Vitamin d3 krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VITAMIN D3 KRKA (VITAMIN D3 KRKA)

Composition:

Active substance: cholecalciferol;

One tablet contains 500 IU (12.5 mcg) or 1000 IU (25 mcg) of cholecalciferol (vitamin D3) in the form of cholecalciferol concentrate (powder form);

Excipients: included in the composition of cholecalciferol concentrate: sodium ascorbate, racemic mixture of all isomers of alpha-tocopherol, modified starch, sucrose, medium-chain triglycerides, colloidal anhydrous silicon dioxide;

mannitol, sodium starch glycolate (type A), maize starch, microcrystalline cellulose (type 102), talc, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties:

tablets of 500 IU: white or almost white, round, slightly biconvex tablets with beveled edges and engraved mark “1 D” on one side;

tablets of 1000 IU: white or almost white, round, biconvex tablets with engraved mark “2” on one side. The engraved mark “2” indicates only the difference between different dosage strengths.

Pharmacotherapeutic group. Vitamins. Vitamin D and analogues. Cholecalciferol. ATC code A11CC05.

Pharmacological properties.

Pharmacodynamics.

Although cholecalciferol (vitamin D3) is considered a vitamin, from the standpoint of its formation, physiological regulation, and mechanism of action, it can be regarded as a precursor of a steroid hormone.

Cholecalciferol 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, also known as 1,25(OH)2D3 or calcitriol) through two stages of hydroxylation (see section "Pharmacokinetics"). It may also enter the body with food or as a medicinal product.

Mechanism of action and pharmacodynamic effects

The primary function of the biologically active metabolite 1,25(OH)2D3 is to maintain calcium and phosphorus balance in the circulation, together with parathyroid hormone (PTH) and calcitonin. 1,25(OH)2D3 stimulates intestinal absorption of calcium, calcium penetration into osteoid (prebone) and release of calcium from bone tissue. It also stimulates active and passive transport of phosphates, regulates excretion of calcium and phosphates via tubular reabsorption, and suppresses PTH secretion by the parathyroid glands.

Vitamin D deficiency may lead to rickets (due to lack of skeletal calcification) and osteomalacia (due to bone decalcification). This causes reversible increase in PTH secretion. Such secondary hyperparathyroidism increases bone metabolism, which may result in bone fragility and fractures.

Pharmacokinetics.

Absorption

Cholecalciferol is absorbed in the small intestine. Studies have shown that approximately 80% of the administered dose is absorbed. Due to the lipophilic properties of the vitamin, absorption is more efficient in the presence of bile salts.

Distribution

Transport of vitamin D from the skin occurs via a specific plasma protein called vitamin D-binding protein, whereas administered vitamin D is transported by chylomicrons. Within several hours after intake or synthesis in the skin, vitamin D is delivered to the liver for conversion or is transferred in the form of vitamin D or its metabolites to storage sites. Long-term storage sites (depots) include adipose tissue, liver, and muscle.

Metabolism

Cholecalciferol is activated through two hydroxylation steps. In the first step, in the liver, hydroxylation at the carbon atom in position 25 forms the major circulating form of vitamin D, 25-hydroxycholecalciferol. This metabolite is not biologically active at physiological levels. The next activation step occurs in the kidneys, where the biologically active form, 1,25-dihydroxycholecalciferol, is formed by hydroxylation at position 1. Normal plasma concentrations of 25(OH)D indicating sufficient vitamin D levels exceed 20–30 ng/mL (50–75 nmol/L), whereas plasma concentration of 1,25(OH)2D3 is approximately 0.04 ng/mL (0.1 nmol/L).

Elimination

Cholecalciferol and its metabolites are primarily excreted via bile and feces; only small amounts are excreted in urine. Some cholecalciferol metabolites are excreted in breast milk. Serum 25(OH)D3 has an average biological half-life of approximately 13 to 15 days.

Clinical characteristics.

Indications.

• For the prevention of vitamin D deficiency in children aged 12 years and older, and adults identified as being at high risk.
• For the treatment of vitamin D deficiency in adults.
• As an adjunct to specific osteoporosis therapy in adults with vitamin D deficiency or identified as being at high risk of vitamin D deficiency.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Hypercalcaemia and/or hypercalciuria.

Severe renal insufficiency.

Vitamin D hypervitaminosis.

Nephrolithiasis, nephrocalcinosis.

Pseudohypoparathyroidism.

Sarcoidosis.

Tuberculosis.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration with phenytoin or barbiturates may reduce the level of 25-hydroxycholecalciferol and enhance its conversion to inactive metabolites due to induction of hepatic enzymes, thus the therapeutic effect of vitamin D may be reduced.

Concomitant use with glucocorticoids may reduce the effectiveness of vitamin D due to increased metabolic conversion.

Rifampicin and isoniazid may enhance vitamin D metabolism, thereby reducing its efficacy.

Ketoconazole interferes with vitamin D activity by inhibiting the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the renal enzyme 25-hydroxyvitamin-D-1-hydroxylase. The effect of vitamin D may be diminished.

Concomitant administration with agents affecting fat absorption, such as orlistat or ion-exchange resins like cholestyramine, or laxatives such as mineral oils, may reduce the gastrointestinal absorption of vitamin D. A similar effect occurs when cholecalciferol is administered with neomycin, which reduces the effect of vitamin D.

Thiazide diuretics may reduce renal calcium excretion and may lead to hypercalcaemia. Therefore, plasma and urinary calcium levels should be monitored during long-term concomitant therapy.

Administration of vitamin D may enhance the therapeutic effect and toxicity of digoxin and other cardiac glycosides due to increased calcium levels (risk of cardiac arrhythmias). Regular ECG monitoring and measurement of plasma and urinary calcium levels should be performed, and if possible, plasma concentrations of digoxin or digitoxin should also be determined.

Vitamin D counteracts the effect of hypercalcaemia treatment with medicinal products such as calcitonin or bisphosphonates (etidronate or pamidronate). Vitamin D administration should be discontinued in cases of hypercalcaemia requiring active treatment.

Concomitant use of the medicinal product Vitamin D3 Krka with vitamin D metabolites or analogues (e.g. calcitriol) is possible only exceptionally, under strict monitoring of serum calcium levels.

Concomitant administration with medicinal products containing high doses of calcium and phosphorus increases the risk of hypercalcaemia. Regular monitoring of serum calcium levels is recommended.

Vitamin D may enhance intestinal absorption of aluminium and magnesium, thereby increasing their serum levels. Long-term and excessive use of aluminium- and magnesium-containing antacids should be avoided.

Special precautions for use

The dosage of the medicinal product VITAMIN D3 KRKA should be taken into account when prescribing other medicinal products containing vitamin D. Additional doses of vitamin D or calcium should be administered only under medical supervision with monitoring of serum and urinary calcium levels.

Recommended doses should not be exceeded due to the risk of developing hypervitaminosis.

In patients with severe renal impairment, cholecalciferol is not metabolized normally; therefore, other forms of vitamin D may be required.

When using VITAMIN D3 KRKA in patients with mild to moderate renal impairment, monitoring of calcium and phosphate levels is recommended. The risk of soft tissue calcification should be considered.

VITAMIN D3 KRKA should not be administered to individuals predisposed to the formation of calcium-containing kidney stones.

VITAMIN D3 KRKA should be used with caution in patients:

• with impaired renal excretion of calcium and phosphates,
• receiving thiazide diuretics (see section "Interaction with other medicinal products and other forms of interaction"),
• immobilized patients,
• receiving cardiac glycosides due to increased toxicity of the latter. Additional monitoring is recommended in such cases (see section "Interaction with other medicinal products and other forms of interaction").

Such patients have an increased risk of developing hypercalcemia; therefore, serum and urinary calcium levels should be monitored.

VITAMIN D3 KRKA should not be administered:

• to patients with sarcoidosis due to the risk of accelerated conversion of vitamin D into its active metabolites;
• to patients with pseudohypoparathyroidism, as the requirement for vitamin D may decrease during phases of normal sensitivity to vitamin D. In such cases, vitamin D derivatives that are easier to control are recommended.

During long-term treatment with doses exceeding 1000 IU (25 mcg) of cholecalciferol, serum and urinary calcium levels should be monitored, and renal function should be assessed, especially in elderly patients and in patients receiving cardiac glycosides or diuretics (see section "Interaction with other medicinal products and other forms of interaction"). In case of hypercalcemia, signs of worsening renal function, or hypercalciuria (7.5 mmol (300 mg) calcium/24 hours), the dose should be reduced or the medicinal product discontinued.

Treatment should be discontinued if symptoms of hypervitaminosis occur, such as fatigue, nausea, diarrhea, or polyuria. Since these symptoms are non-specific, medical advice should be sought to determine whether they may be related to vitamin D excess.

Vitamin D absorption is considered to be more effective when taken together with dietary fats; therefore, VITAMIN D3 KRKA should preferably be taken after one of the main meals.

Intake of vitamin D from vitamin-fortified foods should also be taken into account.

Sucrose

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding

VITAMIN D3 KRKA should be used with caution in pregnant and breastfeeding women.

Adequate intake of vitamin D is necessary during pregnancy and breastfeeding. Monitoring of vitamin D intake is recommended.

Pregnancy

Data on the use of cholecalciferol during pregnancy are limited.

Currently, there are no data indicating risks associated with the use of the maximum daily dose of 600 IU (15 mcg cholecalciferol). However, vitamin D should be used during pregnancy only if deficiency is present and with caution. The daily dose should not exceed 500 IU unless otherwise prescribed by a physician.

Prolonged use of high doses of vitamin D during pregnancy should be avoided, as prolonged hypercalcemia resulting from this may adversely affect physical and mental development and may cause supravalvular aortic stenosis and retinopathy in the child.

Breastfeeding period

Vitamin D and its metabolites pass into breast milk. This should be considered when feeding infants who are breastfed. No signs of overdose have been observed in infants whose mothers took vitamin D.

Fertility

No effects on reproductive function and fertility were observed in studies with cholecalciferol. The benefit-risk balance in humans remains unknown.

Ability to influence reaction speed when driving or operating machinery

VITAMIN D3 KRKA has no effect or has a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Prevention of vitamin D deficiency in children aged 12 years and older and adults at high risk

Adults

The recommended daily dose for adults is 500–1000 IU of vitamin D (12.5–25 mcg of cholecalciferol), corresponding to 1–2 tablets of 500 IU of the medicinal product Vitamin D3 Krka or 1 tablet of 1000 IU per day.

Children

The recommended daily dose for children aged 12 years and older is 500–1000 IU of vitamin D (12.5–25 mcg of cholecalciferol), corresponding to 1–2 tablets of the medicinal product Vitamin D3 Krka 500 IU or 1 tablet of 1000 IU per day.

Treatment of vitamin D deficiency in adults

Treatment for this indication should be initiated and supervised only by a physician.

The dosage should be determined based on the severity of the condition, the required level of 25-hydroxyvitamin D, and the individual patient's response to treatment.

Generally, the following dosage recommendations are applied:

Initial treatment (6–12 weeks)

Age group	Daily dose of cholecalciferol	Dose of medicinal product Vitamin D3 Krka
		Tablets of 500 IU	Tablets of 1000 IU
Adults	4000 IU vitamin D (100 mcg cholecalciferol)	8 tablets per day	4 tablets per day

Maintenance dose

Age group	Daily dose of cholecalciferol	Dosage of medicinal product Vitamin D3 Krka
		Tablets 500 IU	Tablets 1000 IU
Adults	1500–2000 IU vitamin D (37.5–50 mcg cholecalciferol)	3–4 tablets per day	2 tablets per day

As an adjunct to specific osteoporosis therapy in adults with vitamin D deficiency or identified high risk of vitamin D deficiency

The recommended daily dose is 1000 IU of vitamin D (25 mcg cholecalciferol), corresponding to 2 tablets of 500 IU of the medicinal product Vitamin D3 Krka or 1 tablet of 1000 IU.

Patients should receive additional calcium if dietary intake is inadequate.

Special patient groups

Elderly patients

Dose adjustment is not required; however, renal function should be taken into account.

Renal impairment

Vitamin D3 Krka should be used with caution in patients with mild to moderate renal impairment.

It is contraindicated in patients with severe renal impairment (see sections "Contraindications" and "Special warnings and precautions for use").

Hepatic impairment

Dose adjustment is not required.

During long-term treatment with doses exceeding 1000 IU of vitamin D (25 mcg cholecalciferol), serum and urinary calcium levels and renal function should be monitored. Dose adjustments may be necessary depending on serum calcium levels (see section "Special warnings and precautions for use").

Method of administration

The tablet should be swallowed with a glass of water. Vitamin D3 Krka can be taken independently of meals, but preferably after one of the main meals.

Children

Vitamin D3 Krka is used in children aged 12 years and older.

Overdose

Vitamin D overdose may cause hypercalcemia. When the administered dose exceeds the body's requirements, serum concentrations of the active metabolite do not increase because negative feedback limits metabolic activation when intake exceeds the body's needs.

Symptoms

High doses of vitamin D may cause hypercalcemia: from asymptomatic elevation of serum calcium levels to life-threatening hypercalcemic syndrome. Symptoms of intoxication are nonspecific and may include fatigue, muscle weakness, anorexia, weight loss, nausea, vomiting, constipation, diarrhea, polyuria, pancreatitis, nocturia, sweating, headache, thirst, dehydration, hypertension, drowsiness, dizziness, restlessness, irritability, psychiatric disorders, depression, pyrexia. Typical biochemical findings include hypercalcemia, hypercalciuria, and elevated 25-hydroxyvitamin D levels. Arrhythmias may occur in severe cases, while extreme hypercalcemia may even lead to coma or death. Consequences of persistent hypercalcemia include nephrolithiasis, nephrocalcinosis, impaired renal function up to renal failure, and soft tissue calcification (e.g., heart, blood vessels, kidneys). Individual sensitivity to vitamin D varies significantly. Infants and children are more susceptible to its toxic effects.

Patients undergoing long-term treatment with high doses should be informed about the symptoms of possible overdose.

Treatment

There is no specific antidote. In case of overdose, vitamin D intake from any source should be discontinued. Patient rehydration is recommended. A diet low in calcium and phosphorus is recommended. Treatment with glucocorticoids, loop diuretics, calcitonin, or bisphosphonates should be considered depending on the severity of hypercalcemia. Oral or intravenous bisphosphonates have proven effective in the treatment of vitamin D overdose.

Hypercalcemia may persist for a prolonged period after vitamin D overdose. Patients should be monitored due to the risk of recurrent intoxication.

Side effects

Side effects are usually not observed when the product is used at recommended doses. However, in cases of individual hypersensitivity to the drug, which is rare, or following prolonged use of very high doses, vitamin D hypercalcemia may occur.

The following side effects are listed by system organ class according to frequency of occurrence.

Frequency categories are defined as follows: very common (≥ 1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Disorders of metabolism and nutrition

Uncommon: hypercalcemia, hypercalciuria.

Skin and subcutaneous tissue disorders

Rare: pruritus, rash, urticaria.

The frequency of the following adverse reactions is not known, as no large-scale clinical studies have been conducted that would allow estimation of their frequency.

Cardiovascular system disorders

Arrhythmia, arterial hypertension.

Immune system disorders

Hypersensitivity reactions, including anaphylactic reactions, angioedema, and dyspnea.

Metabolism and nutrition disorders

Hypercholesterolemia, weight loss, polydipsia, increased sweating.

Nervous system disorders

Headache, somnolence.

Gastrointestinal disorders

Loss of appetite, dry mouth, constipation, flatulence, nausea, vomiting, abdominal pain, diarrhea, dyspepsia, pancreatitis.

Renal and urinary disorders

Elevated calcium levels in blood and/or urine, nephrolithiasis and tissue calcification, uremia, polyuria.

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia, muscle weakness.

Eye disorders

Conjunctivitis, photophobia.

Hepatobiliary disorders

Increased aminotransferase activity.

Psychiatric disorders

Decreased libido, mental disturbances, depression.

Cases of rhinorrhea and hyperthermia have also been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Information on any suspected adverse reactions should be reported in accordance with applicable regulatory requirements.

Shelf life. 2 years.

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

Packaging. 10 tablets in a blister; 3, 6, 9, or 18 blisters per carton.

Classification of supply.

No. 30, No. 60 — available without prescription.

No. 90, No. 180 — available by prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.