FOSAVANS

Active material: Alendronate, Kolekaltsiferol
When ATH: M05BB03
CCF: An inhibitor of bone resorption in osteoporosis
ICD-10 codes (testimony): M81.0, M81.1
When CSF: 16.04.04.01
Manufacturer: MERCK SHARP & DOHME B.V.. (Netherlands)

Pharmaceutical form, composition and packaging

Pills from white to almost white, kapsulovidnoy form, with print “710” on one side and bone pattern – another.

Excipients: lactose bezvodnaya, microcrystalline cellulose, colloidal silicon dioxide, sodium croscarmellose, magnesium stearate.

* in the form of granules, containing also: trigliceridy, gelatin, sucrose, modified food starch, butylhydroksytoluol, sodium aluminum silicate.

2 PC. – blisters (1) – cardboard covers (1) – packs cardboard.
2 PC. – blisters (1) – cardboard covers (2) – packs cardboard.
2 PC. – blisters (1) – cardboard covers (3) – packs cardboard.
2 PC. – blisters (1) – cardboard covers (10) – packs cardboard.
4 PC. – blisters (1) – cardboard covers (1) – packs cardboard.
4 PC. – blisters (1) – cardboard covers (2) – packs cardboard.
4 PC. – blisters (1) – cardboard covers (3) – packs cardboard.
4 PC. – blisters (1) – cardboard covers (10) – packs cardboard.

Pharmacological action

An inhibitor of bone resorption in osteoporosis. Sodium alendronate belongs to bisphosphonates – connections, that, localizing in areas of active bone resorption, under osteoclasts, inhibit the process of bone resorption, osteoclast-induced, without directly affecting the formation of new bone tissue. Because bone resorption and new bone formation are interconnected, bone formation is also reduced, but less, than resorption, which leads to a progressive increase in bone mass. Normal bone formation during sodium alendronate treatment, in the matrix of which alendronate is embedded, remaining pharmacologically inactive. In therapeutic doses, alendronate does not cause osteomalacia.

Colecalciferol is produced in the skin by converting 7-dehydrocolecalciferol to vitamin D₃ when exposed to ultraviolet radiation. In the absence of sunshine, vitamin D₃ is an irreplaceable component of food. Vitamin D₃ metabolized to 25-hydroxyvitamin D in the liver, where does it accumulate. Converting it to the active calcium-mobilizing hormone 1,25-dihydrovitamin D (calcitriol), occurs in the kidneys and is carefully regulated. The principal mechanism of action of 1,25-dihydrovitamin D is to increase intestinal absorption of calcium and phosphates., as well as regulation of plasma calcium levels, excretion of calcium and phosphate by the kidneys, bone formation and resorption.

Vitamin D₃ essential for normal bone formation. Vitamin D deficiency develops with inadequate sunlight exposure and / or dietary inaccuracies. Vitamin D deficiency is associated with negative calcium balance, bone loss, increased risk of fractures. In acute cases, vitamin deficiency is associated with secondary hypoparathyroidism., hypophosphatemia, myasthenia, osteomalacia, further increased risk of falls and fractures in patients with osteoporosis.

Pharmacokinetics

Absorption

Alendronate sodium

Bioavailability of sodium alendronate per dose 5 – 70 mg when taken orally on an empty stomach no later than, than 2 h before standard breakfast, is 0.64% in women and 0.6% males.

When taking alendronate sodium on an empty stomach for 1-1.5 h before a standard breakfast, bioavailability decreases by approximately 40%.

In patients with osteoporosis, sodium alendronate is effective when administered on an empty stomach., not later, than 30 minutes before the first meal or liquid.

The bioavailability of sodium alendronate is negligible when administered concurrently with meals or during 2 h postprandial.

Simultaneous reception with coffee or orange juice reduces the bioavailability of the drug by approximately 60%.

When taking prednisolone in a dose 20 mg 3 times / day for 5 days, there is no clinically significant change in the bioavailability of sodium alendronate.

Kolekaltsiferol

When using Fosavance^® after a morning sleep on an empty stomach for 2 h before standard breakfast, average AUC_{0-120 no} for vitamin D₃ is 296.4 ng h h / ml.

C_max vitamin D_{3 in} blood plasma is 5.9 ng / ml. The average time to achieve C_max vitamin D₃ in plasma is 12 no.

Bioavailability 2800 ME of vitamin D₃ in a tablet Fosavance^®similar to bioavailability 2800 ME of vitamin D₃ with isolated reception.

Distribution

Alendronate sodium

Average V_d at equilibrium (excluding bone) is at least 28 l. When taken in therapeutic doses, the concentration of the drug in the blood plasma is insignificant (less 5 ng / ml). Binding of sodium alendronate to plasma proteins is approximately 78%.

Kolekaltsiferol

After intestinal absorption, vitamin D₃ enters the bloodstream as part of chylomicrons and is quickly distributed, primarily, to the liver. Smaller amounts of vitamin D₃ distributed into adipose and muscle tissue, where they are cumulated in native form for further gradual release into the bloodstream. Vitamin D₃ circulates in the bloodstream, associated with vitamin D-binding protein.

Metabolism

Alendronate sodium

There is no evidence, that sodium alendronate is metabolized in humans or animals.

Kolekaltsiferol

Vitamin D₃ rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D₃ (the main form of vitamin accumulation) and is gradually metabolized in the kidneys to 1.25-dihydroxyvitamin D₃, which is the active form of the vitamin. Before the excretion of the vitamin, its further hydroxylation occurs.. Low amount of vitamin D₃ before excretion is subjected to glucuronidation.

Deduction

Alendronate sodium

After a single intravenous injection of sodium alendronate, labeled ¹⁴FROM, about 50% the drug is excreted in the urine within 72 no. The excretion of the labeled drug in the feces was insignificant or undetectable. After a single intravenous injection of sodium alendronate in a dose 10 mg its renal clearance is 71 ml / min. Through 6 h after i.v. administration, the concentration in the blood plasma decreases more than, than 95%. The final T_1/2 more than 10 years, which reflects the release of the drug from the bone tissue.

Kolekaltsiferol

When taking radioactive vitamin D₃ in healthy individuals, the average excretion of the radioactive drug in the urine after 48 h was 2.4%, with feces - 4.9% after 4 d. In both cases, the drug was excreted mainly in the form of its metabolites.. T_1/2 vitamin D₃ after oral administration of Fosavance^® approximately 24 no.

Testimony

- treatment of osteoporosis in postmenopausal women in order to prevent the development of fractures, incl. hip fractures and compression fractures of the spine, as well as ensuring an adequate supply of vitamin D;

- treatment of osteoporosis in men to prevent fractures, as well as ensuring an adequate supply of vitamin D.

Dosage regimen

The drug is prescribed for 1 tab., at least, for 30 min before the first meal, liquids or medicines (including antacids, calcium preparations and vitamins), with a full glass of plain water (not mineral water). Other drinks (including mineral water), food and certain medicines can reduce the absorption of Fosavance^®.

The recommended dose is 1 tab. (70 mg / 70 mcg) 1 once a week.

Patients should take additional calcium and / or vitamin D supplements, if the intake of these substances with food is insufficient. Fosavans^® provides a weekly need for vitamin D, based on daily dose 400 ME.

To elderly patients and patients with renal insufficiency of mild to moderate severity (KK from 35 to 60 ml / min) correction dose is not required.

If you accidentally skip taking the drug, be taken 1 pill next morning. Should not be taken 2 doses in one day, but in the future you need to return to taking the drug 1 once a week that day of the week, which was chosen at the beginning of the treatment.

To reduce the risk of esophageal irritation Fosavance^® should be taken, following the rules:

1. The drug should be taken in the morning immediately after getting out of bed., at least, for 30 min before the first meal, liquids or medicines, drink a full glass of water (not mineral) to facilitate the entry of the tablet into the stomach.

2. Do not chew the tablets or dissolve in the mouth due to the possible formation of ulcers in the oral cavity and pharynx. Patients should not take a horizontal position before the first meal, which should be done at least after 30 min after taking Fossavans^®.

3. Fosavans^® should not be taken at bedtime or before getting out of bed.

Side effect

From the digestive system: stomach ache, dyspepsia, esophageal ulcer, dysphagia, flatulence, constipation, diarrhea, acid belching, nausea, distortion of taste, gastritis; rarely (1/10 000, <1/1000) – esophagitis, erosion of the esophagus, gastric ulcer, incl. stomach ulcer, complicated by bleeding (ground), local osteonecrosis of the jaw, associated mainly with previous tooth extraction and / or local infection due to delayed treatment.

On the part of the musculoskeletal system: myalgia, ostealgias, joints; rarely (1/10 000, <1/1000) – muscle cramps.

From the nervous system: headache, dizziness.

On the part of the organ of vision: rarely (1/10 000, <1/1000) – uveitis, scleritis, episcleritis.

Dermatological reactions: rarely (1/10 000, <1/1000) – skin rash, эritema, photosensitivity, itch, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Allergic reactions: hypersensitivity reactions, including urticaria; rarely (1/10 000, <1/1000) – angioedema, transient symptoms, resembling an acute phase reaction (myalgia, malaise, rarely – fever).

Metabolism: hypocalcemia; there was also a decrease in serum calcium and phosphate levels (usually light, asymptomatic and transient) on 18% and 10% respectively.

Contraindications

- diseases of the esophagus, slowing down its emptying (eg, strictures or achalasia);

- inability of the patient to remain upright during 30 m;

- Hypocalcemia;

- Severe renal insufficiency (CC < 35 ml / min);

- severe hypoparathyroidism;

- severe vitamin D deficiency;

- calcium malabsorption;

- Pregnancy;

- Lactation (breast-feeding);

- Childhood and adolescence up 18 years;

- hypersensitivity to any component of the drug.

FROM caution the drug should be prescribed for exacerbation of diseases of the upper gastrointestinal tract (dysphagia, esophageal disease, gastritis, duodenitis or stomach ulcer / incl.. history of peptic ulcer, active gastrointestinal bleeding, surgery on the upper gastrointestinal tract during the year before taking Fosavance^®/), for diseases, associated with overproduction of calcitriol (leukemia, lymphoma, sarkoidoz) and concomitant hypercalcemia and / or hypercalciuria.

Pregnancy and lactation

Fosavans^® should not be prescribed during pregnancy and during breastfeeding due to lack of experience with this category of patients.

Cautions

Fosavans^®, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Patients, receiving treatment with Fosavance^®, such side reactions may occur, like esophagitis, ulcer and erosion of the esophagus, rarely leading to strictures or perforation of the esophagus. In some cases, these adverse events can be severe and require hospitalization.. Concerning, doctors should be especially alert to any signs or symptoms, indicating possible disorders of the esophagus, and patients should be warned about the need to stop taking Fosavance^® and see a doctor if they develop dysphagia, pain when swallowing or behind the breastbone, the appearance or intensification of heartburn.

The risk of severe esophageal adverse events is higher in those patients, who violate the recommendations for taking the drug and / or continue to take it when symptoms of esophageal irritation appear. Especially important, so that the patient has recommendations for taking the drug, understood them and was informed, that the risk of developing damage to the esophagus increases if these recommendations are not followed.

There are rare cases of stomach and duodenal ulcers, sometimes severe and complicated. But, in these cases, a causal relationship with the drug intake has not been established.

Fosavans^® should be prescribed with caution in patients with exacerbations of diseases of the upper gastrointestinal tract, such, as dysphagia, esophageal disease, gastritis, duodenitis and ulcers due to the possible irritating effect of the drug on the mucous membrane of the upper gastrointestinal tract and a deterioration in the course of the underlying disease.

There are known cases of the appearance of local osteonecrosis of the jaw, associated mainly with previous tooth extraction and / or local infection, due to untimely treatment, when ingested bisphosphonates. Most of these cases were reported in patients, cancer patients, in the treatment of which intravenous administration of bisphosphonates was carried out. Known risk factors for jaw necrosis include cancer detection, providing appropriate treatment (chemotherapy, radiotherapy, corticosteroids), poor oral hygiene and comorbidities (dental disease, anemia, coagulopathy, infection). Patients, who have local osteonecrosis of the jaw, should see a maxillofacial surgeon.

Fosavans^® not recommended for patients with severe renal impairment (CC<35 ml / min) due to the lack of experience in this category of patients.

Other causes of osteoporosis should be considered, in addition to estrogen deficiency, age and use of corticosteroids.

In the presence of hypocalcemia, the level of calcium in the blood must be normalized before starting treatment with Fosavance.^®. Other disorders of mineral metabolism (eg, vitamin D deficiency) should also be eliminated. In patients with these disorders, it is necessary to monitor the level of calcium in the blood and symptoms of hypocalcemia..

Since Sodium Alendronate Increases Bone Mineral Content, there may be a slight asymptomatic decrease in serum calcium and phosphorus levels.

Vitamin D supplementation may be considered individually.

Vitamin D₃ may increase the severity of hypercalcemia and / or hypercalciuria when used in patients with medical conditions, associated with overproduction of calcitriol (leukemia, lymphoma, sarkoidoz). In such patients, plasma and urine calcium levels should be monitored..

Patients with malabsorption may have impaired vitamin D absorption..

Effects on ability to drive vehicles and management mechanisms

There is no evidence, what Fosavance^® affects the ability to drive or use other mechanisms.

Overdose

Symptoms: hypocalcemia, gipofosfatemiя, adverse events from the upper gastrointestinal tract (heartburn, esophagitis, gastritis, ulcers of the stomach and esophagus).

Treatment: no specific information available. The patient should take milk or antacids to bind the sodium alendronate. Do not induce vomiting to prevent irritation of the esophagus.. Patients must maintain an upright position.

Drug Interactions

The absorption of the drug may be impaired when taken simultaneously with calcium supplements, antacids and other drugs for oral administration. In this regard, the interval between taking Fosavance^® and other drugs, taken internally, must be at least 30 m.

When using Fosavance together^® with hormone replacement therapy (estrogen + progestin) the safety and tolerability of the combination therapy is the same as for each of these drugs alone.

Olestra, mineral oil, Orlistat, as well as bile acid sequestrants (cholestyramine, colestipol) may interfere with the absorption of vitamin D.

Anticonvulsants, cimetidine, thiazide diuretics may accelerate vitamin D catabolism.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored dry, protected from light, reach of children, at a temperature no higher than 25 ° C. Shelf life – 18 months.