Hydroferol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HİDROFEROL (HIDROFEROL)

Composition:

Active substances: calcifediol monohydrate;

1 soft capsule contains 0.266 mg of calcifediol monohydrate;

Excipients: anhydrous ethanol, medium-chain triglycerides (Miglyol 812 N); capsule shell: gelatin, glycerin, sorbitol (E-420), titanium dioxide (E-171), "Yellow West" FCF (E-110), purified water.

Medicinal form. Soft capsules.

Main physicochemical characteristics: soft gelatin orange-colored capsules with a longitudinal seam. Dimensions (mm): length 15.5 ± 0.5 and diameter 9.2 ± 0.4.

Pharmacotherapeutic group. Vitamin D and its analogues. Calcifediol.

ATC code A11CC06.

Pharmacological properties

Mechanism of action

Vitamin D has two main forms: D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D3 is synthesized in the skin under the influence of sunlight (ultraviolet radiation) and is also obtained from food. To become active, vitamin D3 must undergo a two-step metabolic process: the first step occurs in the microsomal fraction of the liver, where vitamin D is hydroxylated at position 25 (25-hydroxycholecalciferol or calcifediol); the second step occurs in the kidneys, where, due to the activity of the enzyme 25-hydroxycholecalciferol-1-hydroxylase, 1,25-dihydroxycholecalciferol or calcitriol is formed. The conversion to 1,25-dihydroxycholecalciferol is regulated by its own concentration, parathyroid hormone (PTH), and serum calcium and phosphate concentrations. There are other metabolites with unknown functions. 1,25-dihydroxycholecalciferol is transported from the kidneys to target tissues (intestine, bone, and possibly the kidneys and parathyroid glands) by binding to specific plasma proteins.

Pharmacodynamics

Vitamin D increases intestinal absorption of calcium and phosphorus, promotes normal bone formation and mineralization, and acts at three levels.

Intestine: vitamin D enhances the absorption of calcium and phosphorus in the small intestine.

Bone: calcitriol promotes bone formation by increasing calcium and phosphate levels and stimulating osteoblast activity.

Kidneys: calcitriol enhances tubular reabsorption of calcium.

Parathyroid glands: vitamin D inhibits the secretion of parathyroid hormone.

Clinical efficacy and safety

The efficacy and safety of soft capsules containing 0.266 mg of calcifediol monohydrate were evaluated in a randomized, double-blind clinical trial involving postmenopausal women with baseline serum 25(OH)D levels < 50 nmol/L. A total of 303 women were randomized; 298 of them constituted the all-randomized-patients-as-treated population (ITT population). Patients received either calcifediol monohydrate at a dose of 0.266 mg/month (N = 200) or cholecalciferol (N = 98) at a dose of 625 µg/month (25,000 IU). In the calcifediol group, 98 patients received treatment for 4 months; the remaining patients (N = 102) and the cholecalciferol group received treatment for 12 months.

Within 1 month, 13.5% of patients in the calcifediol monohydrate group achieved serum 25(OH)D levels above 30 ng/mL (75 nmol/L); by 4 months, this proportion increased to 35%. The highest serum 25(OH)D levels in the calcifediol monohydrate group were reached after 4 months of treatment, indicating a non-cumulative effect.

The table below shows the increase in blood 25(OH)D concentration compared to baseline, expressed in mean values (standard deviation [SD]) in ng/mL.

*Results shown as mean (CV).

Pharmacokinetics

Absorption. Calcifediol is well absorbed in the intestine.

After oral administration of calcifediol, maximum serum concentration of 25-OH-cholecalciferol is reached in approximately 5.5 hours.

Distribution. Calcifediol has a high degree of binding to plasma proteins (>98%).

It is stored in adipose tissue and muscles for a prolonged period. Accumulation in adipose tissue is less significant than with vitamin D due to its lower lipid solubility.

Metabolism and biotransformation.. The production of calcitriol from calcifediol is catalyzed by the enzyme 1-alpha-hydroxylase, CYP27B1, located in the kidneys and in all vitamin D-sensitive tissues. CYP24A1, located in these tissues, catabolizes both calcifediol and calcitriol into inactive metabolites.

Elimination. The elimination half-life of calcifediol (t1/2) is 18 days. Calcifediol and its metabolites are primarily excreted via bile and feces, with only a small amount eliminated in urine.

Non-clinical safety data

In non-clinical studies, effects were observed only at exposures exceeding the maximum human exposures, indicating limited relevance for clinical use.

High doses of vitamin D (4–15 times higher than the recommended human dose) have been shown to be teratogenic in animals, but few studies involving humans have been conducted. Vitamin D may cause hypercalcemia in pregnant women, which could lead to supravalvular aortic stenosis syndrome, retinopathy, and mental retardation in infants and newborns.

Clinical Characteristics

Indications

For the treatment of vitamin D deficiency (i.e., blood 25(OH)D levels < 25 nmol/L) in adults.

For the prevention of vitamin D deficiency in adults with identified risk factors, such as patients with malabsorption syndrome, mineral and bone disorders associated with CKD (chronic kidney disease), or other identified risks.

As an adjunctive agent in the specific treatment of osteoporosis in patients with vitamin D deficiency or at risk of vitamin D deficiency.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Hypercalcemia (serum calcium > 10.5 mg/dL) or hypercalciuria.
• Calcium kidney stones (nephrolithiasis).
• Hypervitaminosis D.

Interaction with other medicinal products and other forms of interaction

• Phenytoin, phenobarbital, primidone, and other enzyme inducers: enzyme inducers may reduce plasma concentrations of calcifediol and inhibit its effect by inducing its hepatic metabolism. For this reason, monitoring of plasma 25-OH-D levels is generally recommended when calcifediol is administered concomitantly with antiepileptic drugs that are CYP3A4 inducers.
• Cardiac glycosides: calcifediol may cause hypercalcemia, which in turn may enhance the inotropic effects and toxicity of digoxin, potentially leading to cardiac arrhythmias.
• Medications such as cholestyramine, colestipol, or orlistat reduce the absorption of calcifediol, which may result in reduced efficacy. A minimum interval of at least 2 hours is recommended between administration of these agents and vitamin D preparations.
• Paraffin and mineral oil: due to the lipophilic nature of calcifediol, this compound may dissolve in paraffin, potentially reducing intestinal absorption. Alternative laxatives are recommended, or at least a sufficient time interval should be maintained between administrations.
• Thiazide diuretics: concomitant use of thiazide diuretics (e.g., hydrochlorothiazide) with vitamin D analogs in patients with hypoparathyroidism may lead to hypercalcemia, which may be transient or may require temporary discontinuation of vitamin D analog therapy.
• Certain antibiotics, such as penicillin, neomycin, and chloramphenicol, may increase calcium absorption.
• Phosphate-binding agents, such as magnesium salts: since vitamin D affects phosphate transport in the intestine, kidneys, and bone, hypermagnesemia may occur. Doses of phosphate-binding agents should be adjusted based on serum phosphate concentrations.
• Verapamil: some studies have shown a potential inhibition of the antianginal effect of verapamil due to antagonism with calcifediol.
• Vitamin D: concurrent use of any vitamin D analogs should be avoided, as additive effects and hypercalcemia may occur.
• Calcium supplements: uncontrolled use of additional calcium-containing products should be avoided.
• Corticosteroids suppress the action of vitamin D analogs such as calcifediol.
• Food and beverages: vitamin D-fortified foods and drinks should be avoided, as additive effects may occur.

Special precautions for use

Patients with hypercalcemia and hyperphosphatemia

To achieve an adequate clinical response to oral administration of calcifediol monohydrate, adequate dietary calcium intake is also required. Therefore, in addition to monitoring 25(OH)D levels, it is necessary to monitor serum calcium, phosphorus, and alkaline phosphatase, as well as urinary calcium and phosphorus in 24-hour urine. A decrease in serum alkaline phosphatase levels usually precedes the development of hypercalcemia. After parameters have stabilized and the patient has transitioned to maintenance therapy, the aforementioned tests should be performed regularly, especially monitoring serum 25(OH)D and calcium levels.

Patients with renal insufficiency

Use with caution. Administration of this medicinal product to patients with chronic kidney disease should be accompanied by periodic monitoring of serum calcium and phosphorus levels and prevention of hypercalcemia. The conversion of the active substance into calcitriol occurs in the kidneys; therefore, in cases of severe renal impairment (creatinine clearance less than 30 ml/min), a marked reduction in pharmacological effect may occur.

Patients with heart failure

Extreme caution is required. Serum calcium levels should be monitored continuously, especially in patients receiving digitalis preparations, as hypercalcemia and arrhythmias may occur. At the beginning of treatment, testing is recommended twice weekly.

Patients with hypoparathyroidism

1-alpha-hydroxylase is activated by parathyroid hormone. Consequently, in cases of parathyroid gland insufficiency, the activity of calcifediol may be reduced.

Patients with kidney stones

Calcemia should be monitored, as vitamin D increases calcium absorption and may worsen the condition. Vitamin D preparations should be prescribed to these patients only if the benefit outweighs the risk.

Long-term immobilized patients

A reduced dose may be required for long-term immobilized patients to avoid hypercalcemia.

Sarcoidosis, tuberculosis, or other granulomatous diseases

Use with caution, as these conditions may lead to increased sensitivity to vitamin D effects and an increased risk of adverse reactions at doses lower than the recommended dose. In such patients, serum and urinary calcium concentrations must be monitored.

Effect on laboratory test results

Calcifediol may interfere with cholesterol assays (Zlatkis-Zak reaction), leading to falsely elevated serum cholesterol levels.

Precautions regarding excipients

One soft capsule contains 5 mg of alcohol (ethanol). The amount of alcohol in one capsule of this medicinal product is equivalent to less than 1 ml of beer or 1 ml of wine. This small amount of alcohol has no noticeable effects.

One soft capsule contains 22 mg of sorbitol.

This medicinal product contains the colouring agent Sunset Yellow FCF (E110), which may cause allergic reactions.

International Units (IU) should not be used to determine the dose of calcifediol, as this may lead to overdose. Instead, dosage recommendations in the section "Posology and method of administration" must be followed.

Use during pregnancy or breastfeeding

Pregnancy. Controlled studies of calcifediol in pregnant women have not been conducted.

Animal studies have demonstrated reproductive toxicity.

The medicinal product Hydroferol must not be used during pregnancy.

Breastfeeding. Calcifediol passes into breast milk.

Risk to newborns/infants cannot be excluded. High-dose maternal use of calcifediol may increase calcitriol levels in milk and cause hypercalcemia in infants.

The medicinal product Hydroferol must not be used during breastfeeding.

Fertility. Data on the effect of the medicinal product on human fertility are lacking.

Ability to affect reaction speed when driving or operating machinery. Calcifediol has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Doses

Treatment of vitamin D deficiency and prevention of vitamin D deficiency in patients identified as being at risk: one capsule once a month.

As an adjunct to specific treatment of osteoporosis: one capsule once a month.

For certain patients, higher doses may be required following laboratory assessment of the degree of vitamin D deficiency. In such cases, the maximum dose should not exceed one capsule per week. Once plasma 25(OH)D levels stabilize within the desired range, treatment should be discontinued or the frequency of administration reduced.

Hydroferol is not intended for daily use.

The dose, frequency, and duration of treatment are determined by the physician, taking into account the plasma 25(OH)D level, the patient's condition, and other factors such as obesity, malabsorption syndrome, and corticosteroid therapy. Hydroferol is recommended when intermittent administration is preferred.

Serum 25(OH)D concentration should be monitored after initiation of treatment, typically within 3–4 months.

The activity of this medicinal product is sometimes expressed in international units. These units are not interchangeable with units used to express the activity of cholecalciferol (vitamin D3) preparations.

Patients with Renal Impairment

Administration of Hydroferol to patients with chronic kidney disease should be accompanied by periodic monitoring of serum calcium and phosphorus levels and prevention of hypercalcemia.

Elderly Patients

Overall, no differences in treatment efficacy have been observed between elderly patients and younger patients.

Method of Administration

The medicinal product Hydroferol, soft capsules, is intended for oral administration.

Children. Safety and efficacy of Hydroferol in children and adolescents (under 18 years of age) have not yet been established. Data are lacking. This medicinal product is not recommended for use in children.

Overdose

Symptoms

Administration of vitamin D in high doses or over a prolonged period may cause hypercalcemia, hypercalciuria, hyperphosphatemia, and renal failure. Early symptoms of overdose may include weakness, fatigue, drowsiness, headache, anorexia, dry mouth, metallic taste in the mouth, nausea, vomiting, abdominal cramps, polyuria, polydipsia, nocturia, constipation or diarrhea, dizziness, tinnitus, ataxia, rash, arterial hypotension (especially in children), muscle or bone pain, and irritability.

Late symptoms of hypercalcemia include: rhinitis, pruritus, decreased libido, nephrocalcinosis, renal failure, osteoporosis in adults, growth retardation in children, weight loss, anemia, conjunctivitis with calcification, photophobia, pancreatitis, elevated blood urea nitrogen, albuminuria, hypercholesterolemia, elevated transaminase levels (serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase), hyperthermia, generalized vascular calcification, seizures, and soft tissue calcification. In isolated cases, patients may develop arterial hypertension or psychotic symptoms; serum alkaline phosphatase levels may decrease; electrolyte imbalance with mild acidosis may lead to cardiac arrhythmia.

In the most severe cases, when serum calcium levels exceed 3 mmol/L, unconsciousness, metabolic acidosis, and coma may occur. Although symptoms of overdose are usually reversible, overdose may lead to renal or cardiac failure.

Serum 25-OH-cholecalciferol levels above 375 nmol/L are considered to be associated with an increased frequency of adverse reactions.

This type of overdose is characterized by elevated levels of calcium, phosphates, albumins, blood urea nitrogen, cholesterol, and liver transaminases in the blood.

Treatment

Treatment of calcifediol overdose:

1. Discontinue calcifediol and any calcium-containing preparations.
2. Follow a low-calcium diet. To enhance calcium excretion, large volumes of fluids should be administered, both orally and parenterally. If necessary, administer corticosteroids and induce forced diuresis with loop diuretics such as furosemide.
3. If ingestion occurred within the previous 2 hours, gastric lavage and induced emesis are recommended. If vitamin D has already passed through the stomach, a laxative (paraffin or mineral oil) may be administered. If vitamin D has already been absorbed, hemodialysis or peritoneal dialysis using a calcium-free dialysis solution may be performed.

Hypercalcemia caused by prolonged use of calcifediol persists for approximately 4 weeks after discontinuation of treatment. Signs and symptoms of hypercalcemia are usually reversible. However, metastatic calcification may result in severe renal or cardiac failure and death.

Side effects

Side effects are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Vitamin D-related side effects are associated with elevated calcium levels due to excessive intake of vitamin D, i.e., related to overdose or prolonged treatment. The doses of vitamin D analogs causing hypervitaminosis vary significantly between individuals. Side effects related to increased blood calcium levels may occur at the beginning of treatment or at a later stage (see section "Overdose").

Immune system disorders:

Frequency not known: hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnea, rash, local swelling / local edema, and erythema).

Gastrointestinal disorders:

Frequency not known: hypercalcemia and hypercalciuria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It enables ongoing monitoring of the benefit-risk balance of this medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Packaging. 5 soft capsules in a blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Faes Farma, S.A., Spain

Manufacturer's address. Maksimo Agirre, 14, 48940 Leioa (Biscay), Spain