Decristol® forte

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEKRISTOL® FORTE

Composition:

Active substance: cholecalciferol (cholecalciferol);

1 hard capsule contains 1.25 mg of cholecalciferol (equivalent to 50,000 IU of vitamin D3);

Excipients: medium-chain triglycerides, colloidal anhydrous silicon dioxide, butylhydroxytoluene (E321), titanium dioxide (E171), FD&C Yellow No. 6 (E110), quinoline yellow (E104), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules of size 3, opaque yellow and opaque orange in color, sealed with a colorless gelatin strip. Capsules are filled with a colorless or slightly yellow oily liquid.

Pharmacotherapeutic group. 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 tissue (position 25), then in the kidney tissue (position 1). Together with parathyroid hormone and calcitonin, 1,25-dihydroxycholecalciferol plays an important role in regulating calcium and phosphate balance. In its biologically active form, vitamin D3 stimulates intestinal absorption of calcium, calcium penetration into osteoid, and release of calcium from bone tissue. In the small intestine, it promotes both rapid and delayed calcium uptake. 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 suppressed due to increased intestinal calcium absorption induced by biologically active vitamin D3.

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, taking vitamin D with main meals 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, which is the biologically active form.

After a single oral dose of cholecalciferol, 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 approximately 50 days. After administration of high doses of vitamin D, serum concentrations 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 individuals with impaired kidney function, metabolic clearance rate is reduced by 57% compared to healthy volunteers.

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

Clinical characteristics.

Indications.

Decristol® Forte is indicated:

• for the treatment of vitamin D deficiency;
• for the prevention of vitamin D deficiency in high-risk patients.

Contraindications.

• Hypersensitivity to the active substance, to the colouring agent FD&C Yellow No. 6 (E 110), or to any other excipient listed in the section "Composition".
• Hypercalcaemia.
• Hypercalciuria.
• Hypervitaminosis D.
• Pseudohypoparathyroidism.
• Nephrolithiasis.
• Severe renal insufficiency.
• Sarcoidosis.
• Tuberculosis.
• Additional intake of vitamin D (may lead to overdose).

Interaction with other medicinal products and other forms of interaction.

Anticonvulsants and barbiturates

Concomitant use of anticonvulsants (e.g. phenytoin) or barbiturates (and possibly other drugs inducing liver enzymes) may lead to reduced effect of vitamin D3 due to metabolic inactivation.

Rifampicin

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

Isoniazid

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

Ion-exchange resins, laxatives, orlistat

Medicinal products causing fat metabolism alterations, such as orlistat, liquid paraffin, or cholestyramine, may reduce gastrointestinal absorption of vitamin D.

Actinomycin and imidazoles

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

Glucocorticoids

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

Thiazide diuretics

Concomitant use of benzothiadiazine derivatives (thiazide diuretics) increases the risk of hypercalcaemia due to reduced renal excretion of calcium. Therefore, plasma and urinary calcium levels should be monitored.

Vitamin D metabolites and analogues

The concomitant use of Decristol® Forte with vitamin D metabolites or analogues should be avoided.

Cardiac glycosides

Oral administration 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.

Antacids containing aluminium or magnesium

Concomitant use of the product with antacids containing aluminium or magnesium may provoke aluminium-related bone toxicity and hypermagnesaemia in patients with renal insufficiency.

Ketoconazole

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

Calcium and phosphorus

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

Calcitonin, etidronate, pamidronate

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

Special precautions for use

Decristol® Forte is not recommended for individuals who are prone to developing calcium-containing kidney stones.

Decristol® Forte should be used with particular caution in patients with impaired renal function who are receiving benzothiadiazine derivatives, as well as in 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 also be considered. In patients with severe renal insufficiency, the normal metabolic conversion of cholecalciferol is impaired; therefore, other forms of vitamin D should be used.

Decristol® Forte should not be used in patients with sarcoidosis due to the risk of accelerated conversion of vitamin D into its active metabolites. In such patients, plasma and urinary calcium levels should be monitored.

Decristol® Forte should not be used in patients with pseudohypoparathyroidism (vitamin D requirement may be lower than during periods of normal vitamin sensitivity, increasing the risk of prolonged overdose). In such cases, vitamin D derivatives with more easily adjustable doses are recommended.

When treating with daily equivalent doses exceeding 1000 IU of vitamin D, serum and urinary calcium levels should be monitored, and renal function should be assessed by measuring serum creatinine concentration. This monitoring is particularly important for elderly patients and those 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 with a predisposition to forming calcium-containing kidney stones.

If hypercalcemia or signs of worsening renal function occur, the dose should be reduced or treatment discontinued. In case of hypercalciuria (exceeding 7.5 mmol, equivalent to 300 mg calcium/24 hours), the dose should be reduced or treatment discontinued.

The need for additional calcium intake should be evaluated individually for each patient. Calcium supplements should be administered under strict medical supervision to prevent hypercalcemia.

Prior to initiating vitamin D therapy, a physician should carefully assess the patient's condition and consider any other medicinal products containing vitamin D currently used by the patient, as well as additional vitamin D intake from specific food products.

Elderly patients (age > 65 years)

In a recent study, elderly individuals with a history of falls showed an increased risk of falling when receiving monthly doses of 60,000 IU of vitamin D. Therefore, the use of Decristol® Forte in elderly patients is recommended only after careful benefit-risk assessment and only when clearly indicated. For elderly patients with a history of falls, consideration should be given to daily supplementation with additional vitamin D.

Elderly patients (age > 70 years)

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

Decristol® Forte contains FD&C Yellow No. 6 (E 110). FD&C Yellow No. 6 (E 110) may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of cholecalciferol (vitamin D3) in pregnant women are lacking or limited. Animal studies indicate a toxic effect on reproductive functions.

The recommended daily intake for pregnant women is 400 IU; however, women with vitamin D3 deficiency may require higher doses (up to 2000 IU/day). During pregnancy, women should follow their physician's recommendations, as individual requirements may vary depending on disease severity and response to treatment. The use of high-dose vitamin D (as contained in the medicinal product Decristol® Forte) is not recommended during pregnancy.

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

Breastfeeding

Vitamin D and its metabolites are excreted in breast milk. The use of high-dose vitamin D in breastfeeding women is not recommended.

Fertility

No effects on reproductive function or fertility were observed in studies investigating the impact of cholecalciferol. Negative effects of normal endogenous vitamin D levels on fertility are not expected.

Ability to influence reaction speed when driving vehicles or operating machinery

Decristol® Forte has no effect or a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosage

The dosage should be determined individually by a physician, depending on the need for additional vitamin D intake. The dose should be adjusted based on the desired serum level of 25-hydroxycholecalciferol (25(OH)D3), severity of the disease, and the patient's response to treatment.

Adults

Prevention of vitamin D deficiency: 1 capsule (50,000 IU) every 2 months. For patients at high risk of vitamin D deficiency (see below), the dose may be increased to 1 capsule per month.

Treatment of vitamin D deficiency: 1 capsule (50,000 IU) weekly for 6–8 weeks, followed by maintenance therapy (which may require 1,400–2,000 IU/day, i.e., 1 capsule monthly). Three to four months after initiation of maintenance therapy, the 25(OH)D3 level should be measured to confirm achievement of the target level.

National recommendations regarding dosage for the treatment and prevention of vitamin D deficiency should also be followed.

Special Patient Groups

Patients with hepatic impairment

Dosage adjustment is not required in patients with hepatic impairment.

Patients with renal impairment / hypercalcemia

Dosage adjustment is not required in patients with eGFR > 30 mL/min who do not have hyperparathyroidism or hyperphosphatemia (see section "Special Warnings and Precautions for Use").

Decristol® Forte should not be used to treat patients with severe renal impairment (see section "Contraindications").

Certain populations are at high risk of vitamin D3 deficiency and may require higher doses and monitoring of serum 25-hydroxycholecalciferol (25(OH)D3) levels, including:

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

Method of Administration

For oral use.

The capsule should be swallowed whole with sufficient water, preferably during a main meal.

Children

Decristol® Forte should not be used in children (under 18 years of age).

Overdose

Symptoms of overdose

Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) have a relatively low therapeutic index. The toxic dose of vitamin D causing intoxication ranges from 40,000 to 100,000 IU per day over 1–2 months in adults with normal parathyroid function.

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

Symptoms of intoxication are nonspecific and may include thirst, dehydration, nausea, vomiting, initial frequent diarrhea followed by constipation, anorexia, dyspnea, headache, myalgia, arthralgia, muscle weakness, persistent drowsiness, altered consciousness, arrhythmia, azotemia, polydipsia, polyuria, and (in preterminal stages) systemic dehydration. Therefore, vitamin D intake without medical supervision is strongly discouraged.

In addition to elevated serum and urinary phosphate levels, overdose may also cause hypercalcemic syndrome, which subsequently leads to calcium deposition in tissues, particularly in the kidneys (nephrolithiasis, nephrocalcinosis, renal failure), as well as in blood vessels.

Treatment

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

In case of overdose, therapeutic measures are necessary to correct prolonged and potentially life-threatening hypercalcemia. First, vitamin D intake should be discontinued. Normalization of calcium levels after vitamin D intoxication may take several weeks.

Depending on the degree of hypercalcemia, a low-calcium or calcium-free diet should be implemented, high fluid intake encouraged, forced diuresis with furosemide initiated, and glucocorticoids and calcitonin administered.

With normal renal function, calcium levels can be reduced by infusion of isotonic sodium chloride solution (3–6 liters within 24 hours) combined with 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 oligoanuria, hemodialysis (using a calcium-free dialysate) should be performed.

There is no specific antidote.

Patients undergoing long-term treatment with high-dose vitamin D should be advised to report 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 listed below according to system organ classes and frequency of occurrence.

FD&C Yellow No. 6 (E 110) may cause allergic reactions.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua.

Shelf life. 36 months.

Storage conditions.

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

Packaging.

2 capsules per blister; 4 or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer: mibe GmbH & Co. KG.

Manufacturer's address and place of business

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