1. NAME OF THE MEDICINAL PRODUCT

Vitamin D3 Adoh 5.600 IU tablet D3 Adoh 10.000 IU tablet Vitamin D3 Adoh 25.000 IU tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Vitamin D3 Adoh 5.600 IU tablet Each tablet contains 0.14 mg (5.600 IU) (vitamin D3).

Vitamin D3 Adoh 10.000 IU tablet Each tablet contains 0.25 mg (10.000 IU) cholecalciferol (vitamin D3).

Vitamin D3 Adoh 25.000 IU tablet Each tablet contains 0.625 mg (25.000 IU) cholecalciferol (vitamin D3).

Excipient with known effect: sucrose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral tablets.

Vitamin D3 Adoh 5.600 IU tablet White or almost white round, biconvex tablet, scoring line on one side and plain on other with 8 mm in diameter and 3.0-4.0 mm height. The scoring line is not intended to divide into equal doses.

Vitamin D3 Adoh 10.000 IU tablet White or almost white round, biconvex tablet, plain on both sides with 9 mm in diameter and 4.5 mm height.

Vitamin D3 Adoh 25.000 IU tablet White or almost white oval, biconvex tablet, plain on both sides with dimensions 17 mm x 8 mm and 6.5 mm height.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

• Initial treatment of deficiency (serum 25(OH)D < 25 nmol/l). • Prevention of vitamin D deficiency in adults 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.

Vitamin D3 Adoh 5.600 IU, 10.000 IU and 25.000 IU tablets are indicated in adults.

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4.2 Posology and method of administration

Posology

The dose should be established on an individual basis depending on the extent of the necessary vitamin D supplementation. The patient’s dietary habits should be carefully evaluated and artificially added vitamin D content of certain food types should be taken into consideration. The dosage has to be established individually by a physician.

Adults Initial treatment of vitamin D deficiency (serum levels < 25 nmol/l or < 10 ng/ml) (loading dose): 100 000 IU at once.

A maintenance dose of 800-1600 IU/day or weekly or monthly equivalent should be considered one month after loading dose.

Prevention of vitamin D deficiency in adults with an identified risk 800-1600 IU/day or equivalent weekly or monthly dose.

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.

Osteoporosis 800-1000 IU/day or equivalent weekly or monthly dose (5.600 IU/week or 25.000 IU/month).

A daily dosis of 2 000 IU vitamin D can be considered in frail elderly patients who are at particular risk of falls and fractures. Patients should receive supplemental calcium if intake from diet is inadequate.

Alternatively, national posology recommendations in treatment of vitamin D deficiency can be followed.

Paediatric population Due to the lack of data for high-dose treatment, Vitamin D3 Adoh 5.600 IU, 10.000 IU, and 25.000 IU tablets should not be used in children and adolescents (under 18 years).

Special patient groups Hepatic impairment: no dose adjustment is necessary for patients with hepatic impairment.

Renal impairment: Vitamin D3 Adoh 5.600 IU, 10.000 IU, and 25.000 IU tablets should not be used in patients with severe renal impairment.

Method of administration Vitamin D3 Adoh 5.600 IU, 10.000 IU and 25.000 IU tablet may be taken with sufficient amount of water, independently from meals.

4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Diseases and/or conditions associated with hypercalcaemia and/or hypercalciuria. - Calcium nephrolithiasis, nephrocalcinosis. - Hypervitaminosis D. - Severe renal impairment.

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4.4 Special warnings and precautions for use

During vitamin D therapy, calcium and phosphor intake has fundamental significance with respect to the success of the treatment. Before starting the vitamin D therapy, the patient’s dietary habits should be carefully evaluated by the doctor and artificially added vitamin D content of certain food types should be taken into consideration.

Long-term treatment During long-term treatment, serum calcium level and renal function should be monitored by measuring the serum creatinine level.

Monitoring is especially important for elderly patients who concomitantly take cardiac glycosides or diuretics (see section 4.5), and in the case of hyperphosphataemia, as well as for patients with an increased risk of lithiasis. In hypercalcaemia or renal impairment the dose should be reduced or the therapy discontinued.

Renal impairment Vitamin D should be used with caution in patients with impaired renal function. In this case monitoring of calcium and phosphate levels is necessary, and the risk of soft tissue calcification should be taken into consideration. In patients with severe renal insufficiency, cholecalciferol (i.e. vitamin D3) is not metabolised normally and other forms of vitamin D should be used.

Pseudohypoparathyroidism Vitamin D3 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 Vitamin D3 may be carefully administered to patients with sarcoidosis because of the risk of increased transformation of vitamin D3 to its active form. Blood and urine calcium levels should be regularly monitored in these patients.

Concomitant use with other vitamin D-containing products In the case of concomitant use with other medicinal products containing vitamin D, its vitamin D content should be taken into consideration. The concomitant use of products and dietary supplements containing vitamin D should be avoided.

Concomitant use with medicines influencing bone metabolism 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.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use with calcium containing products administered in large doses may increase the risk of hypercalcaemia.

Thiazide diuretics reduce the excretion of calcium with urine. Regular monitoring of the serum calcium level is necessary in the case of concomitant use with thiazide diuretics or with calcium containing products taken in large doses because of the increased risk of hypercalcaemia.

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Systemic corticosteroids may increase vitamin D metabolism and elimination. During concomitant use, it may be necessary to increase the dose of vitamin D.

Simultaneous treatment with ion exchange resins (e.g. colestyramin or colestipol), or laxatives (like paraffin oil) may impair the absorption of vitamin D.

Orlistat may reduce the absorption cholecalciferol as it is fat-soluble.

Products containing magnesium (like antacids) may not be taken during vitamin D treatment because of the risk of hypermagnesaemia.

In cases of treatment with drugs containing digitalis and other cardiac glycosides, the administration of vitamin D may increase the risk of digitalis toxicity (arrhythimia). Strict medical supervision is needed and, if necessary monitoring of ECG and calcium.

Anticonvulsants, such as phenobarbital, hydantoin and other barbiturates or primidone may reduce the effect of vitamin D due to the activation of the microsomal system.

Concomitant use of calcitonin, gallium nitrate, pamidronate or plicamycin with vitamin D may antagonise the effect of these products in hypercalcaemia treatment.

Products containing phosphor used in large doses, given concomitantly may increase the risk of hyperphosphataemia.

Rifampicin can accelerate the hepatic catabolism of vitamin D and can lead to reduced serum concentrations of and osteomalacia.

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

4.6 Fertility, pregnancy and lactation

Pregnancy There are limited data from the use of cholecalciferol in pregnant women. Vitamin D deficiency is harmful for mother and child.

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.

Breastfeeding Vitamin D and its metabolites are excreted in breast-milk. No adverse events have been observed in infants. Vitamin D3 can be used at recommended doses during lactation in case of a vitamin D deficiency. This should be considered when giving additional vitamin D to the child.

Fertility

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There are no data on the effect of cholecalciferol 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

No studies on the effects on the ability to drive or use machines have been performed. Cholecalciferol 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 frequencies are not known (cannot be estimated from available data).

Immune system disorders: Hypersensitivity reactions.

Metabolism and nutrition disorders: Hypercalcaemia and hypercalciuria.

Skin and subcutaneous disorders: 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 national reporting system listed in Appendix V.

4.9 Overdose

Overdose of the product may cause hypervitaminosis, hypercalcaemia and hyperphosphatemia. Symptoms of hypercalcaemia: anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, confusion, polydipsia, polyuria, bone pain, calcification in the kidneys, hypercalciuria, kidney stones, and cardiac arrhythmia in severe cases. Acute or chronic overdose of vitamin D can cause hypercalcaemia which may be persisting and possibly life-threatening. Persistently high levels of calcium may cause irreversible renal impairment and soft tissue calcification.

Treatment of hypercalcaemia: treatment with vitamin D (and calcium) should be discontinued. At the same time, the use of thiazide diuretics, lithium, vitamin D and A as well as cardiac glycosides should also be discontinued. In the case of patients with impaired consciousness gastric emptying is also necessary. Rehydration and mono- or combined therapy with loop diuretics, bisphosphonates, calcitonin and corticosteroids may be used depending on the severity of the overdose. Serum electrolyte levels, renal function and diuresis should be monitored. In severe cases ECG and central venous pressure monitoring may be necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: vitamin D and analogues, cholecalciferol ATC code: A11CC05

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Mechanism of action

Vitamin D increases the intestinal absorption of calcium, increases the calcium reabsorption in the kidneys and bone formation, and decreases the level of parathyroid hormone (PTH). 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 realisation 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 from foods is absorbed throughout the small intestine, mostly in the distal small intestine. Studies using radiolabeled compounds indicate that the absorption efficiency of vitamin D varies between 55% and 99% (mean 78%) in humans, acids are essential for intestinal vitamin D absorption.

Distribution The vitamin D absorbed from the intestine is incorporated into chylomicrons that reach the systemic circulation through the lymphatic system where it is released from chylomicrons by action of lipoprotein lipase upon arrival in the tissues. Transport of vitamin D from skin to storage tissue or to the liver is carried out by a specific plasma protein called vitamin D-binding protein (DBP). Transport of D3 from the diet to storage depots or liver is on chylomicrons, although some evidence indicates that transfer from chylomicrons to DBP occurs. Within hours of ingestion or synthesis in the skin, vitamin D is distributed to the liver or delivered as either vitamin D or its metabolites to the storage tissues, especially skeletal muscle and adipose tissue. The long-term storage sites of vitamin D include mainly the adipose tissue, muscle, liver and other tissues.

Biotransformation Activation of vitamin D involves two steps. The first occurs after vitamin D is released from DBP to the liver, where it undergoes 25-hydroxylation to 25(OH)D3. The product of the 25-hydroxylation step, 25(OH)D3, is bound to DBP and transported to the kidneys. The second step is the 1-alpha-hydroxylation of 25(OH)D primarily in the kidney. Apart from the kidneys, 1,25(OH)2D3 is also produced in an autocrine way in other organs such as bone cells and parathyroid cells. The placenta is one of the extrarenal sites for production of 1,25(OH)2D3 by the 1-alpha-hydroxylase. After its production, 1,25(OH)2D3 is transported bound to DBP in the blood to the target tissues. The catabolism of 25(OH)D3 and 1,25(OH)2D3 in the body involves inactivation by 24-hydroxylation, which gives rise initially to 24,25(OH)2D3 (preventing the activation of 25(OH)D3 to 1,25(OH)2D3 and to 1,24,25(OH)3D3 (i.e. 1,24,25-trihydroxyvitamin D3, then leading to calcitroic acid)). There are two main pathways of degradation, the C23 lactone pathway, and the C24 oxidation pathway. Vitamin D metabolites in the body are degraded in an oxidative pathway involving stepwise side-chain modifications by the actions of CYP24A1 (24-hydroxylase).

Elimination After several steps, one of the final product of the C24 oxidation pathway, i.e. calcitroic acid, is excreted, mainly in the bile and thus in the faeces. The majority (around 70%) of the metabolites of the vitamin D pathways of degradation are excreted in the bile. Due to active renal re-uptake, the urinary excretion of vitamin D metabolites is low.

Special patient groups

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Hepatic impairment: In cholestatic liver disease, there is a decrease in the intestinal availability of bile salts. This may result in malabsorption of fat-soluble such as vitamin D.

Renal impairment: In patients with severe renal insufficiency, renal metabolism of cholecalciferol can be altered and in such cases, vitamin D in smaller doses and in a daily dosing regimen is preferred, with close monitoring of calcium-phosphate metabolism and renal functions.

Elderly: Older adults are often considered at increased risk of vitamin D deficiency due to limited sun exposure, decreased capacity for cutaneous vitamin D synthesis and reduced intake of dietary vitamin D. Per se, older age is not associated with altered vitamin D pharmacokinetics.

Obesity: Obesity is associated with decreased bioavailability of dietary and cutaneously synthesized vitamin D. This is likely secondary to the sequestration of vitamin D into a larger pool of adipose tissue.

5.3 Preclinical safety data

Apart from those mentioned in sections 4.6 and 4.9 of this Summary of Product Characteristics, there are no further specific toxicological hazards for humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, microcrystalline (E460) Hydroxypropylcellulose, low-substituted (E463) Silica, anhydrous colloidal (E551) DL-alpha- (E307) Modified food starch Medium chain triglycerides Sodium ascorbate crystalline (E301) Sucrose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Vitamin D3 Adoh 5.600 IU tablets

9 months in PVC/PVdC//Al blister. 9 months in plastic container.

Vitamin D3 Adoh 10.000 IU tablets

18 months in PVC/PVdC//Al blister.

Vitamin D3 Adoh 25.000 IU tablets

12 months in PVC/PVdC//Al blister.

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12 months in plastic container.

6.4 Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

Vitamin D3 Adoh 5.600 IU tablets

4 tablets in transparent clear PVC/PVdC//Al blisters and carton. 13 tablets in transparent clear PVC/PVdC//Al blisters and carton. 30 tablets in transparent clear PVC/PVdC//Al blisters and carton. 100 tablets in transparent clear PVC/PVdC//Al blisters and carton. 500 tablets in 125 ml Polyethylene container closed with knurled on side Polypropylene lid and carton. 1000 tablets in 250 ml Polyethylene container closed with knurled on side Polypropylene lid and carton.

Vitamin D3 Adoh 10.000 IU tablets

10 tablets in transparent clear PVC/PVdC//Al blisters and carton. 20 tablets in transparent clear PVC/PVdC//Al blisters and carton. 50 tablets in transparent clear PVC/PVdC//Al blisters and carton.

Vitamin D3 Adoh 25.000 IU tablets

3 tablets in transparent clear PVC/PVdC//Al blisters and carton. 4 tablets in transparent clear PVC/PVdC//Al blisters and carton. 6 tablets in transparent clear PVC/PVdC//Al blisters and carton. 12 tablets in transparent clear PVC/PVdC//Al blisters and carton. 1000 tablets in 950 ml Polyethylene container closed with knurled on side Polypropylene lid and carton.

6.6 Special precautions for disposal and other handling

This medicinal product does not require any special precautions for disposal.

7. MARKETING AUTHORISATION HOLDER

ADOH B.V. Godfried Bomansstraat 31, 6543 JA Nijmegen, The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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10. DATE OF REVISION OF THE TEXT

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