Decristol® drops

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DECRISTOL® DROPS

Composition:

Active substance: cholecalciferol;

1 ml of solution (40 drops) contains 0.5 mg cholecalciferol (equivalent to 20,000 IU of vitamin D3). 1 drop contains approximately 500 IU of vitamin D3.

Excipients: medium-chain triglycerides, butylhydroxytoluene.

Pharmaceutical form. Oral drops, solution.

Main physicochemical characteristics: clear, oily solution ranging from colorless to pale yellow.

Pharmacotherapeutic group. Vitamins. Vitamin D and analogues. Cholecalciferol.

ATC code A11C C05.

Pharmacological Properties

Pharmacodynamics

Cholecalciferol (vitamin D3) is synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet radiation and is converted into its biologically active form (1,25-dihydroxycholecalciferol) through two hydroxylation steps: first in the liver (at position 25), then in the kidney tissue (at position 1). Together with parathyroid hormone and calcitonin, 1,25-dihydroxycholecalciferol plays a significant role in regulating calcium and phosphate balance. In its biologically active form, vitamin D3 stimulates intestinal absorption of calcium, calcium penetration into osteoid, and calcium release from bone tissue. In the small intestine, it promotes both rapid and delayed calcium uptake. In addition, passive and active transport of phosphates is enhanced. In the kidneys, it reduces excretion of calcium and phosphates by stimulating tubular reabsorption. The biologically active form of cholecalciferol directly inhibits parathyroid hormone (PTH) production in the parathyroid glands. PTH secretion is further suppressed due to increased intestinal calcium absorption induced by biologically active vitamin D3.

From the standpoint of its formation, physiological regulation, and mechanism of action, vitamin D3 can be considered a precursor of a steroid hormone. In addition to endogenous synthesis in the skin, cholecalciferol can enter the body through dietary intake or as a medicinal product. The latter route may lead to overdose and intoxication, as physiological inhibition of vitamin D synthesis in the skin does not occur in this case.

Occurrence in nature and meeting requirements

The daily requirement of vitamin D for adults is 20 µg, equivalent to 800 IU per day. Healthy adults can meet their vitamin D needs through endogenous synthesis provided sufficient sunlight exposure. Dietary intake of vitamin D is of secondary importance but may be critical under certain conditions (climate, lifestyle).

Foods particularly rich in vitamin D include fish oil and fish, although small amounts are also present in meat, eggs, yolks, milk, dairy products, and avocado.

Signs of vitamin D deficiency

Signs of vitamin D deficiency may appear, for example, in premature newborns, infants exclusively breastfed for more than 6 months without calcium supplementation, or in children on a strict vegetarian diet. Rare vitamin D deficiency in adults may result from inadequate dietary intake, lack of sufficient ultraviolet exposure, impaired absorption and digestion, liver cirrhosis, or renal insufficiency.

In vitamin D deficiency, skeletal calcification does not occur (leading to rickets) or decalcification of bones develops (leading to osteomalacia). Deficiency of calcium and/or vitamin D causes reversible increase in parathyroid hormone secretion. This secondary hyperparathyroidism increases bone tissue metabolism, potentially leading to bone fragility and fractures.

Pharmacokinetics

Absorption

Vitamin D, in the amounts present in food, is almost completely absorbed from the diet. It is absorbed together with dietary lipids and bile acids; therefore, administration of vitamin D during the main meal of the day may enhance its absorption.

Distribution and biotransformation

Metabolic conversion of cholecalciferol occurs in the liver via microsomal hydroxylase, forming 25-hydroxycholecalciferol (25(OH)D3). This is subsequently converted in the kidneys into 1,25-dihydroxycholecalciferol, the biologically active form.

After a single oral dose of cholecalciferol, maximum serum concentration of 25(OH)D3—the main storage form—is reached approximately one week later. Subsequently, 25(OH)D3 is slowly eliminated, with an apparent half-life in serum of approximately 50 days. After administration of high doses of vitamin D, serum concentration of 25-hydroxycholecalciferol may remain elevated for several months. Hypercalcemia caused by overdose may persist for several weeks (see section "Overdose").

Elimination

Metabolites bound to specific α-globulin circulating in the blood are primarily excreted via bile and feces.

Special patient groups

In patients with impaired renal function, the rate of metabolic clearance is reduced by 57% compared to healthy volunteers.

In malabsorption syndromes, absorption of vitamin D3 is reduced and its elimination increased. Obese individuals show a reduced ability to maintain vitamin D3 levels upon sun exposure, and may require higher oral doses of vitamin D3 to correct deficiency.

Clinical characteristics.

Indications.

• Prophylaxis of alimentary rickets in infants, newborns, and premature children.
• Prophylaxis of vitamin D deficiency in adults and children with identified risk factors.
• Treatment of vitamin D deficiency in adults and children.
• As an adjunct to specific therapy of osteoporosis in patients with vitamin D deficiency or at risk of vitamin D insufficiency.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Hypercalcaemia.
• Hypercalciuria.
• Hypervitaminosis D.
• Pseudohypoparathyroidism (the requirement for vitamin D may be lower than during normal sensitivity to vitamin D; risk of prolonged overdose exists).
• Nephrolithiasis (urolithiasis).
• High-grade renal insufficiency.
• Sarcoidosis.
• Tuberculosis.
• Additional intake of vitamin D may lead to overdose.

Interaction with other medicinal products and other types of interactions.

Anticonvulsants and antiepileptic drugs

When anticonvulsants such as phenobarbital, hydantoin derivatives (e.g. phenytoin), other barbiturates or primidone are used concomitantly, a reduced effect of vitamin D3 may occur due to metabolic inactivation, for example, as a result of activation of the microsomal enzyme system.

Rifampicin

Rifampicin may reduce the efficacy of cholecalciferol due to induction of hepatic enzymes.

Isoniazid

Isoniazid may reduce the efficacy of cholecalciferol by inhibiting its metabolic activation.

Ion-exchange resins, laxatives, orlistat

Concomitant treatment with agents that interfere with fat absorption, such as orlistat, laxatives (liquid paraffin, mineral oils), or ion-exchange resins (cholestyramine or colestipol), may reduce the absorption of vitamin D in the gastrointestinal tract.

Actinomycin and imidazoles

The cytostatic agent actinomycin and the antifungal imidazole may interfere with the activity of vitamin D3 by inhibiting the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol by the renal enzyme 25-hydroxyvitamin D-1-hydroxylase.

These may reduce the conversion of vitamin D metabolites and thus decrease its effectiveness.

Glucocorticoids

Due to increased vitamin D metabolism, its effect may be reduced.

Thiazide diuretics, hydrochlorothiazide

When used concomitantly with benzothiadiazine derivatives (thiazide diuretics), the risk of hypercalcaemia increases due to reduced renal excretion of calcium. Therefore, monitoring of plasma and urinary calcium levels is required.

Vitamin D metabolites or analogues (e.g. calcitriol)

The combination of Decristol® drops with vitamin D metabolites or analogues should be avoided. Concomitant administration of vitamin D3 with metabolites or analogues of vitamin D is possible only exceptionally and only under control of serum calcium levels (increases the risk of toxic effects).

Cardiac glycosides

Oral intake of vitamin D may enhance the efficacy and toxicity of cardiac glycosides due to elevated calcium levels (risk of cardiac arrhythmias). Patient status should be monitored by ECG, plasma and urinary calcium levels, and, if necessary, digoxin or digitoxin levels.

Calcium dietary supplements

When calcium dietary supplements are used concomitantly, all sources of calcium should be considered; the total daily dose should not exceed 1000 mg.

Calcitonin, gallium nitrate, bisphosphonates, etidronate, pamidronate, plomycidin

When calcitonin, gallium nitrate, bisphosphonates, or plomycidin are used concomitantly with vitamin D, an antagonistic effect on the action of these agents used to correct hypercalcaemia may occur.

Magnesium

Magnesium-containing preparations (such as antacids) should not be taken during vitamin D therapy due to the risk of developing hypermagnesaemia.

Phosphorus

High-dose phosphorus-containing preparations used concomitantly may increase the risk of hyperphosphataemia.

Aluminium

Vitamin D may increase intestinal absorption of aluminium and thus elevate serum aluminium levels. Prolonged or excessive use of aluminium-containing antacids should be avoided.

Ketoconazole

Ketoconazole may reduce the biosynthesis and catabolism of 1,25(OH)2-cholecalciferol.

Special precautions for use.

Prior to initiating vitamin D therapy, a thorough assessment of the patient's condition by a physician is required, along with consideration of any additional intake of vitamin D from specific food products. Additional vitamin D or calcium should be administered only under medical supervision to prevent hypercalcemia. In such cases, serum and urinary calcium levels should be monitored.

In patients with mild to moderate renal insufficiency receiving Decristol® drops, the impact on calcium and phosphate balance should be monitored. In patients with severe renal insufficiency, the normal metabolic conversion of cholecalciferol is impaired; therefore, these patients require other forms of vitamin D (see section "Contraindications").

In patients with hepatic insufficiency, hepatic hydroxylation of cholecalciferol to 25(OH)D may be impaired.

Decristol® drops should not be used in patients with pseudohypoparathyroidism (vitamin D requirement may be reduced, sometimes to normal vitamin D sensitivity; there is a risk of prolonged overdose). In such cases, vitamin D derivatives with more easily adjustable doses are recommended.

Decristol® drops should not be administered to patients prone to forming calcium-containing kidney stones.

Decristol® drops should be used with particular caution in patients with impaired renal excretion of calcium and phosphates, patients receiving benzothiadiazine derivatives, and immobilized patients (risk of hypercalcemia, hypercalciuria). In such patients, plasma and urinary calcium levels should be monitored. The risk of soft tissue calcification should be considered.

When using Decristol® drops in patients with sarcoidosis, there is a risk of enhanced conversion of vitamin D into its active metabolites. In such patients, serum and urinary calcium levels should be monitored.

During vitamin D treatment with daily doses exceeding 1000 IU, serum calcium and urinary calcium levels should be monitored, and renal function should be assessed by measuring serum creatinine. This monitoring is particularly important for elderly patients and patients receiving concomitant treatment with cardiac glycosides or diuretics (see section "Interaction with other medicinal products and other forms of interactions"). If hypercalcemia or signs of impaired renal function occur, the dose should be reduced or treatment discontinued. In case of hypercalciuria (more than 7.5 mmol, equivalent to 300 mg calcium/day), the dose should be reduced or treatment discontinued.

For elderly patients aged > 70 years

When treating with vitamin D according to a loading dose protocol, serum 25(OH)D3 levels should also be regularly checked. Treatment should be discontinued when levels reach ≥ 50 ng/mL.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of cholecalciferol in pregnant women are lacking or limited. There is no evidence that vitamin D3, when used at recommended doses, is harmful to the embryo/fetus. Animal studies have demonstrated teratogenic effects of high doses of vitamin D.

Prolonged overdose during pregnancy should be avoided, as prolonged hypercalcemia resulting from this may lead to delayed physical and mental development, supravalvular aortic stenosis, and retinopathy in the child. Decristol® drops are not recommended for pregnant patients without vitamin D deficiency. In cases of vitamin D deficiency, the recommended dose should be selected according to national guidelines, but usually does not exceed 600 IU/day, and the maximum dose should not exceed 4000 IU/day.

Breastfeeding

Vitamin D and its metabolites are excreted in breast milk. No adverse reactions have been observed in infants who were breastfed. Decristol® drops may be used during breastfeeding at recommended doses if there is vitamin D deficiency; however, the need for additional vitamin D supplementation in the infant should be considered.

Fertility

Normal endogenous levels of vitamin D are not expected to have any adverse effect on fertility.

Ability to influence reaction speed when driving or operating machinery.

Decristol® drops do not affect or have a negligible effect on the ability to drive or operate machinery.

Caution is recommended during use of the medicinal product due to the potential for adverse reactions affecting the nervous system.

Dosage and Administration

Dosage

The physician determines the dosage regimen individually, in accordance with recommendations of national protocols.

Generally, the following dosage recommendations should be observed:

Adults

Prophylaxis of vitamin D deficiency:

• 1–2 drops of Decristol® drops per day (500 IU – 1000 IU vitamin D).

Treatment of vitamin D deficiency:

• 2 drops of Decristol® drops per day (1000 IU vitamin D). Higher doses may be required for patients with severe disease or patients with malabsorption syndrome. Higher doses should be adjusted according to the desired serum level of 25-hydroxycholecalciferol (25[OH]D), severity of the disease, and response to treatment.

The daily dose should not exceed 8 drops of Decristol® drops (4000 IU vitamin D).

Adjunct to specific therapy of osteoporosis in patients with vitamin D deficiency or at risk of vitamin D insufficiency:

• 2 drops of Decristol® drops per day (1000 IU vitamin D).

Children

Prophylaxis of vitamin D deficiency (hypovitaminosis due to dietary vitamin D deficiency, nutritional rickets):

• Preterm newborns with birth weight > 1500 g: 1 drop of Decristol® drops per day (500 IU vitamin D);
• Preterm newborns with birth weight < 1500 g (700–1500 g): 2 drops of Decristol® drops per day (1000 IU vitamin D);
• Newborns and infants (up to 23 months of age): 1 drop of Decristol® drops per day (500 IU vitamin D).

Prophylaxis of vitamin D deficiency in patients at risk:

• Children aged 2–18 years: 1–2 drops of Decristol® drops per day (500 IU–1000 IU vitamin D).

Treatment of vitamin D deficiency and nutritional rickets:

The dose should be adjusted according to the desired serum level of 25-hydroxycholecalciferol (25[OH]D), severity of the disease, and response to treatment.

The following doses should not be exceeded:

• Infants aged 1–23 months: 2 drops of Decristol® drops per day (1000 IU vitamin D);
• Children aged 2–11 years: 4 drops of Decristol® drops per day (2000 IU vitamin D);
• Children aged 12–18 years: 8 drops of Decristol® drops per day (4000 IU vitamin D).

Higher doses may be required for the treatment of nutritional rickets. The treating physician selects the appropriate dose considering the severity and course of the disease.

As an alternative, national recommendations for the treatment of vitamin D deficiency and nutritional rickets may be followed.

Special patient groups

Patients with hepatic impairment

In severe hepatic dysfunction, the dose should be adjusted by the treating physician (see also section "Special warnings and precautions for use").

Patients with renal impairment/hypercalcemia

Patients with estimated glomerular filtration rate (eGFR) > 30 mL/min without hyperparathyroidism and hyperphosphatemia do not require dose adjustment (see section "Special warnings and precautions for use"). Decristol® drops should not be administered to patients with severe renal impairment (see section "Contraindications").

During long-term treatment with Decristol® drops, serum and urinary calcium levels should be monitored regularly, and renal function should be assessed by measuring serum creatinine. If necessary, the dose should be adjusted according to serum calcium levels (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Administration and duration of treatment

For oral use.

Prophylaxis of nutritional rickets in newborns and infants:

Decristol® drops should be administered to newborns and infants starting from the second week of life until the end of the first year of life. During the second year of life, continued administration of Decristol® drops should be recommended, especially during winter months.

The drops should be added to a teaspoon of water, milk, or puree. If the drops are added to a bottle of infant formula or puree, ensure that the child consumes the entire content, otherwise the full dose of active ingredient will not be received. The drops should be added only after food preparation and cooling.

Children and adults

Children and adults should take Decristol® drops with a teaspoon of liquid.

The duration of treatment depends on the course of the disease.

Treatment of rickets caused by vitamin D deficiency should last one year.

Children

For information on administration and dosage in children, see the section "Dosage and Administration".

Overdose.

Symptoms of overdose

Acute and chronic overdose of vitamin D3 may lead to hypercalcemia, which may become persistent and even life-threatening.

Symptoms of intoxication are not very specific and include thirst, dehydration, nausea, vomiting, initial frequent diarrhea which later changes to constipation, anorexia, dizziness, headache, myalgia, arthralgia, muscle weakness, persistent drowsiness, impaired consciousness, arrhythmia, azotemia, polydipsia and polyuria, and also (at the preterminal stage) exicosis.

Daily doses up to 500 IU/day

Chronic overdose of vitamin D may lead to hypercalcemia and hypercalciuria. Prolonged excessive dosing may result in calcification of parenchymal organs.

Daily doses exceeding 500 IU/day

Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) have only a relatively narrow therapeutic range. For adults with normal parathyroid function, the threshold dose of vitamin D that does not cause intoxication ranges from 40,000 to 100,000 IU per day for 1–2 months. However, newborns and infants may exhibit sensitivity even at much lower concentrations. Therefore, administration of vitamin D preparations without medical supervision is not recommended.

In addition to increased serum and urinary phosphate levels, overdose may also lead to hypercalcemia syndrome, resulting in calcium deposition in tissues, particularly in the kidneys (nephrolithiasis, nephrocalcinosis, renal failure), as well as in blood vessels.

Treatment in case of overdose

Daily doses up to 500 IU/day

In the presence of symptoms of chronic vitamin D overdose, forced diuresis as well as administration of glucocorticoids and calcitonin are required.

Daily doses exceeding 500 IU/day

In case of overdose, measures for hypercalcemia are necessary, which may often be chronic and even life-threatening.

The primary measure is to discontinue vitamin D intake; normalization of calcium levels after vitamin D intoxication-induced hypercalcemia may take several weeks.

Depending on the degree of hypercalcemia, a calcium-free or low-calcium diet may be applied, along with recommendation to consume large amounts of fluids, forced diuresis with furosemide, and administration of glucocorticoids and calcitonin.

With normal renal function, serum calcium levels can be reliably reduced by infusion of isotonic sodium chloride solution (3–6 L within 24 hours) with addition of furosemide, and in some cases, administration of sodium edetate at a dose of 15 mg/kg body weight/hour under continuous monitoring of calcium levels and ECG. However, in cases of oligo-anuria, hemodialysis should be performed (using dialysate without calcium).

There is no known specific antidote.

Patients undergoing long-term treatment with vitamin D at higher doses should be informed about symptoms of possible overdose (nausea, vomiting, initial frequent diarrhea changing to constipation, anorexia, dizziness, headache, myalgia, arthralgia, muscle weakness, drowsiness, azotemia, polydipsia and polyuria).

Adverse reactions.

The adverse reactions are listed below for each system organ class by frequency of occurrence.

System organ class (MedDRA)	Frequency of adverse reactions
	Uncommon (from ≥ 1/1000 to < 1/100)	Rare (from ≥ 1/10000 to < 1/1000)	Frequency not known (cannot be estimated based on available data)
Cardiac disorders			Arrhythmia, hypertension
Gastrointestinal disorders			Loss of appetite, nausea, vomiting, colic (including exacerbation of colic), spasms, dyspepsia, dry mouth
Nervous system disorders			Headache, mental disturbance, depression, somnolence
Renal and urinary disorders			Elevated calcium levels in blood and/or urine, nephrolithiasis and tissue calcification, polyuria, uremia
Musculoskeletal and connective tissue disorders			Muscle and joint pain, muscle weakness
Eye disorders			Conjunctivitis, photosensitivity
Metabolism and nutrition disorders	Hypercalcemia and hypercalciuria		Hypercholesterolemia, weight loss, polydipsia, increased sweating, pancreatitis
Skin and subcutaneous tissue disorders		Pruritus, skin rash, urticaria
Immune system disorders			Hypersensitivity reaction (e.g. angioedema or laryngeal edema)
Hepatobiliary disorders			Increased aminotransferase activity
Psychiatric disorders			Decreased libido

Cases of rhinorrhea and hyperthermia have also been reported.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Shelf life after first opening – 12 months.

Storage conditions.

Keep in the original packaging to protect from light. Keep out of reach and sight of children.

Packaging.

10 ml of solution in a dropper bottle with a screw cap; 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address and place of business.

Muenchenstrasse 15, Brehna, Saxony-Anhalt, 06796, Germany.