MULTIZAN D3    (Multizan D3)  
Vitamin D 3  50 000 IU coated tablets for oral administration

Description
They are red-brown, oval, coated tablets.

Pharmacotherapeutic group
Vitamin preparation. Vitamin D.
ATC code: A11CC05.

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pharmacological properties
Pharmacodynamics
Vitamin D3 is a regulator of calcium and phosphorus metabolism, accelerates the absorption of calcium from the small intestine, regulates the reabsorption of calcium and phosphates in the kidneys, maintains the concentration of mineral salts in the blood, ensures the calcification process of bones, the correct formation of the skeleton and the protection of the bone structure. The concentration of calcium ions in the blood affects the maintenance of the tone of skeletal muscles and myocardial function, the transmission of nerve impulses, a number of important biochemical processes that determine the blood coagulation process, as well as the improvement of the activity of the immune system by influencing the generation of lymphokines. Vitamin D3 is necessary for the normal function of the thyroid gland. 
The ability to synthesize vitamin D3 in the skin decreases as the time spent under the sun's rays decreases with age. Due to the weakening of kidney function, the level of 1,25(OH)2D, the active metabolite of vitamin D produced in the kidneys, decreases, which contributes to the widespread prevalence of vitamin D deficiency among the elderly.
During vitamin D deficiency, skeletal calcification is impaired in children (which leads to the development of rickets), and bone decalcification is observed in adults (which causes osteomalacia). 
Vitamin D is required for calcium absorption and normal bone metabolism. Its chronic deficiency leads to an increase in parathormone synthesis, secondary hyperparathyroidism, activation of metabolism in bone tissue, and as a result, rapid loss of bone mass, bone fragility and fractures. The need for vitamin D increases in menopausal women as a result of the development of osteoporosis, often due to hormonal disorders. Taking vitamin D, especially in combination with calcium, slows bone loss and reduces fractures. Taking vitamin D and calcium is an important part of osteoporosis treatment and prevention. 
Carcinogenicity, mutagenicity, impairment of reproductive function
Cholecalciferol intake in animals at high doses (4-15 times higher than the permissible dose for humans) has been found to have a teratogenic effect and cause anatomical defects (supravalvular aortic narrowing).

Pharmacokinetics
The pharmacokinetics of vitamin D have been well studied. After oral administration, cholecalciferol is well absorbed from the digestive tract (in the small intestine) (60-90%; during hypovitaminosis, almost completely). It undergoes metabolism in the liver and kidneys. In the liver, it is oxidized by the action of the 25-hydroxylase enzyme and turns into its inactive metabolite 25-hydroxycholecalciferol - 25(OH)D3 (calcifediol), then this metabolite is re-oxidized in the kidneys by the action of the 1-alpha hydroxylase enzyme and turns into its active metabolite 1,25-hydroxycholecalciferol (calcitriol) - 1, 25(OH)2D3 is converted. These metabolites circulate in the form of chylomicrons and lipoproteins, binding to special alpha-globulin in the blood, plasma and lymphatic system. 
It accumulates in large quantities in the bones, in smaller quantities - in the liver, muscles, blood and small intestine. Vitamin D is stored in fat and muscle tissue in the body. Vitamin D crosses the placental barrier and passes into breast milk in small amounts.
A large part of vitamin D and its metabolites are excreted from the body with bile and feces, and a small part with the kidneys. It has a cumulative feature.
An increase in the amount of Ca2+ in the blood begins 12-24 hours after taking the drug, the therapeutic effect is noted after 10-14 days and lasts up to 6 months.
Features of the pharmacokinetics of the drug in a special group of patients
A 57% reduction in the rate of metabolic clearance was observed in patients with impaired renal function compared to healthy volunteers. In volunteers with malabsorption syndrome, a decrease in the absorption of vitamin D and an acceleration of its excretion were observed.
Overweight volunteers are unable to maintain vitamin D levels even when exposed to sunlight, requiring higher doses.

Instructions for use
Treatment of vitamin D deficiency.

 

Contraindications
- Hypersensitivity to vitamin D or any of the other components of the drug. 
- D hypervitaminosis.
- Renal osteodystrophy with hyperphosphatemia.
- Hypercalcemia and/or hypercalciuria (increased levels of calcium in the blood and urine).
- Nephrocalcinosis.
- Kidney stone disease.
- Severe renal failure.
- Children up to 18 years old.
- Pregnancy period.
Take vitamin D with caution in the following situations:
- sarcoidosis.

 

Special instructions and precautions
To prevent hypercalcemia, treatment should be carried out under the supervision of a doctor. Calcium supplements should be used under medical supervision and calcium and phosphate levels should be monitored. The risk of soft tissue calcification should also be considered. Calcium absorption can be reduced by oral sodium sulfate or parenteral magnesium sulfate. 
Vitamin D should be used with caution in patients with impaired renal function, monitoring of calcium and phosphate levels while taking the drug is recommended. 
Since cholecalciferol cannot be metabolized normally in patients with severe renal failure, other forms of vitamin D should be prescribed to such patients.
Care should be taken when using vitamin D in patients with cardiovascular diseases who are treated with appropriate drugs (cardiac glycosides, diuretics). 
In the elderly, high-dose oral vitamin D (500,000 IU single dose) has been reported to increase the risk of fracture, and this increase is most pronounced in the first 3 months after dosing.
Treatment with vitamin D may detect previously undiagnosed primary hyperparathyroidism. Corrected serum calcium levels should be checked 1 month after the end of the loading regimen, or after starting vitamin D if primary hyperparathyroidism is detected.
In the case of hypercalciuria (more than 300 mg (7.5 mmol)/24 hours) or in the presence of signs of impaired renal function, the dose should be reduced or the treatment discontinued.
In patients already receiving treatment with vitamin D3, the total dose of vitamin D3 should be adjusted when using foods rich in vitamin D3, milk, and in cases related to the patient's exposure to the sun.
Cholecalciferol should be used with caution in patients with sarcoid due to the high risk of metabolism to the active form of vitamin D. In such patients, the calcium level in blood serum and urine should be monitored. Similar monitoring should be done for children whose mothers receive therapeutic doses of vitamin D. Some children may react with hypersensitivity to vitamin D. Patients with rare hereditary problems such as galactose and fructose intolerance, glucose-galactose malabsorption, lactase deficiency and sucrose-isomaltose deficiency should not take this drug.

Interaction with other drugs
Concomitant use with anticonvulsants (eg, phenytoin), hydantoin, barbiturates or pyrimidone (and other drugs that induce liver enzymes), glucocorticoids may weaken the effect of vitamin D (due to metabolic inactivation). 
During the simultaneous use of vitamin D with digitalis or other cardiac glycosides, their toxic effect (arrhythmia) may increase. Therefore, these patients require strict medical supervision, as well as monitoring of the level of calcium in the blood and ECG.
Concomitant use of ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce gastrointestinal absorption of vitamin D.
Thiazide diuretics reduce the urinary excretion of potassium. Taking high doses of vitamin D with diuretics can lead to an increase in the amount of calcium in the body. Blood calcium concentration should be monitored during co-treatment with thiazide diuretics.
Actinomycin, a cytotoxic agent, and antifungal agents such as imidazole inhibit the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol during their interaction with vitamin D. 
The use of high doses of calcium-containing foods or preparations increases the risk of hypercalcemia.
Due to the risk of metastatic calcification, phosphate solutions should not be used to reduce hypercalcemia in hypervitaminosis D. Products containing magnesium (such as antacids) should not be taken, as this increases the risk of hypermagnesemia.
Vitamin D increases the absorption of phosphorus-containing preparations and the risk of hyperphosphatemia.
During the treatment of hypercalcemia, the simultaneous use of vitamin D with drugs such as calcitonin, etidronate, gallium nitrate, pamidronate, and plikamycin can cause an antagonistic effect of these drugs.

 

Use during pregnancy and lactation
There are limited data on the use of cholecalciferol in pregnant women. Animal studies have shown its reproductive toxicity. Also, vitamin D overdose should be avoided in pregnant women, because long-term hypercalcemia is sometimes associated with retardation of physical and mental development, supravalvular aortic stenosis and retinopathy in children.
The recommended daily dose for pregnant and lactating women is 400 IU, but women with vitamin D deficiency may need a higher dose (up to 2000 IU per day). During pregnancy, women should follow the recommendations of their treating physicians.
Vitamin D and its metabolites pass into breast milk; however, cases of vitamin D overdose in infants have not been recorded. When prescribing vitamin D to the child, the doctor should also take into account the dose of vitamin D taken by the mother. High doses of vitamin D (50,000 IU) are not recommended during pregnancy and lactation.

Effects on the ability to drive vehicles and other potentially dangerous mechanisms
It does not affect the ability to drive vehicles and other potentially dangerous mechanisms.

 

Method of use and dosage
Multizan D3 coated tablets are taken regardless of food intake. 
For correction of vitamin D deficiency, as well as supportive therapy, the dose is determined individually depending on the severity of vitamin D deficiency and response to treatment. The duration of treatment depends on the course of the disease.
It is recommended to take Multizan D3 coated tablets without chewing inside, with enough liquid.
Treatment of vitamin D deficiency: for 6-8 weeks, Multizan D3 1 tablet (50,000 BV) 1 time per week, then should be transferred to supportive treatment.
Supportive therapy: at the rate of 1400 - 2000 IU/day, which corresponds to taking Multizan D3 1 tablet (50 000 IU) once a month. The treatment is carried out under the control of the concentration of 25-(OH) D in the blood serum for the next 3-4 months to confirm that the target level has been reached.
Osteoporosis: 800 - 1000 IU/day, which corresponds to a weekly dose of 7000 IU of Multizan D3.
For elderly patients at risk of falls and fractures, the recommended dose of vitamin D is 2000 IU per day. If the intake of calcium with food intake is insufficient, calcium preparations should be prescribed additionally.
Vitamin D deficiency in adults and the elderly (serum 25-(OH) D <25 nmol/l or <10 ng/ml): 
Accepted for 12 weeks at the rate of 800-4000 BV/day.
Vitamin D deficiency in adults and the elderly (serum 25-(OH) D = 25-50 nmol/l or 10-20 ng/ml): 800-1600 IU/day is taken long-term.
For some patients at high risk of vitamin D deficiency, higher doses may be required and blood 25-(OH) D levels should be monitored:
- hospitalized persons;
- people with dark skin;
- patients with impaired absorption - including those suffering from malabsorption, gluten enteropathy, intestinal inflammatory diseases;
- people deprived of sunlight   due to constant use of protective clothing or sun protection products;
- people suffering from obesity;
- persons diagnosed with osteoporosis;
- people taking concomitant medications (e.g. anticonvulsants, glucocorticoids)
- People who are being treated for vitamin D deficiency and need supportive therapy. 
Before starting treatment, it is necessary to determine the levels of calcium and phosphorus in the blood.
In order for the treatment to be effective, sufficient intake of calcium with food should be ensured.
Otherwise, taking calcium supplements is recommended.
When choosing the dose of vitamin D, it is necessary to take into account the amount of its consumption from other sources (food products, nutritional supplements and sunlight). The dose is selected individually. In order to achieve the effect during treatment with vitamin D, the level of intake of calcium and phosphorus is of great importance.
If vomiting occurs in patients taking therapeutic doses of vitamin D, serum calcium levels should be checked regularly.
Administration of phosphate-binding agents (phosphate-binders) should be evaluated to control high serum phosphate concentrations in hemodialysis patients. Due to the acceleration of phosphate absorption during treatment with vitamin D, it may be necessary to increase the dose of phosphate binders.
The product of calcium and phosphorus in blood serum (Ca×P, mg/dL) should not exceed 60.
In cases of malabsorption or liver disease, higher doses (6000-10000 IU per day) are required to treat vitamin D deficiency. Vitamin D in doses up to 2.5 mg (100,000 IU) can be used to treat hypocalcemia due to hypoparathyroidism.
 

Patient monitoring
The following indicators may be useful in monitoring patients (if necessary, indicators of other tests may be required depending on the patient's condition):
•    Blood calcium concentration or plasma ionized calcium level. Due to the narrow therapeutic range, it is recommended to determine these indicators at least once a week in the early period of treatment, and then periodically. If possible, it is recommended to determine the concentration of both free and combined calcium in the blood. 
•    Alkaline phosphatase level in blood plasma, phosphate concentration in blood, calcium concentration in daily urine, calcium/creatinine ratio in urine. During treatment, it is recommended to determine these indicators every 1-3 months.
•    Urea and creatinine in blood plasma. Routine determination is recommended in patients receiving therapeutic doses.
Additional information on special groups of patients
Use in children
Children under the age of 18 are not recommended for use at this age as they cannot safely swallow the tablet.
Use in the elderly
Studies show that the need for vitamin D may increase in the elderly due to reduced skin synthesis of vitamin D3, decreased time spent in the sun, decreased kidney function, or decreased absorption of vitamin D. Dose selection should be based on the concentration of 25-hydroxycholecalciferol in blood serum.
Use in renal/hepatic insufficiency
Dose adjustment is not required. In cases where long-term use of D3 is required, monitoring of renal function should be carried out. In severe renal failure, it should not be used in combination with calcium.
In case of liver diseases, higher doses are required to treat vitamin D deficiency. Dose selection should be based on the concentration of 25-hydroxycholecalciferol in blood serum.
If you forget to take the drug, do not take a double dose instead of the missed dose!
Do not stop taking the medicine without consulting your doctor!
If you have any doubts or questions, contact your doctor.
 

Side effects
Observed additional reactions are classified according to organ systems and frequency of occurrence as follows: very often (≥1/10); often (≥1/100 to <1/10); sometimes (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10000); with an unknown frequency (the available data are insufficient to determine the frequency of occurrence).
The use of vitamin D3 in high doses and for an uncontrolled period of time can lead to the appearance of the following undesirable effects.
To the immune system
With unknown frequency: hypersensitivity reactions such as angioedema, edema of the larynx.
To metabolism and nutrition
Sometimes: hypercalcemia and hypercalciuria.
To the skin and subcutaneous adipose tissue
Rarely: itching, rash and urticaria.
Growth retardation may occur in children, especially after long-term administration of cholecalciferol at a dose of 45 mcg (1800 IU)/day.
Early signs of vitamin D hypervitaminosis due to hypercalcemia: constipation, usually in children and adolescents; diarrhea; dry mouth; prolonged headache; excessive thirst (polydipsia); increased urination or the amount of urine passed (polyuria), especially at night; decreased appetite; metallic taste in the mouth; nausea or vomiting (usually in children and adolescents); fatigue or weakness.
Delayed symptoms of vitamin D hypervitaminosis due to hypercalcemia: bone pain; turbidity of urine; arterial hypertension; photosensitivity or eye irritation; arrhythmia; itching of the skin; lethargy (drowsiness); muscle pain; nausea or vomiting; pancreatitis (acute pain in the abdomen); psychosis; rapid loss of body weight.
Consult a doctor if unwanted effects occur. If you experience any side effects not listed in this package insert, tell your doctor. 

Overdose
Overdose may cause hypercalcemia and associated effects (hypercalciuria, ectopic calcification, renal and cardiovascular damage). 
Symptoms: anorexia, nausea, vomiting, diarrhea, fatigue, polyuria, sweating, thirst, headache, dizziness, bone pain, heart rhythm disorders, kidney dysfunction. Toxic effects of vitamin D are usually observed in newborns and children.
Means: drug intake should be stopped. A diet low in calcium and plenty of fluids should be taken.
If necessary, treatment can be carried out in a hospital setting. If hypercalcemia persists, prednisolone should be started. Severe hypercalcemia can be treated with calcitonin, etidronate, pamidronate, or gallium nitrate. During a hypercalcemic crisis, intensive dehydration should be carried out with the use of sodium chloride solution and loop diuretics in order to accelerate the removal of calcium from the body. Cardiac arrhythmias can be treated with small doses of potassium with continuous cardiac monitoring.

Release form
Multizan D3 50 000 BV coated tablets. 
8 or 15 tablets in an aluminum blister. 1 blister is packed in a cardboard box with an insert. 

Store condition
It should be stored at a temperature not higher than 30ºC, in a dry place and out of the reach of children. 

Shelf life
3 years. 
Do not use after the expiration date.

Condition of release from pharmacy
It is released on the basis of a prescription.

Producer
Quest Vitamins Middle East Fze.
Dubai, UAE, Jebel-Ali Free Zone, Plot S20708A. 

Licensee
LAMYRA LLP, UK.
49 Farringdon  Road, London.