Decristol® 20000 iu

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEKRISTOL® 20000 IU

Composition:

Active substance: cholecalciferol;

1 soft capsule contains cholecalciferol (as 1.0 mMO/g concentrate (oil form)) 20.0 mg, equivalent to 0.5 mg, or 20,000 IU, of vitamin D3;

Excipients: peanut oil, gelatin, glycerol 85%, medium-chain triglycerides, purified water, alpha-tocopherol.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: round transparent soft capsules of light yellow color.

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

ATC code A11CC05.

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) in two hydroxylation steps: first in the liver (at position 25), then in 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 calcium absorption in the intestine, calcium penetration into osteoid, and calcium release from bone tissue. In the small intestine, it promotes both rapid and delayed calcium absorption. In addition, passive and active phosphate transport is enhanced. In the kidneys, it reduces excretion of calcium and phosphates by stimulating tubular reabsorption. The biologically active form of cholecalciferol directly suppresses parathyroid hormone production in the parathyroid glands. Parathyroid hormone secretion is further inhibited due to increased calcium absorption in the small intestine under the influence of biologically active vitamin D3.

So-called vitamin D3, in terms of its formation, physiological regulation, and mechanism of action, can be considered a precursor of a steroid hormone. Cholecalciferol, in addition to endogenous synthesis in the skin, can enter the body through food or as a medicinal product. The latter route may lead to overdose and intoxication, as it does not inhibit the physiological production of vitamin D, such as its synthesis in the skin.

Natural occurrence and requirement fulfillment

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

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

Symptoms 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. Causes of rare vitamin D deficiency in adults may include inadequate dietary intake, lack of sufficient ultraviolet exposure, impaired absorption and digestion, liver cirrhosis, and renal insufficiency.

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

Pharmacokinetics.

Absorption

Vitamin D, as 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 cholecalcifer0l, peak 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 about 50 days. After administration of high-dose 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 kidney function, metabolic clearance rate is reduced by 57% compared to healthy volunteers.

In malabsorption syndromes, absorption of vitamin D3 is decreased and elimination increased. In individuals with obesity, the ability to maintain vitamin D3 levels upon sun exposure is reduced, and higher oral doses of vitamin D3 may be required to correct deficiency.

Clinical characteristics.

Indications.

• Treatment of clinically confirmed vitamin D deficiency in adults.
• Prevention of vitamin D deficiency in patients at high risk.
• As an adjunct to specific osteoporosis therapy in patients with vitamin D deficiency or at high risk of vitamin D insufficiency.

Contraindications.

• Hypersensitivity to the active substance, peanuts, soy, or any of the other excipients contained in the medicinal product.
• Hypercalcemia.
• Hypercalciuria.
• Hypervitaminosis D.
• Pseudohypoparathyroidism (vitamin D requirement may be lower than during periods of normal vitamin sensitivity, with a risk of prolonged overdose).
• Nephrolithiasis (urinary stone disease).
• Renal insufficiency.
• Sarcoidosis.
• Tuberculosis.
• Additional intake of vitamin D (may lead to overdose).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of anticonvulsants (e.g., phenytoin and phenobarbital) or barbiturates (and possibly other drugs that induce liver enzymes) may lead to reduced vitamin D3 efficacy due to metabolic inactivation.

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

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

Ion-exchangers, laxatives, orlistat may reduce the gastrointestinal absorption of vitamin D.

The cytotoxic agent actinomycin and imidazole antifungal agents reduce the activity of vitamin D3 by inhibiting the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol by renal enzymes, specifically 25-hydroxyvitamin D-1α-hydroxylase.

Glucocorticoids increase vitamin D metabolism, which may lead to reduced efficacy of vitamin D.

Concomitant administration of benzothiadiazine derivatives (thiazide diuretics) increases the risk of hypercalcemia due to reduced renal calcium excretion. Therefore, monitoring of plasma and urinary calcium levels is necessary.

The use of Decristol**®** 20000 IU in combination with metabolites or analogs of vitamin D should be avoided. Concomitant administration of vitamin D3 with metabolites or analogs of vitamin D is possible only exceptionally and only with monitoring of serum calcium levels (increases the risk of toxic effects).

Oral intake of vitamin D together with cardiac glycosides may enhance the efficacy and toxicity of digoxin due to increased calcium levels (risk of cardiac arrhythmias). In such patients, regular ECG monitoring and measurement of plasma and urinary calcium levels are required, as well as determination of digoxin or digitoxin concentrations, if possible.

Concomitant use with antacids containing aluminum or magnesium may provoke toxic effects of aluminum on bone and hypermagnesemia in patients with renal insufficiency.

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

Concomitant use with medicinal products containing high doses of calcium and phosphorus increases the risk of hyperphosphatemia.

Vitamin D may antagonize medicinal products used in the treatment of hypercalcemia, such as calcitonin, etidronate, and pamidronate.

Special precautions for use

Decristol**®** 20000 IU is not recommended for individuals predisposed to developing calcium-containing kidney stones.

Decristol**®** 20000 IU should be administered with particular caution to patients with impaired renal function who are receiving benzothiadiazine derivatives, as well as to immobilized patients (due to the risk of developing hypercalcemia and hypercalciuria). In such patients, serum and urinary calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be considered. In patients with severe renal insufficiency, normal metabolic conversion of cholecalciferol is impaired; therefore, other forms of vitamin D should be used (see section "Contraindications").

Decristol**®** 20000 IU should not be administered to patients with sarcoidosis due to the risk of accelerated conversion of vitamin D into its active metabolites. In these patients, serum and urinary calcium levels should be monitored.

When administering the drug at an equivalent daily dose exceeding 1000 IU of vitamin D, serum calcium and urinary calcium levels should be monitored, and renal function should be assessed by measuring serum creatinine concentration. This monitoring is particularly important in elderly patients and in patients receiving concomitant treatment with cardiac glycosides or diuretics (see section "Interaction with other medicinal products and other forms of interaction"). This also applies to patients predisposed to developing calcium-containing kidney stones.

For certain patients, additional calcium supplementation may be considered. Calcium-containing dietary supplements should be used under strict medical supervision to prevent hypercalcemia.

Prior to initiating vitamin D therapy, a thorough clinical assessment of the patient should be performed by a physician, and additional intake of vitamin D from specific food sources should be taken into account.

Elderly patients (age > 65 years)

In a recent study in elderly individuals with a history of falls, an increased risk of falling was observed when administering 60000 IU of vitamin D monthly. Therefore, use of Decristol**®** 20000 IU in elderly patients is recommended only after careful benefit-risk assessment and only when clearly indicated. The dose should not exceed 24000 IU per month (one capsule). For elderly patients with a history of falls, daily supplementation with additional vitamin D should be considered.

For elderly patients aged > 70 years

During vitamin D treatment using a loading dose regimen, serum 25(OH)D3 levels should also be monitored regularly. Treatment should be discontinued when levels reach ≥ 50 ng/mL.

The medicinal product contains peanut oil. If you are allergic to peanuts or soy, do not take this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

During pregnancy, Decristol**®** 20000 IU may be prescribed only when clearly indicated and only if it is absolutely necessary to correct vitamin D deficiency.

Vitamin D overdose should be avoided during pregnancy, as prolonged hypercalcemia may result in delayed physical and psychomotor development in the child, as well as supravalvular aortic stenosis and retinopathy.

Breastfeeding

Vitamin D and its metabolites are excreted in breast milk. Cases of overdose in newborns who are breastfed have not been reported. However, this should be taken into account when additional vitamin D supplementation is prescribed for the infant. High-dose vitamin D treatment (e.g., 20000 IU capsules) is not recommended for breastfeeding women.

Fertility

In animal studies, no effects of cholecalciferol on reproductive function or fertility were observed. The benefit-risk ratio in humans remains unknown.

Effect on ability to drive and use machines

Decristol**®** 20000 IU has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage.

Method of administration.

For oral use.

Adults should take the capsule whole, swallowing it with sufficient water, preferably during the main meal of the day.

Dosage.

Vitamin D dosage depends on the severity of the condition and the patient's response to treatment. Depending on individual needs, possibilities, and patient preference, daily, weekly, or monthly administration regimens may be considered. Lower-dose formulations (e.g., 400 IU, 500 IU, 800 IU, and 1000 IU) are suitable for daily vitamin D supplementation, whereas higher-dose formulations, such as 20000 IU capsules, contain amounts corresponding to weekly or monthly vitamin D doses and should be used accordingly. The dose must be prescribed by a physician in each individual case.

Certain patient groups are at higher risk of vitamin D deficiency and may require higher doses and monitoring of serum 25-hydroxycholecalciferol (25(OH)D3) concentration:

• individuals residing in specialized institutions or hospitalized patients;
• individuals with dark skin;
• individuals with limited effective sun exposure due to wearing protective clothing or regular use of sunscreen;
• patients with osteoporosis;
• obese individuals;
• individuals taking certain concomitant medications (e.g., anticonvulsants, glucocorticoids);
• individuals who have recently undergone treatment for vitamin D deficiency and require maintenance therapy;
• patients with malabsorption, including inflammatory bowel disease and celiac disease.

Dosage recommendations:

Initial treatment of vitamin D deficiency:

40000 IU weekly for 6–12 weeks.

Treatment of vitamin D deficiency and maintenance of its levels:

60000 to 120000 IU monthly for up to 6 months.

Prevention of vitamin D deficiency:

20000 IU weekly, regardless of initial levels, during the period from November to April.

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

Adults and elderly patients:

20000 to 40000 IU monthly, in combination with a calcium supplement if necessary.

Elderly patients with a history of falls should avoid doses exceeding 24000 IU monthly (see also section “Special precautions for use”).

Patients with renal impairment / hypercalcemia

In the presence of hypercalcemia or signs of reduced renal function, the dose should be reduced or treatment discontinued. If hypercalciuria occurs (more than 7.5 mmol, corresponding to 300 mg calcium in 24 hours), the dose should be reduced or treatment stopped.

Children.

The use of this medicinal product is not recommended in children and adolescents (under 18 years of age) due to lack of data on dosing regimens and the risk of choking on capsules. Instead, drops or dispersible tablets are recommended.

Overdose.

Vitamin D3 regulates calcium and phosphate metabolism. After overdose, hypercalcemia, hypercalciuria, renal calculi, bone damage, and cardiovascular changes may occur. Hypercalcemia typically develops after daily intake of 50000–100000 IU of vitamin D3.

Symptoms of overdose

Acute or chronic vitamin D3 overdose may cause hypercalcemia, which can become persistent and life-threatening. Symptoms may be nonspecific and include cardiac arrhythmia, thirst, dehydration, adynamia, and impaired consciousness. Additionally, chronic overdose may lead to calcium deposition in blood vessels and tissues.

Besides elevated serum and urinary phosphate levels, overdose may also cause hypercalcemic syndrome, leading subsequently to calcium deposition in tissues, particularly in the kidneys (nephrolithiasis, nephrocalcinosis, renal failure), and in blood vessels.

Symptoms of intoxication are not very specific and may include muscle weakness, loss of appetite, nausea, vomiting, initial frequent diarrhea followed by constipation, anorexia, dyspnea, headache, myalgia, arthralgia, muscle weakness, persistent drowsiness, arrhythmia, azotemia, polydipsia, and polyuria, as well as (in preterminal stages) dehydration, photosensitivity, pancreatitis, rhinorrhea, hyperthermia, decreased libido, conjunctivitis, hypercholesterolemia, increased transaminase activity, arterial hypertension, and uremia. Common symptoms include muscle and joint pain.

Renal function impairment may develop, characterized by albuminuria, erythrocyturia, polyuria, increased potassium loss, hypostenuria, nocturia, and moderate elevation of blood pressure.

In severe cases, corneal clouding may occur; rarely, optic disc edema, uveitis, or even cataract development may be observed.

Renal calculi may form, and calcification may occur in soft tissues such as blood vessels, heart, lungs, and skin.

Cholestatic jaundice may rarely develop.

Characteristic biochemical abnormalities include hypercalcemia, hypercalciuria, and elevated serum 25-hydroxycholecalciferol concentration.

Treatment. The appearance of symptoms of chronic vitamin D overdose may require forced diuresis and administration of glucocorticoids and calcitonin.

In case of overdose, measures must be taken to eliminate often chronic and potentially life-threatening hypercalcemia.

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 used, along with recommendations for high fluid intake, forced diuresis with furosemide, and administration of glucocorticoids and calcitonin.

In patients with normal renal function, calcium levels can likely be reduced by infusion of isotonic sodium chloride solution (3–6 liters within 24 hours) with furosemide. In some cases, sodium edetate at a dose of 15 mg/kg body weight/hour may also be administered under continuous monitoring of calcium levels and ECG. However, in cases of oligoanuria, hemodialysis (using calcium-free dialysate) must be performed.

There is no known specific antidote.

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

Adverse reactions.

Adverse reactions are generally not observed when the product is used at recommended doses.

In cases of individual sensitivity to the drug, which is rare, or as a result of using very high doses over a prolonged period, vitamin D hypervitaminosis may occur.

The adverse reactions listed below are categorized by organ system class and frequency of occurrence.

There have also been reports of rhinorrhea and hyperthermia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions is very important. Healthcare professionals and patients should report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C, in a place protected from light and moisture. Keep out of reach of children.

Packaging.

10 capsules in a blister. 1, 2, or 5 blisters per carton.

20 capsules in a blister. 1 blister per carton.

25 capsules in a blister. 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer’s address and location of operations.

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