Olidetrim® d3 forte 50 000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLIDETRIM® D3 FORTE 50 000 (OLIDETRIM D3 FORTE 50 000)

Composition:

Active substance: cholecalciferol;

1 soft capsule contains 1.25 mg cholecalciferol, equivalent to 50,000 IU vitamin D3;

Excipients: capsule contents: all-rac-α-tocopheryl acetate (E 307), medium-chain triglycerides; capsule shell: gelatin, glycerin, purified water.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: transparent, light-yellow, oval, soft capsules with a seam line in the middle, filled with oily liquid.

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

ATC code A11C C05.

Pharmacological Properties

Pharmacodynamics

Cholecalciferol (vitamin D3) is synthesized in the skin under the influence of ultraviolet radiation, including sunlight, and is converted into its biologically active form, 1,25-dihydroxycholecalciferol, in two steps: first in the liver (hydroxylation at position 25 to calcifediol), and then in the kidneys (hydroxylation at position 1 to calcitriol). Calcifediol and calcitriol, the active metabolites of cholecalciferol, regulate transcription and translation processes via steroid receptors in the DNA of cell nuclei, thereby promoting the synthesis of proteins responsible for calcium absorption in the body, as well as proteins involved in bone mineralization.

Vitamin D plays a key role in regulating calcium and phosphate homeostasis (calcemic effect). In its biologically active form, cholecalciferol enhances intestinal absorption of calcium, promotes calcium penetration into osteoid, and stimulates calcium release from bone tissue. In the small intestine, cholecalciferol also increases both passive and active transport of phosphorus. In bones, it enhances osteoclastic bone resorption and increases osteoclast activity. In the kidneys, it reduces calcium and phosphorus excretion by stimulating tubular reabsorption.

Vitamin D also exerts immunomodulatory effects. High levels of the highly specific vitamin D receptor (VDR) have been detected in immunocompetent cells, particularly in macrophages, dendritic cells, and T- and B-lymphocytes, which may positively modulate immune function. Thus, adequate vitamin D levels may enhance resistance to infections.

Vitamin D deficiency is defined as a serum concentration of 25-hydroxycholecalciferol (25(OH)D) < 20 ng/mL (< 50 nmol/L); the target concentration for optimal vitamin D effect is considered to be 30–50 ng/mL (75–125 nmol/L).

Vitamin D deficiency may lead, in particular, to impaired immunity (frequent colds and infections) and reduced muscle strength. Prolonged vitamin D deficiency may result in more serious disorders, such as the development of osteoporosis and bone deformities.

In cases of muscle weakness or reduced muscle mass (e.g., in elderly individuals or post-stroke patients), vitamin D supplementation reduces the number of falls and has a beneficial effect on muscle mass. Even mild vitamin D deficiency reduces skeletal muscle strength, and its correction improves physical performance, reduces the risk of falls, and accelerates recovery after fractures in rehabilitated patients.

Vitamin D deficiency causes impaired bone mineralization (osteomalacia in adults), and in children, also affects the growth cartilage (rickets). Deficiency of calcium and/or vitamin D leads to reversible elevation of parathyroid hormone (PTH) secretion. This secondary hyperparathyroidism results in increased bone remodeling, which may lead to bone deformities in children and reduced bone mass in adults, and in severe cases, to bone fractures.

Parathyroid hormone (PTH) secretion by the parathyroid glands is directly suppressed by the biologically active form of cholecalciferol. PTH secretion is further suppressed by increased intestinal calcium absorption induced by the biologically active form of cholecalciferol.

Causes of vitamin D deficiency include inadequate dietary intake, insufficient exposure to ultraviolet radiation [residents of high latitudes (>35°), individuals spending most of their time indoors, night workers, or those with dark skin], malabsorption from the intestine and poor nutrient digestion, liver cirrhosis, and renal insufficiency.

Pharmacokinetics

Absorption

Cholecalciferol from food is almost completely absorbed in the gastrointestinal tract in the presence of lipids and bile acids. Therefore, taking vitamin D during a main meal may enhance its absorption.

Distribution

Cholecalciferol accumulates in adipocytes, and its biological half-life in the form of 25(OH)D3 is approximately 2–3 weeks. After a single oral dose of cholecalciferol, the maximum serum concentration of 25(OH)D3—the main storage form—is reached after a prolonged period.

Biotransformation

Cholecalciferol is metabolized by microsomal hydroxylase to 25-hydroxycholecalciferol (25(OH)D3, calcifediol), the primary storage form of vitamin D3. 25(OH)D3 is further hydroxylated in the kidneys to form the main active metabolite—1,25-dihydroxycholecalciferol (1,25(OH)₂D₃, calcitriol). Circulating metabolites are bound to α-globulin in the blood.

Elimination

25(OH)D3 is slowly eliminated from serum with a half-life of approximately 50 days.

Cholecalciferol and its metabolites are primarily excreted via bile and feces.

Serum concentrations of 25(OH)D3 may remain elevated for several months after high-dose cholecalciferol administration. Hypercalcemia caused by overdose may persist for several weeks (see section "Overdose").

Clinical characteristics

Indications

• Treatment of vitamin D deficiency and conditions caused by vitamin D deficiency in adults (particularly during initial treatment of confirmed severe deficiency).
• Prevention of vitamin D deficiency in adult patients at high risk.

Vitamin D deficiency is defined as serum 25-hydroxycholecalciferol (25(OH)D) level < 20 ng/mL (< 50 nmol/L); the target concentration to ensure optimal vitamin D effect is defined as 30–50 ng/mL (75–125 nmol/L).

Contraindications

• Hypersensitivity to the active substance or to any of the other excipients contained in the medicinal product.
• Hypercalcaemia and/or hypercalciuria.
• Pseudohypoparathyroidism (vitamin D requirement may be lower than during normal vitamin sensitivity, and there is a risk of prolonged overdose).
• Sarcoidosis.
• Nephrolithiasis and/or nephrocalcinosis.
• Severe renal insufficiency.
• Tuberculosis.
• Hypervitaminosis D.

Interaction with other medicinal products and other forms of interaction

Phenytoin or barbiturates

Concomitant use of anticonvulsants (e.g., phenytoin) or barbiturates (and possibly other enzyme-inducing medicinal products) may lead to reduced vitamin D effect due to metabolic inactivation.

Thiazide diuretics

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

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.

Digitalis (cardiac glycosides)

During treatment with digitalis and other cardiac glycosides, concomitant intake of high doses of vitamin D may increase digitalis toxicity and cause severe arrhythmia due to additive negative inotropic effect. Close medical supervision, monitoring of plasma and urinary calcium levels, and ECG monitoring are required.

Glucocorticoids

Glucocorticosteroids may enhance the metabolism and elimination of vitamin D. When used concomitantly, an increased dose of Olidetrim® D3 Forte 50,000 may be required.

Ketoconazole

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

Medicinal products containing high doses of 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 act antagonistically to medicinal products used in the treatment of hypercalcaemia, such as calcitonin, etidronate, and pamidronate.

Ion-exchange resins, laxatives, orlistat

Concomitant treatment with ion-exchange resins (e.g., cholestyramine) or laxatives (e.g., liquid paraffin) may reduce the gastrointestinal absorption of vitamin D. Orlistat may potentially interfere with the absorption of cholecalciferol, as it is fat-soluble.

Actinomycin and imidazoles

The cytotoxic agent actinomycin and antifungal imidazole derivatives reduce vitamin D activity by inhibiting the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol by the renal enzyme 1-α-hydroxylase.

Antacids containing magnesium

Antacids containing magnesium and used concomitantly with vitamin D may increase serum magnesium concentration.

Antacids containing aluminium

Antacids containing aluminium and used concomitantly with vitamin D may increase serum aluminium concentration, increasing the risk of aluminium-induced bone toxicity.

Metabolites or analogues of vitamin D (e.g., calcitriol)

Concomitant use with vitamin D analogues increases the risk of toxicity.

Special precautions for use

Patients taking the medicinal product OliDetrim® D3 Forte 50 000 in monthly doses are advised not to take products containing vitamin D, dietary supplements containing vitamin D, and to limit sun exposure.

Vitamin D is contraindicated in patients with sarcoidosis due to the risk of increased conversion of vitamin D into its active form.

During prolonged treatment, serum calcium levels and kidney function should be monitored by measuring plasma creatinine levels. This is particularly important for elderly patients who are concurrently taking cardiac glycosides or diuretics (see section "Interaction with other medicinal products and other forms of interaction"), as well as for patients with an increased predisposition to kidney stone formation. If hypercalciuria (calcium level exceeding 300 mg (7.5 mmol) per day) or symptoms of impaired kidney function occur, the dose should be reduced or treatment discontinued.

There is insufficient data on the effect of vitamin D administration on kidney stone formation, although such a risk is possible, especially with concomitant use of calcium supplements. The need for additional calcium intake should be considered on an individual basis. Calcium supplementation should be carried out under strict medical supervision.

Vitamin D should be used with caution in patients with impaired kidney function, and its effect on calcium and phosphate concentrations should be monitored. The risk of soft tissue calcification should be considered. In patients with severe renal insufficiency, vitamin D in the form of cholecalciferol is not properly metabolized; therefore, other forms of vitamin D should be used. The vitamin D content in OliDetrim® D3 Forte 50 000 should be taken into account when prescribing other medicinal products containing vitamin D. Additional doses of vitamin D should be taken under strict medical supervision. In such cases, frequent monitoring of serum and urinary calcium levels is required.

Careful monitoring of the treatment response is recommended to prevent hypercalcemia.

OliDetrim® D3 Forte 50 000 should not be used in children (under 18 years of age).

Elderly patients

Age > 65 years

According to published data, in elderly patients with a history of falls, the risk of falling increased when taking 60,000 IU of vitamin D monthly. Therefore, the use of cholecalciferol in elderly patients is recommended only after careful assessment of benefit-risk ratio and only when clear indications exist. The dose should not exceed 24,000 IU per month. For elderly patients with a history of falls, daily vitamin D supplementation should be considered.

Age > 70 years

When treating with vitamin D according to a protocol involving a loading dose, serum levels of 25(OH)D3 should also be regularly monitored. Treatment should be discontinued if the 25(OH)D3 level reaches ≥ 50 ng/mL.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product OliDetrim® D3 Forte 50 000 should not be used during pregnancy except in cases where the woman's clinical condition requires treatment with cholecalciferol at a dose necessary to correct deficiency.

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

Breastfeeding

Cholecalciferol and its metabolites pass into breast milk. Cases of overdose in infants during breastfeeding have not been observed. However, this should be taken into account when prescribing additional vitamin D to the infant. Women who are breastfeeding should not take high-dose vitamin D supplements, such as 50,000 IU capsules, to increase vitamin D supply to the newborn.

Fertility

No negative effects on fertility have been observed with vitamin D intake at recommended daily doses.

Ability to influence the speed of reactions when driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Adverse effects of cholecalciferol that could affect the ability to drive or operate machinery are unknown.

Method of Administration and Dosage

Dosage

The dosage regimen and administration schedule should be individually adjusted depending on the clinical manifestations of each patient.

Depending on the daily dose of vitamin D determined individually for each patient, an appropriate dosing regimen of the medicinal product should be established, specifying the recommended dose and the interval between administrations.

The usual recommended dose is given below.

Certain population groups are at high risk of vitamin D deficiency and may require higher doses and monitoring of serum vitamin D levels. These include:

• individuals residing in institutional care or who have been hospitalized;
• individuals with dark skin pigmentation;
• individuals whose effective sun exposure is limited due to wearing protective clothing or using sunscreen;
• individuals with obesity;
• patients under medical supervision for osteoporosis;
• individuals taking certain medications (e.g., anticonvulsants, glucocorticoids);
• patients with malabsorption, including inflammatory bowel disease and celiac disease;
• individuals who have recently been treated for vitamin D3 deficiency and require maintenance therapy.

Treatment of vitamin D deficiency and conditions caused by vitamin D deficiency should be conducted for three months or until achieving a 25(OH)D concentration of 30–50 ng/mL. After this, it is advisable to continue vitamin D supplementation at preventive doses recommended for the general population and determined according to age and body weight.

National recommendations for the treatment and prevention of vitamin D deficiency may also be followed.

Treatment of vitamin D deficiency and vitamin D deficiency-related conditions in adults

Typically, for patients with laboratory-confirmed vitamin D deficiency, the recommended dose is:

• 20,000 IU twice weekly or 40,000 IU once weekly for 1–3 months
• or 50,000 IU once weekly for 1–3 months.

After this, continuation of vitamin D treatment at a dose of 2,000 IU daily or 10,000 IU weekly is recommended. The dosage and frequency of administration should be individually determined by the physician. Some patients may require higher doses.

Further measurements of 25(OH)D concentration should be performed no later than 3–4 months after the start of treatment, or earlier, to confirm that the target 25(OH)D concentration has been achieved and maintenance therapy can be initiated.

After completion of treatment, the physician may recommend preventive vitamin D supplementation.

Dosing in patients with obesity

Adults with obesity (BMI ≥ 30 kg/m²) may require higher doses of vitamin D. Typically, patients with obesity are recommended to double the dose compared to the dose recommended for patients with normal body weight.

Dosing in patients with low body weight

Adults with low body weight (BMI < 18.5 kg/m²) may require doses lower than those recommended for patients with normal body weight, depending on the degree of underweight.

Prevention of vitamin D deficiency in adult patients at high risk

It is recommended to take 2 or 3 capsules of 20,000 IU monthly or 1 capsule of 50,000 IU monthly.

Special patient groups

Hepatic impairment

Dosage adjustment is not required.

Renal impairment

Olidetrim® D3 Forte 50,000 should not be used in patients with severe renal impairment (see sections "Special warnings and precautions for use" and "Contraindications").

Elderly patients

Elderly patients with a history of falls should avoid doses exceeding 24,000 IU per month (see section "Special warnings and precautions for use").

Method of Administration

Oral administration.

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

Children

Olidetrim® D3 Forte 50000 is not recommended for use in children (under 18 years of age).

Overdose

Symptoms

Acute and chronic overdose of vitamin D may cause hypercalcemia (increased calcium concentration in blood plasma) and hypercalciuria (increased excretion of calcium in urine). Hypercalcemia occurs after administration of 50,000–100,000 IU of vitamin D3 per day.

Symptoms of hypercalcemia may be nonspecific and include nausea, vomiting, and diarrhea in the early stages, and constipation, anorexia, increased fatigue, headache, muscle and joint pain, muscle weakness, polydipsia, polyuria, kidney stone formation, nephrocalcinosis, renal failure, calcium deposition in tissues, ECG changes, arrhythmias, and pancreatitis in later stages. In preterminal stages, dehydration, photosensitivity, pancreatitis, rhinorrhea, hyperthermia, decreased libido, conjunctivitis, hypercholesterolemia, increased transaminase activity, arterial hypertension, and uremia may occur. In rare and isolated cases, severe hypercalcemia due to vitamin D poisoning has led to fatal outcomes.

In severe cases, corneal clouding may occur, and rarely, optic disc edema, uveitis, and even cataract development.

Kidney stones 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-hydroxycalciferol concentration.

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

Treatment

Treatment of hypercalcemia caused by vitamin D intake may last several weeks.

Recommended treatment includes discontinuation of all sources of vitamin D, including dietary supplements and vitamin D-enriched diets, and avoidance of sun exposure. A low-calcium diet or calcium-free diet may also be considered.

High fluid intake and treatment with diuretics such as furosemide are recommended to ensure adequate diuresis. Additional treatment with calcitonin or corticosteroids may also be considered.

Infusion of phosphates should not be used to reduce vitamin D overdose-induced hypercalcemia due to the risk of metastatic calcification.

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

There is no known specific antidote.

Side effects

Frequency is defined as follows: uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10000 to < 1/1000); and frequency not known (cannot be estimated based on available data)

System organ class (MedDRA)	Frequency of adverse reactions	Adverse reactions
Cardiovascular system	Frequency unknown	Arrhythmia, arterial hypertension
Immune system	Frequency unknown	Hypersensitivity reactions such as angioedema or laryngeal edema
Metabolism and nutrition	Uncommon	Hypercalcaemia, hypercalciuria
	Frequency unknown	Hypercholesterolemia, weight loss, polydipsia, increased sweating, pancreatitis
Gastrointestinal system	Frequency unknown	Constipation, flatulence, nausea, abdominal pain, diarrhea, loss of appetite, vomiting, dry mouth, dyspepsia
Skin and subcutaneous tissue	Rare	Hypersensitivity reactions including urticaria, rash, and pruritus
Nervous system	Frequency unknown	Headache, somnolence, psychiatric disturbances, depression
Renal and urinary system	Frequency unknown	Elevated blood and/or urine calcium levels, nephrolithiasis and tissue calcification, uremia, polyuria
Musculoskeletal system	Frequency unknown	Myalgia, arthralgia, muscle weakness
Eye disorders	Frequency unknown	Conjunctivitis, photophobia
Hepatobiliary system	Frequency unknown	Increased aminotransferase activity
Psychiatric disorders	Frequency unknown	Decreased libido

There have been isolated reports of fatal outcomes (see section "Overdose").

Reporting of 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. Healthcare professionals and patients, as well as patients' legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store at a temperature not exceeding 25 °C. Keep in the original packaging to protect from light. Keep out of the reach of children.

Packaging

2, 4 or 10 capsules in a blister. 1 (No. 2 × 1 or No. 4 × 1 or No. 10 × 1) or 2 (No. 2 × 2) blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Pharmaceutical Works "POLFA" S.A.

Manufacturer's address and site of operations

Medana Division in Sieradz, ul. Wladyslawa Lokietka 10, 98-200 Sieradz, Poland.