Universal reference book for medicines
Product name: FOSAVANS ® FORTE (FOSAVANCE ® FORTE)

Active substance: alendronic acid, colecalciferol

Type: Inhibitor of bone resorption in osteoporosis

Manufacturer: MERCK SHARP & DOHME (Netherlands) manufactured by FROSST IBERICA (Spain) packed with MERCK SHARP & DOHME (Netherlands)
Composition, form of production and packaging
Tablets
1 tab.

alendronic acid 70 mg

colcalciferol 140 μg

4 things.
- blisters made of PVC / aluminum foil (1) - packs of cardboard.
4 things.
- blisters of PVC / aluminum foil (3) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

The drug Fosavans ® forte is a combined preparation containing two active substances: alendronate sodium trihydrate and colcalciferol (vitamin D3).

Alendronate

Alendronate sodium is a bisphosphonate that inhibits osteoclast-mediated bone resorption without directly affecting the formation of new bone tissue.
Preclinical studies show that alendronate is predominantly localized in areas of active bone resorption. It suppresses the activity of osteoclasts, but does not affect the involvement and attachment of osteoclasts. During treatment with alendronate, normal bone tissue is formed.
Kolekaltsiferol (vitamin D 3 )

Vitamin D 3 is formed in the skin by converting 7-dehydrocholesterol to vitamin D 3 under the influence of ultraviolet radiation.
With a lack of sunlight, vitamin D 3 is an indispensable component of food.
Vitamin D 3 is metabolized to 25-hydroxyvitamin D 3 in the liver, where it accumulates.
Turning it into an active calcium-mobilizing hormone 1,25-dihydroxyvitamin D 3 (calcitriol) occurs in the kidneys and is carefully regulated. The main effect of 1,25-dihydroxyvitamin D 3 is to increase the intestinal absorption of calcium and phosphate, as well as to regulate the level of calcium in the plasma, excretion of calcium and phosphate by the kidneys, the formation of bone tissue and its resorption.
Vitamin D 3 is necessary for the normal formation of bone tissue.
Insufficiency of vitamin D 3 develops in cases when, exposure to sun and consumption of vitamin D3 with food do not cover human needs. Hypovitaminosis causes a negative balance of calcium, loss of bone mass, an increased risk of fractures. In severe cases, vitamin deficiency leads to secondary hypoparathyroidism, hypophosphatemia; myasthenia gravis and osteomalacia with a further increase in the risk of falls and fractures in patients with osteoporosis. The additional intake of vitamin D 3 reduces these risks and their consequences.
PHARMACOKINETICS

Alendronate

Suction

The bioavailability of alendronate in a dose of 5-70 mg when administered on an empty stomach no later than 2 hours before a standard breakfast is 0.64% in women and 0.6% in men from the intravenous dose.
When taking alendronate on an empty stomach for an hour or half an hour before a standard breakfast, bioavailability decreased to 0.46% and 0.39%, respectively. In osteoporosis, alendronate is effective when applied on an empty stomach no later than 30 minutes before the first intake of food or liquid.
The bioavailability of alendronate in the combined preparation Fosavans ® forte (70 mg / 5600 ME) is equivalent to its bioavailability in the alendronate 70 mg tablet.

Alendronate bioavailability is insignificant when administered concomitantly with food intake or within 2 hours after a standard breakfast.
Simultaneous intake of alendronate with coffee or orange juice reduces its bioavailability by approximately 60%.
When taking prednisone orally (20 mg 3 times a day for 5 days), a clinically significant change in the bioavailability of alendronate does not occur in healthy individuals (the average increase in bioavailability was 20-44%).

Distribution

Studies in rats show that after intravenous administration at a dose of 1 mg / kg, alendronate is distributed into soft tissues, and then quickly redistributed into bones or excreted in the urine.
In humans, the average volume of distribution in the equilibrium state, with the exception of bone tissue, is at least 28 liters. When administered orally at therapeutic doses, the concentration of alendronate in the blood plasma can not be determined analytically (less than 5 ng / ml). The binding to plasma proteins is approximately 78%.
Metabolism

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

Excretion

After a single intravenous administration of alendronate labeled with 14 C, approximately 50% of radioactive alendronate is excreted in urine for 72 hours. The excretion of labeled alendronate with feces was insignificant or not determined.
After a single intravenous injection of alendronate at a dose of 10 mg, its renal clearance is 71 ml / min, the systemic clearance does not exceed 200 ml / min. After 6 hours after intravenous administration, the concentration in the blood plasma is reduced by more than 95%. The final half-life in humans exceeds 10 years, which reflects the release of alendronate from the bones of the skeleton. Alendronate is not excreted through acid or basic renal transport in rats, its effect on the excretion of other drugs in this way in humans is not expected.
Kolekaltsiferol

Suction

When using the preparation Fosavans ® fort 70 mg / 5600 ME in healthy volunteers (male and female) after fasting 2 hours before eating, the average area under the concentration-time curve (AUC 0-80 h ) for vitamin D 3 , ( without correction for endogenous vitamin D 3 ) is 490.2 ng · h / ml.
The average maximum concentration in the serum (C max ) of vitamin D 3 is 12.2 ng / ml, and the average time to reach the maximum concentration in the serum (T max ) is 10.6 hours. The bioavailability of 5600 ME vitamin D 3 in the preparation of Fosavans ® forte is similar with the bioavailability of 5,600 IU of vitamin D 3 when isolated.
Distribution

After absorption, vitamin D 3 enters the blood in the composition of chylomicrons and is quickly distributed mainly to the liver, where it is metabolized to its basic form of accumulation of 25-hydroxyvitamin D 3 .
Smaller amounts are distributed to adipose and muscle tissue, where they are accumulated in the form of vitamin D3 for further gradual release into the bloodstream. Vitamin D 3 circulates in the bloodstream associated with the vitamin-D-binding protein.
Metabolism

Vitamin D 3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D 3 , which in turn is metabolized in the kidneys to 1,25-dihydroxyvitamin D 3, which is a biologically active form of the vitamin.
Before excretion of the vitamin, its further hydroxylation takes place. A small amount of vitamin D 3 is glucuronized before being excreted.
Excretion

When receiving radioactive vitamin D 3 in healthy individuals, the average excretion of radioactive colcalciferol in the urine was 2.4% after 48 hours, with feces 4.9% after 4 days.
In both cases, radioactive colcalciferol was excreted predominantly in the form of metabolites.
The average half-life of vitamin D 3 after oral administration of the preparation Fosavans ® fort 70 mg / 5600 ME is approximately 24 hours.

Renal insufficiency

Preclinical studies show that alendronate not ingested in bone tissue is rapidly excreted in the urine.
After repeated intravenous administration in a total dose of up to 35 mg / kg in animals, evidence of the deposition of the drug in the bones was not found.
Despite the lack of clinical data, it is likely that, like in animals, renal function impairment leads to alendronate excretion in the urine.
If the renal function is impaired, it is possible to increase the accumulation of alendronate in bone tissue.
INDICATIONS

- for the treatment of postmenopausal osteoporosis in patients who are not taking vitamin D supplements and who are at risk for developing vitamin D deficiency. The drug reduces the risk of vertebral and hip fractures;

- to increase bone mass in men with osteoporosis.

DOSING MODE

1 tablet, at least 30 minutes before the first meal, liquid 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 some medicines can reduce the absorption of the drug Fosavans ® forte.

To reduce the risk of esophageal irritation, the Fosavans ® forte preparation should be taken, following the rules listed below:

1. Take in the morning immediately after getting up from bed, at least 30 minutes before the first meal, liquid or medicines, with a full glass of water (not mineral water) to facilitate the intake of the tablet into the stomach.

2. Do not chew the tablets and dissolve them in the mouth due to the possible formation of ulcers in the mouth and throat.
Patients should not go to the first meal, which should be made at least 30 minutes after taking the drug Fosavans ® forte.
3. The drug Fosavans ® forte should not be taken before going to bed or before rising from bed.

The recommended dose is 1 tablet of the drug Fosavans ® forte once a week.

Patients should additionally take calcium supplements if their intake with food is insufficient.
The drug Fosavans ® forte meets a weekly requirement for vitamin D, based on a daily dose of 800 IU.
For elderly patients and patients with mild and moderate renal failure (CK from 35 to 60 ml / min), dose adjustments are not required.
The recommended dose is 1 tablet of the drug Fosavans ® forte once a week.
If you miss an appointment, take 1 tablet in the morning of the next day.
Do not take 2 doses on the same day, but in the future you should return to taking the drug 1 time a week on the day of the week that was chosen at the beginning of treatment.
SIDE EFFECT

The most frequently reported undesirable reactions are unwanted reactions from the upper gastrointestinal tract, including abdominal pain, dyspepsia, ulcer of the esophagus, dysphagia, bloating and acid burps (? 1/100, <1/10).

The following adverse reactions were reported during clinical trials and / or post-marketing use of alendronate.

Additional unwanted reactions for the drug Fosavans ® forte was not established.

The frequency of unwanted reactions is established as follows: very frequent (> 1/10);
frequent (> 1/100, <1/10); infrequent (> 1/1000, <1/100); rare (> 1/10000, <1/1000); very rare (<1/10000).
Violations from
side of the immune system Rare: hypersensitivity reactions, including, hives and angioedema
Disorders from the Metabolism and Nutrition Rare: symptomatic hypocalcemia, often against the background of predisposing factors 1

Nervous system disorders Frequent: headache, dizziness 2 Infrequent: a taste disorder 2

Impaired vision : Inflammation of the eye (uveitis, scleritis, episcleritis)

Hearing impairments and labyrinthine disorders Frequent: systemic dizziness 2

Disorders from the gastrointestinal tract Frequent: abdominal pain, indigestion, constipation, diarrhea, flatulence, oesophageal ulcer 3 , dysphagia 3 , bloating, acidic eructation Infrequent: nausea, vomiting, gastritis, esophagitis 3 , erosion of esophagus 3 , melena 2 Rare: stricture esophagus 3 , ulceration of the esophagus 3 , perforation, ulcers, upper gastrointestinal bleeding 1 , gastroesophageal reflux

Skin and subcutaneous tissue disorders Frequent: alopecia 2 , itching 2 Infrequent: skin rash, erythema Rare: skin rash with photosensitivity, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis 4

Musculoskeletal and connective tissue disorders Very frequent: musculoskeletal (bones, muscles or joints) pain, sometimes severe pain 1.2 Frequent: swelling of the joints 2 Rare: osteonecrosis of the jaw 1.4 , atypical, susceptible and diaphyseal fractures of the thigh (undesired bisphosphonate reaction) 5

General disorders and disorders at the site of administration Frequent: asthenia 2 , peripheral edema 2 Infrequent: transient symptoms as an acute phase reaction (myalgia, malaise and rarely fever), usually due to the onset of treatment 2

1 See the section "Specific instructions"

2 In clinical trials, the frequency was comparable for the drug group and the placebo group.

3 See sections "Method of administration and dose" and "Special instructions"

4 This unwanted reaction was established during post-marketing surveillance.
The frequency of "rare" was established on the basis of relevant clinical studies.
5 Established in postmarketing applications.

CONTRAINDICATIONS

- diseases of the esophagus, slowing its emptying, for example, stricture or achalasia;

- inability to sit or stand straight for 30 minutes;

hypersensitivity to any component of the drug;

- hypocalcemia;

- severe renal failure (CK <35 ml / min);

- Pregnancy and breastfeeding;

- Children's age (up to 18 years);

- severe hypoparathyroidism;

- severe vitamin D deficiency;

- malabsorption of calcium;

- hereditary lactase deficiency, sugarase / isomaltase deficiency, glucose-galactose malabsorption.

Carefully

- with exacerbation of diseases of the upper gastrointestinal tract, such as dysphagia, esophageal diseases, gastritis, duodenitis or stomach ulcer (including anamnestic information about the peptic ulcer, active gastrointestinal bleeding, surgical intervention in the upper gastrointestinal tract during the year to reception of the preparation Fosavans ® forte).

- in diseases associated with hyperproliferation of calcitriol (leukemia, lymphoma, sarcoidosis) and concomitant hypercalcemia and / or hypercalciuria.

PREGNANCY AND LACTATION

The drug Fosavans ® forte is designed to treat women only in the post-menopausal period and is contraindicated in pregnancy and during breastfeeding.

Pregnancy

Data on the use of the drug Fosavans ® forte during pregnancy are absent.
Studies of alendronate in animals have not revealed a direct damaging effect on pregnancy, embryo / fetus development, or postnatal development. The use of alendronate in rats during pregnancy caused disruption of labor due to hypocalcemia. Animal studies show hypercalcemia and reproductive toxicity when using vitamin D in high doses.
Breast-feeding

It is not known whether alendronate passes into breast milk.
Kolekaltsiferol and some active metabolites penetrate into breast milk.
Fertility

Bisphosphonates are built into the bone tissue, from which they are gradually released for many years.
The amount of bisphosphonate that can build into the bone and, thus, get back into the systemic bloodstream, is directly proportional to the dose and duration of bisphosphonate. Data on the risk for the fetus in humans are not available, but there is a theoretical risk of damage to the fetus, especially the bone skeleton, if the pregnancy occurs after the bisphosphonate course. The effect of variables such as the length of the period between discontinuing bisphosphonate therapy and conception, the specific form of the bisphosphonate and the route of administration (intravenous or oral) for this risk have not been studied.
APPLICATION FOR FUNCTIONS OF THE LIVER

Contraindicated in severe renal failure (CK <35 mL / min).
For patients with mild and moderate renal failure (CK from 35 to 60 ml / min), dose adjustment is not required.
APPLICATION FOR CHILDREN

Contraindicated in children under 18 years.

APPLICATION IN ELDERLY PATIENTS

For elderly patients, dose adjustment is not required.

SPECIAL INSTRUCTIONS

Alendronate

Undesirable reactions from the upper gastrointestinal tract

Alendronate can cause local irritation of the mucous membrane of the upper gastrointestinal tract.
In connection with the possibility of worsening, the main disease during the administration of alendronate, caution should be exercised in prescribing patients with diseases of the upper gastrointestinal tract, for example, with dysphagia, esophageal disease, gastritis, duodenitis, ulcers, and serious gastrointestinal disease, transferred to previous 12 months, for example, peptic ulcer, with gastrointestinal bleeding, surgical, operations on the upper gastrointestinal tract, with the exception of pyroplasty. For patients with a diagnosed Barrett's esophagus, the question of the appointment of alendronate should be decided on an individual basis by assessing the relationship between the expected benefit and the potential risk.
In the treatment of alendronate, cases of adverse reactions from the side of the esophagus (esophagitis, ulcer or erosion of the esophagus), sometimes occurring in severe form, requiring hospital treatment, and in rare cases complicated by the formation of stricture, are known.
In this regard, doctors need to pay special attention to any signs or symptoms that indicate possible abnormalities on the part of the esophagus, and patients should be warned about the need to stop taking alendronate and consult a doctor if symptoms of esophageal irritation such as dysphagia, swallowing pain or pain behind the sternum, the appearance or intensification of heartburn.
The risk of severe adverse events on the side of the esophagus is higher in those patients who violate the recommendations for alendronate and / or continue to take it when symptoms of esophageal irritation appear.
It is extremely important to fully inform patients about the importance of compliance with the rules of taking the drug and make sure that they understand this. It should be warned that the risk of developing an esophageal lesion increases if these recommendations are not followed.
Although increased clinical trials of alendronate did not increase the risk, post-marketing reports reported rare cases of development. The stomach and duodenal ulcers, sometimes severe and complicated.

Osteonecrosis of the jaw

In cancer patients treated by intravenous administration of bisphosphonates conducted, there were cases of osteonecrosis of the jaw due primarily preceding tooth extraction and / or local infection. (including osteomyelitis). Many of them also receiving chemotherapy and corticosteroids.
Also, there are cases of osteonecrosis of the jaw in patients with ostsoporozom when administered bisphosphonates.
In assessing individual risk of jaw necrosis following risk factors should be considered:
- the power of action of the bisphosphonate (highest in the zoledronic acid), route of administration (see above.) And the total dose;
- cancer, chemotherapy, radiotherapy, corticosteroids, smoking;
- dental disease history, poor oral hygiene, periodontal disease, invasive dental procedures and poorly selected prosthesis.
Before starting therapy with oral bisphosphonates in patients with poor dental status recommended dental examination and preventive therapeutic measures.
During the course of bisphosphonates in these patients is recommended as far as possible, avoid invasive dental procedures. If the patient developed osteonecrosis during bisphosphonate therapy, surgical dental treatment can worsen his condition. It is unknown whether the reduced risk of discontinuation of bisphosphonate osteonecrosis of the jaw in patients requiring dental procedures. In each case, the decision should be made by the attending physician on the basis of an estimate of the expected benefit to the possible risk for the individual patient.
During bisphosphonate therapy should explain to patients the importance of proper oral hygiene, preventive examinations, and warn them of the need for communication of any symptoms of the oral cavity, such as loose teeth, pain or swelling appears.
Pain in bones and muscles
is known about the occurrence of cases of pain in the bones, joints and / or muscles during the course of bisphosphonates. During post-marketing use in rare cases, these symptoms are severe and / or lead to disability. Time of onset of symptoms varied from one day to several months after starting treatment. In most patients, symptoms resolved after cessation of treatment. Some of these symptoms occur again when you resume receiving the same drug or another bisphosphonate.
Atypical femur fractures
Known cases of subtrochanteric or diaphyseal femur fractures with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or oblique fractures can occur along the entire length of the femur lesser trochanter of the femur to the supracondylar extension. These fractures occur posle.neznachitelnoy injury or not, some patients experience severe pain in the hip or groin, which is often combined with radiological signs of stress fractures, weeks to months before the appearance of a complete picture of hip fracture. Fractures are often bilateral, so patients with a hip fracture who take bisphosphonates, should be examined second (contralateral) thigh. It is known that these fractures are bad fuse.If you suspect that an atypical femur fracture should consider discontinuation of therapy with bisphosphonates prior to the individual assessment of the relationship of the expected benefits to the possible risk.
During bisphosphonate therapy patients should be advised to report any pain in the hip or groin. All patients admitted with such complaints should be examined for hip fracture.
Renal insufficiency

Preparation Fosavans ® forte contraindicated in patients with renal failure at the glomerular filtration rate of less than 35 ml / min.
Bone and mineral metabolism
should be taken into account other causes of osteoporosis, in addition to age and estrogen deficiency.
In the presence gikaltsiemii blood calcium concentration must be normalized prior to treatment with Fosavans ® forte.
Other disorders of mineral metabolism (for example, deficiency of vitamin D and hypoparathyroidism) should also be effectively treated before beginning treatment with Fosavans ® forte. The content of vitamin D in the preparation Fosavans ®forte insufficient correction hypovitaminosis D. Patients with these disorders during treatment with Fosavans ® forte necessary to control the concentration of calcium in serum and symptoms of hypocalcemia.
Since alendronate increases mineral content in bones, reducing the level of calcium and phosphate in the serum can be observed, especially when taking glucocorticosteroids reducing calcium absorption. Typically, such a decline is small and asymptomatic. However, known rare cases symptomatic hypocalcemia, which sometimes reaches and developed severe patients with a corresponding predisposition (e.g., hypoparathyroidism, hypovitaminosis D and calcium malabsorption).
Kolekaltsiferol
Vitamin D 3can increase the severity of hypercalcemia and / or hypercalciuria when used in patients with diseases that cause an uncontrolled overproduction of calcitriol (e.g., leukemia, lymphoma, sarcoidosis). In these patients, it is necessary to control the content of calcium in the urine and
serum.
Patients with malabsorption may experience malabsorption of vitamin D 3 .
Excipients
This drug contains lactose and sucrose. Patients with rare hereditary disorders of fructose and galactose intolerance, lactase deficiency, glucose-galactose malabsorption and saharazno-izomaltaznoy insufficiency should not take this medicine.
Influence on ability to drive and other mechanisms

There is no evidence that the drug Fosavans ® forte directly affects the ability to drive or use other mechanisms. Some adverse events; such as blurred vision, dizziness, severe pain in the joints or muscles (see. the section "Side effect") observed while taking the drug Fosavans ® forte, may affect the ability to drive and other mechanisms.
OVERDOSE

Alendronate
Prix. possible overdose hypocalcemia, hypophosphatemia, and adverse reactions on the part of upper GI: indigestion, heartburn, esophagitis, gastritis, gastric ulcer and esophagus.
Specific treatment alendronate overdose there. If overdose Fosavans ® Forte should take milk or antacids to bind alendronate. To avoid irritation of the esophagus should not induce vomiting. Patients should maintain an upright position.
Kolekaltsiferol
Vitamin D toxicity has not been reported in healthy adults with chronic reception at doses below 10,000 IU / day. In clinical studies involving healthy adults, vitamin D 3 a daily dose of 4000 ME for 5 months did not cause hypercalciuria and hypercalcemia.
DRUG INTERACTION

Alendronate
Absorption alendronate may be violated if the drug is taken together with food, beverages (including mineral water), calcium preparations, antacids and other drugs for oral administration. In this regard, the interval between doses of the drug Fosavans ® forte and other drugs taken orally, should be at least 30 minutes.
Since the use of NSAIDs is associated with the development of erosive-ulcerous lesions of the gastrointestinal tract, caution should be exercised while the use of NSAIDs and alendronate.
Kolekaltsiferol
Olestra, mineral oils, orlistat and bile acid sequestrants (cholestyramine, colestipol) may hinder the absorption of vitamin D.
Anticonvulsants, cimetidine, thiazide diuretics can accelerate the catabolism of vitamin D.
TERMS OF RELEASE FROM PHARMACY

On prescription.

TERMS AND CONDITIONS OF STORAGE

In a dry, protected from light place at a temperature of no higher than 25 ° C.
Keep out of the reach of children. Shelf life - 18 months.
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