may increase during treatment with vitamin D due to increased calcium levels (risk of cardiac arrhythmias). The ECG as well as plasma and urinary calcium levels should be monitored in such patients.
Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.
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.
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.
Combination of HELIODREI 25.000 IU with metabolites or analogues of Vitamin D have to be avoided.
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
Vitamin D deficiency is harmful for mother and child. High doses of vitamin D have been shown to have teratogenic effects in animal experiments (see section 5.3).
Overdose of vitamin D must be avoided during pregnancy, as prolonged hypercalcaemia can 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 dose should not exceed 4,000 IU/day. Treatment of pregnant women with high-dose vitamin D is not recommended.
Breast-feeding
Vitamin D3 and metabolites pass into the breast-milk. This should, however, be borne in mind when administering additional vitamin D to the child. Treatment with high-dose vitamin D in breast-feeding women is not recommended.
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
There are no data on the effects of HELIODREI 25.000 IU on the ability to drive.
However, an effect on this ability is unlikely.
4.8 Undesirable effects
Cholecalciferol can cause the following undesirable effects, especially in overdose:
Adverse reactions are ranked by frequency and system organ classes. Frequency categories are defined using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known ( cannot be estimated from the available data).
Frequencies of adverse reactions are not known, as no larger clinical trials have been conducted, which would allow estimation of frequencies. The following reactions have been reported:
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:
Not known (cannot be estimated from the available data): hypercalcaemia, hypercalciuria
Gastrointestinal disorders:
Not known (cannot be estimated from the available data): constipation, flatulence, nausea, abdominal pain, stomachache, diarrhoea.
Skin and subcutaneous tissue disorders:
Not known (cannot be estimated from the available data): hypersensitivity reactions such as pruritus, 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 at www.mhra.gov.uk/yellowcard.
4.9 Overdose
4.9 OverdoseSymptoms of overdose
Ergocalciferol (vitamin D2) and cholecalciferol (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.
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-hydroxycholecalciferol 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 liters 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).
5.1 Pharmacodynamic properties
Code: A11CC05
Cholecalciferol (vitamin D3) is formed in the skin on exposure to UV light and converted into its biologically active form, 1,25-dihydroxycholecalciferol, 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– dihydroxycholecalciferol has a considerable impact on the regulation of calcium and phosphate metabolism. In vitamin D deficiency the skeleton does not calcify (resulting in rickets) or decalcification of bones occurs (resulting in osteomalacia).
According to production, physiological regulation and mechanism of action, vitamin D3 is to be considered as precursor of a steroid hormone. In addition to physiological production in the skin, cholecalciferol can be supplied via the diet or in the form of a drug. Since in the latter case the product inhibition of cutaneous vitamin D synthesis is circumvented, overdose and intoxications may occur. Ergocalciferol (vitamin D2) is synthesised by plants. Human beings activate it metabolically in the same way as cholecalciferol. It has the same qualitative and quantitative effects.
Adults require 5 ^g daily, equivalent to 200 IU. Healthy adults can cover their requirement by producing vitamin D on their own through sufficient exposure to the sun. Alimentary vitamin D supply plays a subordinate role, but can be important under critical conditions (climate, lifestyle).
Fish liver oil and fish are particularly rich in vitamin D; small amounts are found in meat, egg yolk, milk, dairy products and avocado.
Deficiency diseases can occur, among others, in immature pre-term new-born infants, infants exclusively breast-fed for more than six months without calcium-containing foods and children fed a strictly vegetarian diet. The causes of rarely occurring vitamin D deficiency in adults may be inadequate alimentary intake, insufficient exposure to UV light, malabsorption and maldigestion, liver cirrhosis as well as renal insufficiency.
5.2 Pharmacokinetic properties
In alimentary doses vitamin D is almost completely absorbed from the food together with alimentary lipids. Higher doses are absorbed at a ratio of approx. 2:3. Skin exposed to UV light synthesises vitamin D from 7– dehydrocholesterol. Vitamin D is
transferred to the liver via a specific transport protein. In the liver it is metabolised by a microsomal hydroxylase to 25– hydroxycholecalciferol. Vitamin D and its metabolites are excreted with bile and faeces.
Vitamin D is stored in the fatty tissue and has therefore a long biological half-life. After high vitamin D doses, the 25-hydroxyvitamin D concentrations in the serum may be increased for several months. Hypercalcaemia due to overdose can persist over several weeks (see section 4.9 ‚Overdose‘).
Vitamin D is stored in the fatty tissue and has therefore a long biological half-life. After high vitamin D doses, the 25-hydroxyvitamin D concentrations in the serum may be increased for several months. Hypercalcaemia induced by overdose can persist for several weeks.
5.3 Preclinical safety data
5.3 Preclinical safety dataCholecalciferol has been shown to be teratogenic in high doses in animals (4–15 times the human dose). Offspring from pregnant rabbits treated with high doses of vitamin D had lesions anatomically similar to those of supravalvular aortic stenosis and offspring not showing such changes show vasculotoxicity similar to that of adults following acute vitamin D toxicity.
6.1
6.2
-all-rac-a-Tocopheryl acetate
-Olive oil,refined,
-Gelatin
Not applicable.
2 years
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original package, in order to protect from light and moisture.
6.5 Nature and contents of container
PVC/aluminium blister packs containing 1, 2, 3, 4, 12 and 48 (4×12 or 6×8) (hospital pack) hard capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Laboratoires SMB S.A. Rue de la pastorale 26–28
1080 Bruxelles
BELGIUM
Tel. +32 2 4114828
Fax +32 2 4112828
8 MARKETING AUTHORISATION NUMBER(S)
PL 15190/0030
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/12/2017