Fortedetrim (Capsules) Instructions for Use

ATC Code

A11CC05 (Colecalciferol)

Active Substance

Colecalciferol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug regulating calcium and phosphorus metabolism

Pharmacotherapeutic Group

Vitamins; vitamin A and D, including their combinations; vitamin D and its analogues

Pharmacological Action

Mechanism of action, pharmacodynamic effects

Colecalciferol is the natural form of vitamin D, which is formed in human skin under the influence of sunlight. Compared to vitamin D₂, it is characterized by 25% higher activity.

Vitamin D binds to the specific vitamin D receptor (VDR), which regulates the expression of many genes, including the TRPV6 ion channel gene (provides calcium absorption in the intestine), CALB1 (calbindin; provides calcium transport into the bloodstream), BGLAP (osteocalcin; provides bone tissue mineralization and calcium homeostasis), SPP1 (osteopontin; regulates osteoclast migration), REN (renin; provides blood pressure regulation, being a key element of the renin-angiotensin-aldosterone regulatory system), IGFBP (insulin-like growth factor binding protein; enhances the action of insulin-like growth factor), FGF23 and FGFR23 (fibroblast growth factor 23; regulates calcium levels, phosphate anion, fibroblast cell division processes), TGFB1 (transforming growth factor beta-1; regulates cell division and differentiation processes of osteocytes, chondrocytes, fibroblasts and keratinocytes), LRP2 (LDL receptor-related protein 2; mediates endocytosis of low-density lipoproteins), INSR (insulin receptor; provides the effects of insulin on any cell types).

Colecalciferol is an active antirachitic factor. The most important function of vitamin D₃ is the regulation of calcium and phosphate metabolism, which contributes to proper mineralization and skeletal growth.

Colecalciferol plays a significant role in the absorption of calcium and phosphates in the intestine, in the transport of mineral salts and in the process of bone calcification, and also regulates the excretion of calcium and phosphates by the kidneys.

The concentration of calcium ions in the blood determines the maintenance of skeletal muscle tone, myocardial function, promotes nerve impulse conduction, and regulates the blood clotting process.

Lack of vitamin D in the diet, impaired absorption, calcium deficiency, as well as insufficient exposure to sunlight during a child’s period of rapid growth leads to rickets, in adults – to osteomalacia, in pregnant women symptoms of tetany may occur, and impaired calcification processes in newborns’ bones.

Increased need for vitamin D occurs in women during menopause, as they often develop osteoporosis due to hormonal disorders. Vitamin D has a number of so-called extraskeletal effects.

Vitamin D is involved in the functioning of the immune system by modulating cytokine levels and regulates the division of T-helper lymphocytes and the differentiation of B-lymphocytes. A number of studies have noted a reduction in the incidence of respiratory tract infections while taking vitamin D.

It has been shown that vitamin D is an important link in immune system homeostasis: it prevents autoimmune diseases (including type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases).

Vitamin D has antiproliferative and prodifferentiating effects, which determine the oncoprotective action of vitamin D. It has been noted that the incidence of some tumors (breast cancer, colon cancer) increases against the background of low blood levels of vitamin D.

Vitamin D is involved in the regulation of carbohydrate and lipid metabolism by influencing the synthesis of IRS1 (insulin receptor substrate 1; involved in intracellular signaling pathways of the insulin receptor), IGF (insulin-like growth factor; regulates the balance of adipose and muscle tissue), PPAR-δ (peroxisome proliferator-activated receptor, type δ; promotes the processing of excess cholesterol).

According to epidemiological studies, vitamin D deficiency is associated with the risk of metabolic disorders (metabolic syndrome and type 2 diabetes mellitus).

Vitamin D receptors and metabolizing enzymes are expressed in arterial vessels, the heart, and almost all cells and tissues related to the pathogenesis of cardiovascular diseases. Animal models have shown antiatherosclerotic action, renin suppression, and prevention of myocardial damage, among others. Low levels of vitamin D in humans are associated with adverse risk factors for cardiovascular pathology, such as diabetes mellitus, dyslipidemia, arterial hypertension, and are associated with the risk of cardiovascular events, including strokes. In studies on experimental models of Alzheimer’s disease, it was shown that vitamin D₃ reduced amyloid accumulation in the brain and improved cognitive function. In non-interventional studies in humans, it was shown that the incidence of dementia and Alzheimer’s disease increases against the background of low vitamin D levels and low dietary intake of vitamin D. Worsening of cognitive function and incidence of Alzheimer’s disease were observed with low levels of vitamin D.

Pharmacokinetics

Absorption

Colecalciferol (vitamin D₃) is almost completely absorbed (80%) in the small intestine after oral administration. After a single oral dose of colecalciferol, C_max of the main form in the blood serum is reached in approximately 7 days.

Distribution

Colecalciferol accumulates in the liver, bones, skeletal muscles, kidneys, adrenal glands, myocardium, and adipose tissue. The maximum concentration in tissues is reached in 4-5 hours, after which the concentration decreases somewhat, remaining at a constant level for a long time. It undergoes enterohepatic recirculation. The serum concentration of the inactive metabolite 25-hydroxycalciferol (25(OH)D₃, calcidiol) can be increased for several months after taking large doses of colecalciferol. Hypercalcemia caused by overdose can persist for several weeks.

Colecalciferol crosses the placental barrier and is excreted in breast milk.

Metabolism

Colecalciferol in the blood plasma binds to alpha-2-globulins and partially to albumins and is transported to the liver, where microsomal hydroxylation occurs to form the inactive metabolite 25-hydroxycalciferol (25(OH)D₃, calcidiol). The concentration of calcidiol circulating in the blood is an indicator of the level of vitamin D in the body. Calcidiol undergoes repeated hydroxylation in the kidneys to form the dominant active metabolite 1,25-hydroxycolecalciferol (1,25(OH)2D₃, calcitriol).

Excretion

25(OH)D₃ is slowly excreted with a T_1/2 of about 50 days. The main route of excretion of colecalciferol, as well as its metabolites, is bile (feces), and at least 2% of these substances are excreted by the kidneys.

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Indications

Capsules 4000 IU and 10000 IU

• Treatment and prevention of vitamin D deficiency in adults

Capsules 20000 IU

• Treatment of hypoparathyroidism in adults

Capsules 50000 IU

• Treatment of vitamin D deficiency and insufficiency in adults.

ICD codes

Dosage Regimen

Capsules

Capsules should be taken orally, swallowed whole with water, preferably during the main meal.

Capsules 4000 IU

Treatment of vitamin D deficiency (25(OH)D level ≤20 ng/ml) in adults – 8000 IU (2 caps. 4000 IU)/day for 8 weeks.

Treatment of vitamin D insufficiency (25(OH)D level – 20-29 ng/ml) in adults – 8000 IU (2 caps. 4000 IU)/day for 4 weeks.

Capsules 10000 IU

Treatment of vitamin D deficiency (25(OH)D level ≤20 ng/ml) in adults – 50000 IU (5 caps. 10000 IU) once a week for 8 weeks.

Treatment of vitamin D insufficiency (25(OH)D level – 20-29 ng/ml) in adults – 50000 IU (5 caps. 10000 IU) once a week for 4 weeks.

Maintenance of normal vitamin D level (25(OH)D level ≥30 ng/ml) in adults – 10000 IU (1 cap.) once a week.

During long-term treatment, the concentration of calcium in the blood and urine should be regularly determined, and kidney function should be assessed by measuring serum creatinine concentration. If necessary, the dose should be adjusted taking into account the serum calcium concentration.

Capsules 20000 IU

Treatment of hypoparathyroidism in adults – 20000 IU (1 capsule) per day is prescribed. Blood calcium concentration should be determined within 4-6 weeks, then every 3-6 months, and if necessary, the dose should be adjusted according to the blood calcium level.

Capsules 50000 IU

Treatment of vitamin D deficiency (25(OH)D level ≤20 ng/ml) in adults – it is necessary to take 50000 IU (1 capsule) once a week for 8 weeks.

Treatment of vitamin D insufficiency (25(OH)D level 20-29 ng/ml) in adults – it is necessary to take 50000 IU (1 capsule) once a week for 4 weeks.

During long-term treatment, the levels of markers of phosphorus-calcium metabolism (calcium, phosphorus, ALP) in blood plasma and urine and kidney function (serum creatinine) should be regularly assessed. If necessary, the dose should be adjusted taking into account the serum calcium concentration.

Special patient groups

The drug should not be prescribed to patients with severe renal impairment.

No dose adjustment is required for patients with impaired liver function.

Fortedetrim is contraindicated in children and adolescents under 18 years of age. The use of other dosage forms and dosages of colecalciferol that may better meet the needs of this group, such as Aquadetrim, is recommended.

Adverse Reactions

Classification of the frequency of adverse reactions: very common (≥ 1/10), common (from ≥ 1/100, but <1/10), uncommon (from ≥ 1/1000, but <1/100), rare (from ≥ 1/10000, but <1/1000), very rare (<1/10000), unknown (cannot be estimated from the available data).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of the medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to colecalciferol or to any of the excipients included in the drug;
• Hypervitaminosis D;
• Renal osteodystrophy with hyperphosphatemia;
• Hypercalcemia and/or hypercalciuria;
• Severe renal impairment
• Urolithiasis (formation of calcium oxalate stones);
• Pseudohypoparathyroidism;
• Sarcoidosis;
• Active form of pulmonary tuberculosis;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (efficacy and safety have not been established).

With caution

When taking additional amounts of colecalciferol and calcium (for example, as part of other drugs), in case of impaired excretion of calcium and phosphates in the urine, when treating immobilized patients, with simultaneous use of thiazides, cardiac glycosides (especially digitalis glycosides), benzothiazidine derivatives in patients with atherosclerosis.

Use in Pregnancy and Lactation

Pregnancy

The use of Fortedetrim during pregnancy is contraindicated in these dosages due to exceeding the recommended daily dose of 1000 IU. During pregnancy, the use of colecalciferol preparations in lower doses, such as Aquadetrim, is recommended.

Breastfeeding period

The use of the drug during breastfeeding is contraindicated in these dosages due to exceeding the recommended daily dose of 1000 IU. During breastfeeding, the use of colecalciferol preparations in lower doses, such as Aquadetrim, is recommended.

Use in Hepatic Impairment

No dose adjustment is required in patients with liver disease.

Use in Renal Impairment

The drug is contraindicated in patients with severe renal impairment.

Pediatric Use

Fortedetrim is contraindicated in children and adolescents under 18 years of age.

Special Precautions

If other drugs containing Colecalciferol are prescribed simultaneously, the dose of colecalciferol contained in Fortedetrim should be taken into account. Additional use of colecalciferol or calcium should only be carried out under medical supervision. In this case, it is necessary to monitor the concentration of calcium in the blood serum and urine.

In patients with renal impairment receiving treatment with Fortedetrim, indicators of calcium and phosphate metabolism should be monitored.

The drug should not be used in patients predisposed to calcium nephrourolithiasis.

The drug should be used with caution in patients with impaired excretion of calcium and phosphates in the urine, when treating with benzothiazidine derivatives and in immobilized patients (risk of hypercalcemia and hypercalciuria). In such patients, the concentration of calcium in the blood plasma and urine should be monitored.

The drug should not be taken in pseudohypoparathyroidism, since in the phase of normal sensitivity to colecalciferol, the need for colecalciferol may decrease, which leads to the risk of delayed overdose. In such cases, it is better to use active metabolites of vitamin D, which allow more precise dose regulation.

During long-term treatment with Fortedetrim, the concentration of calcium in the blood plasma and urine should be monitored, and kidney function should be assessed by measuring serum creatinine concentration. This is especially important for elderly patients and during concomitant treatment with cardiac glycosides or diuretics.

In case of hypercalcemia or signs of impaired renal function, the dose of the drug should be reduced or treatment should be discontinued.

If the level of calcium in the urine exceeds 7.5 mmol/24 h (300 mg/24 h), it is recommended to reduce the dose of the drug or discontinue treatment.

During long-term treatment with Fortedetrim at a daily dose exceeding 1000 IU of vitamin D₃, the level of calcium in the blood serum should be monitored.

Excipients

Fortedetrim contains glycerol, which may cause headache, stomach upset and diarrhea.

Effect on ability to drive and operate machinery

Studies on the effect on the ability to drive vehicles and operate machinery have not been conducted.

Overdose

Symptoms

The intoxication threshold for colecalciferol varies between 40,000 and 100,000 IU/day for 1-2 months in adults with normal parathyroid function. Newborns and young children may be sensitive to much lower concentrations.

Acute and chronic overdose can lead to increased levels of phosphorus in the blood serum and urine and hypercalcemia, which can be persistent and potentially life-threatening.

Typical changes in biochemical parameters include hypercalcemia, hypercalciuria, as well as an increase in the serum level of 25-hydroxycalciferol (25(OH)D₃, calcidiol). Chronic overdose of colecalciferol can lead to the deposition of calcium in tissues and parenchymal organs, primarily in the kidneys (urolithiasis, nephrocalcinosis) and blood vessels.

Symptoms are general and manifest as nausea, vomiting, also initially as diarrhea, later as constipation, loss of appetite, weakness, headache, muscle and joint pain, muscle weakness, azotemia, persistent drowsiness, polydipsia and polyuria and, in the final stage, as dehydration of the body. Overdose of colecalciferol can cause ECG changes, heart rhythm disturbances, pancreatitis, and renal failure.

Treatment

First of all, it is necessary to stop taking colecalciferol. It takes several weeks to eliminate hypercalcemia caused by an overdose of colecalciferol. Depending on the degree of hypercalcemia, treatment measures include a diet low in calcium or completely without calcium, consumption of large amounts of fluid, forced diuresis with the use of furosemide, as well as corticosteroids and calcitonin. With preserved renal function, the calcium concentration can be significantly reduced by infusion of isotonic sodium chloride solution (3-6 L over 24 hours) with the addition of furosemide and, in some cases, also sodium edetate at a dose of 15 mg/kg/h, while monitoring calcium levels and ECG data. Phosphate infusion should not be used to reduce hypercalcemia caused by an overdose of colecalciferol due to the danger of metastatic calcification. In case of oligo-, anuria, hemodialysis should be performed (dialysate without calcium).

There is no specific antidote.

It is recommended to draw patients’ attention to the symptoms of a possible overdose during long-term use of the drug in high doses (nausea, vomiting, initially diarrhea, later constipation, loss of appetite, weakness, headache, muscle and joint pain, muscle weakness, persistent drowsiness, polydipsia and polyuria).

Drug Interactions

Concomitant use of anticonvulsant drugs (such as phenytoin) or barbiturates (and possibly other drugs that induce liver enzymes) may reduce the effectiveness of colecalciferol by increasing the rate of biotransformation of colecalciferol into inactive metabolites.

Concomitant therapy with corticosteroids may reduce the effectiveness of colecalciferol.

Oral administration of colecalciferol may enhance the therapeutic effect and toxic potential of digitalis and other cardiac glycosides (risk of arrhythmia) due to the development of hypercalcemia. Careful medical supervision, monitoring of ECG parameters and calcium levels in blood plasma and urine is required, and, if necessary, adjustment of the dose of cardiac glycosides.

In case of concomitant therapy with thiazide diuretics, which reduce the excretion of calcium in the urine and, accordingly, increase the risk of hypercalcemia. It is recommended to monitor calcium levels in blood serum and urine.

Concomitant treatment with ion-exchange resins (such as cholestyramine), orlistat preparations, or laxatives (such as paraffin oil) may reduce the absorption of colecalciferol in the digestive tract.

Concomitant use of rifampicin and isoniazid may reduce the effectiveness of the drug due to an increased rate of biotransformation of colecalciferol.

During concomitant use of antacids containing magnesium and colecalciferol, the concentration of magnesium in the blood may increase.

During concomitant use of antacids containing aluminum and colecalciferol, the concentration of aluminum in the blood may increase, which increases the risk of aluminum toxicity.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging (blister in a carton), at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life of 4000 IU and 10000 IU capsules is 3 years, of 20000 IU and 50000 IU capsules is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.