Fosavance^® Forte (Tablets) Instructions for Use

Marketing Authorization Holder

Merck Sharp & Dohme, B.V. (Netherlands)

Manufactured By

Frosst Iberica, S.A. (Spain)

Labeled By

MERCK SHARP & DOHME, B.V. (Netherlands)

ATC Code

M05BB03 (Alendronic acid and Colecalciferol)

Active Substances

Colecalciferol (Rec.INN registered by WHO)

Alendronic acid (Rec.INN registered by WHO)

Dosage Form

Fosavance® Forte

Tablets 70 mg+140 mcg: 4 or 12 pcs.

Dosage Form, Packaging, and Composition

4 pcs. – PVC/aluminum foil blisters (1) – cardboard packs.
4 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Bone resorption inhibitor for osteoporosis

Pharmacotherapeutic Group

Osteoporosis treatment agent (bone resorption inhibitor + calcium-phosphorus metabolism regulator)

Pharmacological Action

The drug Fosavance^® forte is a combined preparation containing two active substances: alendronate sodium trihydrate and Colecalciferol (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 osteoclast activity but does not affect the recruitment and attachment of osteoclasts. During treatment with alendronate, normal bone tissue is formed.

Colecalciferol (vitamin D₃)

Vitamin D₃ is formed in the skin by the conversion of 7-dehydrocholesterol into vitamin D₃ under the influence of ultraviolet radiation. With insufficient sunlight, vitamin D₃ is an essential component of the diet.

Vitamin D₃ is metabolized to 25-hydroxyvitamin D₃ in the liver, where it is stored. Its conversion to the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D₃ (calcitriol) occurs in the kidneys and is tightly regulated. The main action of 1,25-dihydroxyvitamin D₃ is to increase intestinal absorption of calcium and phosphates, as well as to regulate plasma calcium levels, renal excretion of calcium and phosphates, bone formation, and its resorption.

Vitamin D₃ is necessary for normal bone formation. Vitamin D₃ deficiency develops when sun exposure and dietary intake of vitamin D₃ do not meet a person’s needs. Hypovitaminosis causes negative calcium balance, bone loss, and an increased risk of fractures. In severe cases, vitamin deficiency leads to secondary hypoparathyroidism, hypophosphatemia; myasthenia and osteomalacia with a further increase in the risk of falls and fractures in patients with osteoporosis. Additional intake of vitamin D₃ reduces these risks and their consequences.

Pharmacokinetics

Alendronate

Absorption

The bioavailability of alendronate at a dose of 5-70 mg when taken orally on an empty stomach no later than 2 hours before a standard breakfast is 0.64% in women and 0.6% in men of the intravenous dose. When alendronate was taken on an empty stomach one hour or half an hour before a standard breakfast, bioavailability decreased to 0.46% and 0.39%, respectively. In osteoporosis, alendronate is effective when taken on an empty stomach no later than 30 minutes before the first meal or liquid.

The bioavailability of alendronate in the combined preparation Fosavance^® forte (70 mg/5600 IU) is equivalent to its bioavailability in the 70 mg alendronate tablet.

Alendronate bioavailability is negligible when administered simultaneously with food or within 2 hours after a standard breakfast. Concurrent administration of alendronate with coffee or orange juice reduces its bioavailability by approximately 60%.

When prednisone was taken orally (20 mg three times a day for 5 days) in healthy individuals, there was no clinically significant change in alendronate bioavailability (mean increase in bioavailability was 20-44%).

Distribution

Studies in rats show that after intravenous administration at a dose of 1 mg/kg, alendronate distributes into soft tissues and then rapidly redistributes to bones or is excreted in the urine. In humans, the mean steady-state volume of distribution, excluding bone tissue, is at least 28 L. When taken orally at therapeutic doses, the plasma concentration of alendronate is not analytically determinable (less than 5 ng/ml). Plasma protein binding is approximately 78%.

Metabolism

There is no evidence that alendronate undergoes metabolism in humans or animals.

Excretion

After a single intravenous administration of ¹⁴C-labeled alendronate, approximately 50% of the radioactive alendronate is excreted in the urine within 72 hours. Excretion of labeled alendronate in feces was negligible or undetectable. After a single intravenous administration of alendronate at a dose of 10 mg, its renal clearance is 71 ml/min, and systemic clearance does not exceed 200 ml/min. Six hours after intravenous administration, the plasma concentration decreases by more than 95%. The terminal half-life in humans exceeds 10 years, reflecting the release of alendronate from the skeletal bones. Alendronate is not excreted via acid or basic renal transport in rats, and its effect on the excretion of other drugs by this pathway in humans is not assumed.

Colecalciferol

Absorption

When using the drug Fosavance^® forte 70 mg/5600 IU in healthy volunteers (male and female) after overnight fasting 2 hours before meals, the mean area under the concentration-time curve (AUC_{0-80 h}) for vitamin D₃, (uncorrected for endogenous vitamin D₃) is 490.2 ng×h/ml. The mean maximum serum concentration (C_max) of vitamin D₃ is 12.2 ng/ml, and the mean time to reach maximum serum concentration (T_max) is 10.6 h. The bioavailability of 5600 IU of vitamin D₃ in the drug Fosavance^® forte is similar to the bioavailability of 5600 IU of vitamin D₃ when taken alone.

Distribution

After absorption, vitamin D₃ enters the blood as part of chylomicrons and is rapidly distributed mainly to the liver, where it is metabolized to its main storage form, 25-hydroxyvitamin D₃. Smaller amounts are distributed to adipose and muscle tissue, where they accumulate as vitamin D₃ for subsequent gradual release into the bloodstream. Vitamin D₃ circulates in the bloodstream bound to vitamin-D-binding protein.

Metabolism

Vitamin D₃ is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D₃, which in turn is metabolized in the kidneys to 1,25-dihydroxyvitamin D₃, which is the biologically active form of the vitamin. Further hydroxylation occurs before vitamin excretion. A small amount of vitamin D₃ undergoes glucuronidation before excretion.

Excretion

When radioactive vitamin D₃ was taken by healthy individuals, the mean excretion of radioactive colecalciferol in urine was 2.4% after 48 hours, and in feces – 4.9% after 4 days. In both cases, radioactive Colecalciferol was excreted mainly as metabolites.

The mean half-life of vitamin D₃ after oral administration of the drug Fosavance^® forte 70 mg/5600 IU is approximately 24 hours.

Renal impairment

Preclinical studies show that alendronate that has not entered bone tissue is rapidly excreted in the urine. After repeated intravenous administration in a total dose of up to 35 mg/kg in animals, no evidence of drug deposition in bones was found.

Despite the lack of clinical data, it is likely that, as in animals, in case of impaired renal function, the urinary excretion of alendronate is impaired. In case of impaired renal function, increased accumulation of alendronate in bone tissue is possible.

Indications

• For the treatment of postmenopausal osteoporosis in patients not additionally taking vitamin D preparations and at risk of developing vitamin D deficiency. The drug reduces the risk of vertebral and hip fractures;
• To increase bone mass in men with osteoporosis.

ICD codes

Dosage Regimen

1 tablet, at least 30 minutes before the first meal, liquid, or medications (including antacids, calcium preparations, and vitamins), swallowed with a full glass of plain water (not mineral water). Other beverages (including mineral water), food, and some medications may reduce the absorption of the drug Fosavance^® forte.

To reduce the risk of esophageal irritation, the drug Fosavance^® forte should be taken by following the rules listed below

1. Take in the morning immediately after getting out of bed, at least 30 minutes before the first meal, liquid, or medications, swallow with a full glass of water (not mineral) to facilitate the passage of the tablet into the stomach.
2. Do not chew the tablets or allow them to dissolve in the mouth due to the possible formation of ulcers in the oral cavity and pharynx. Patients should not lie down until the first meal, which should be taken at least 30 minutes after taking the drug Fosavance^® forte.
3. The drug Fosavance^® forte should not be taken before going to bed or before getting out of bed.

The recommended dose is 1 tablet of Fosavance^® forte once a week.

Patients should additionally take calcium preparations if dietary intake is insufficient. The drug Fosavance^® forte meets the weekly requirement for vitamin D, based on a daily dose of 800 IU.

For elderly patients and patients with mild to moderate renal impairment (CrCl from 35 to 60 ml/min), no dose adjustment is required. The recommended dose is 1 tablet of Fosavance^® forte once a week.

If a dose is accidentally missed, take 1 tablet on the morning of the next day. Do not take 2 doses in one day, but subsequently return to taking the drug once a week on the day of the week that was chosen at the start of treatment.

Adverse Reactions

The most frequently reported adverse reactions are adverse reactions from the upper gastrointestinal tract, including abdominal pain, dyspepsia, esophageal ulcer, dysphagia, abdominal distension, and acid regurgitation (≥ 1/100, < 1/10).

The following adverse reactions have been reported during clinical studies and/or post-marketing use of alendronate.

No additional adverse reactions for the drug Fosavance^® forte have been established.

The frequency of adverse reactions is defined as follows: very common (>1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000).

¹ See section “Special Precautions”

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

³ See sections “Dosage Regimen” and “Special Precautions”

⁴ This adverse reaction was identified during post-marketing surveillance. The frequency “rare” was established based on relevant clinical studies.

⁵ Identified during post-marketing use.

Contraindications

• Esophageal diseases that delay its emptying, for example, strictures or achalasia;
• Inability to sit or stand upright for 30 minutes;
• Hypersensitivity to any component of the drug;
• Hypocalcemia;
• Severe renal impairment (CrCl < 35 ml/min);
• Pregnancy and breastfeeding;
• Children under 18 years of age;
• Severe hypoparathyroidism;
• Severe vitamin D deficiency;
• Calcium malabsorption;
• Hereditary lactase deficiency, sucrase/isomaltase deficiency, glucose-galactose malabsorption.

With caution

• In exacerbation of upper gastrointestinal diseases such as dysphagia, esophageal disease, gastritis, duodenitis, or gastric ulcer (including a history of peptic ulcer, active gastrointestinal bleeding, upper gastrointestinal tract surgery within one year prior to taking the drug Fosavance^® forte).
• In diseases associated with overproduction of calcitriol (leukemia, lymphoma, sarcoidosis) and concomitant hypercalcemia and/or hypercalciuria.

Use in Pregnancy and Lactation

The drug Fosavance^® forte is intended for the treatment of women only in the postmenopausal period and is contraindicated during pregnancy and breastfeeding.

Pregnancy

There are no data on the use of the drug Fosavance^® forte during pregnancy. Animal studies of alendronate have not revealed direct damaging effects on pregnancy, embryonic/fetal development, or postnatal development. The use of alendronate in rats during pregnancy caused impaired labor due to hypocalcemia. Animal studies show hypercalcemia and reproductive toxicity when using vitamin D in high doses.

Breastfeeding

It is not known whether alendronate passes into breast milk. Colecalciferol and some active metabolites pass into breast milk.

Fertility

Bisphosphonates are incorporated into bone tissue, from which they are gradually released over many years. The amount of bisphosphonate that can be incorporated into bone and thus re-enter the systemic circulation is directly proportional to the dose and duration of bisphosphonate use. There are no data on the risk to the human fetus, but there is a theoretical risk of fetal harm, especially to the skeletal system, if pregnancy occurs after completion of a course of bisphosphonate. The influence of variables such as the length of time between discontinuation of bisphosphonate therapy and conception, the specific type of bisphosphonate, and the route of administration (intravenous or oral) on this risk has not been studied.

Use in Renal Impairment

Contraindicated in severe renal impairment (CrCl < 35 ml/min). For patients with mild to moderate renal impairment (CrCl from 35 to 60 ml/min), no dose adjustment is required.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

For elderly patients, no dose adjustment is required.

Special Precautions

Alendronate

Adverse reactions from the upper gastrointestinal tract

Alendronate can cause local irritation of the upper gastrointestinal mucosa. Due to the possibility of worsening the underlying disease during alendronate administration, caution should be exercised when prescribing the drug to patients with upper gastrointestinal diseases, for example, dysphagia, esophageal disease, gastritis, duodenitis, ulcer, as well as with serious gastrointestinal disease suffered within the previous 12 months, for example, peptic ulcer, with gastrointestinal bleeding, surgical operation on the upper gastrointestinal tract, except for pyloroplasty. For patients with diagnosed Barrett’s esophagus, the issue of prescribing alendronate should be decided individually based on an assessment of the expected benefit versus the possible risk.

Cases of adverse reactions from the esophagus (esophagitis, esophageal ulcer or erosion) are known during treatment with alendronate, sometimes severe, requiring hospitalization, and in rare cases complicated by the formation of strictures. In this regard, physicians should pay special attention to any signs or symptoms indicating possible esophageal disorders, and patients should be warned to discontinue alendronate and consult a doctor if symptoms of esophageal irritation appear, such as dysphagia, pain when swallowing or retrosternal pain, the appearance or worsening of heartburn.

The risk of severe adverse events from the esophagus is higher in those patients who violate the recommendations for taking 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 following the rules for taking the drug and to ensure that they understand this. They should be warned that the risk of developing esophageal damage increases if these recommendations are not followed.

Although no increased risk was noted in extended clinical trials of alendronate, post-marketing reports have described rare cases of gastric and duodenal ulcers, sometimes severe and complicated.

Jaw Osteonecrosis

Cases of jaw osteonecrosis have been reported in cancer patients treated with intravenous bisphosphonates, primarily associated with prior tooth extraction and/or local infection (including osteomyelitis). Many of these patients also received chemotherapy and glucocorticosteroids.

Cases of jaw osteonecrosis have also been reported in osteoporosis patients taking oral bisphosphonates.

When assessing the individual risk of developing jaw necrosis, the following risk factors should be considered

• Potency of the bisphosphonate (highest for zoledronic acid), route of administration (see above) and total cumulative dose;
• Cancer, chemotherapy, radiotherapy, glucocorticosteroids, smoking;
• History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures.

Before initiating therapy with oral bisphosphonates, patients with poor dental status are recommended to undergo a dental examination and receive preventive treatment.

During the course of bisphosphonate treatment, such patients should be advised to avoid invasive dental procedures if possible. If a patient develops osteonecrosis during bisphosphonate therapy, surgical dental treatment may worsen the condition. It is not known whether discontinuing bisphosphonates reduces the risk of jaw osteonecrosis in patients requiring dental procedures. In each case, the decision should be made by the treating physician based on an assessment of the benefit-risk ratio for the individual patient.

During bisphosphonate therapy, patients should be informed about the importance of proper oral hygiene, regular preventive check-ups, and should be advised to report any oral symptoms, such as loose teeth, pain, or swelling.

Bone and Muscle Pain

Cases of bone, joint, and/or muscle pain have been reported during the course of bisphosphonate treatment. During post-marketing use, these symptoms have been severe and/or disabling in rare cases. The time to onset of symptoms varied from one day to several months after starting treatment. In most patients, symptoms resolved after discontinuation of treatment. In some patients, symptoms recurred upon rechallenge with the same drug or another bisphosphonate.

Atypical Femoral Fractures

Cases of subtrochanteric or diaphyseal femoral fractures have been reported in patients treated with bisphosphonates, primarily in patients on long-term therapy for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to above the supracondylar flare. These fractures occur with minimal or no trauma, and some patients experience prodromal thigh or groin pain, often associated with imaging features of stress fractures, weeks or months before a complete fracture occurs. Fractures are often bilateral; therefore, the contralateral femur should be examined in patients treated with bisphosphonates who present with a femoral fracture. These fractures are known to heal poorly. If an atypical femoral fracture is suspected, discontinuation of bisphosphonate therapy should be considered pending an individual assessment of the benefit-risk ratio.

During bisphosphonate therapy, patients should be advised to report any thigh or groin pain. All patients presenting with such complaints should be evaluated for a femoral fracture.

Renal Impairment

Fosavance^® forte is contraindicated in patients with renal impairment where glomerular filtration rate is less than 35 ml/min.

Bone and Mineral Metabolism

Other causes of osteoporosis besides estrogen deficiency and aging should be considered.

If hypocalcemia is present, blood calcium levels must be corrected prior to initiating therapy with Fosavance^® forte.

Other disturbances of mineral metabolism (e.g., vitamin D deficiency and hypoparathyroidism) should also be effectively treated before starting therapy with Fosavance^® forte. The vitamin D content in Fosavance^® forte is not sufficient to correct vitamin D deficiency. In patients with these disturbances, serum calcium levels and symptoms of hypocalcemia should be monitored during treatment with Fosavance^® forte.

As alendronate increases bone mineral content, slight, usually asymptomatic decreases in serum calcium and phosphate levels may occur, especially in patients taking glucocorticosteroids, which may decrease calcium absorption. Nevertheless, rare cases of symptomatic hypocalcemia have been reported, sometimes severe, usually in patients with predisposing conditions (e.g., hypoparathyroidism, vitamin D deficiency, and calcium malabsorption).

Colecalciferol

Vitamin D₃ may exacerbate hypercalcemia and/or hypercalciuria in patients with diseases associated with uncontrolled overproduction of calcitriol (e.g., leukemia, lymphoma, sarcoidosis). Urine and serum calcium levels should be monitored in such patients.

Patients with malabsorption may have impaired absorption of vitamin D₃.

Excipients

This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicinal product.

Effects on Ability to Drive and Use Machines

There is no evidence that Fosavance^® forte directly affects the ability to drive or use machines. However, certain adverse reactions; for example, blurred vision, dizziness, severe bone, joint, or muscle pain (see section “Adverse Reactions”), that may occur during treatment with Fosavance^® forte could affect the ability to drive and use machines.

Overdose

Alendronate

Overdose may lead to hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse reactions: dyspepsia, heartburn, esophagitis, gastritis, gastric and esophageal ulcer.

There is no specific antidote for alendronate overdose. In case of overdose with Fosavance^® forte, milk or antacids should be given to bind alendronate. To avoid esophageal irritation, vomiting should not be induced. Patients should remain upright.

Colecalciferol

Toxicity from vitamin D has not been reported in healthy adults receiving chronic doses below 10,000 IU/day. In clinical studies involving healthy adults, administration of vitamin D₃ at a daily dose of 4,000 IU for 5 months did not cause hypercalciuria or hypercalcemia.

Drug Interactions

Alendronate

The absorption of alendronate may be impaired if it is taken simultaneously with food, beverages (including mineral water), calcium supplements, antacids, and other oral medications. Therefore, the interval between taking Fosavance^® forte and other orally administered medications should be at least 30 minutes.

Since NSAIDs are associated with gastrointestinal irritation, caution should be used when NSAIDs and alendronate are co-administered.

Colecalciferol

Olestra, mineral oils, orlistat, and bile acid sequestrants (cholestyramine, colestipol) may impair the absorption of vitamin D.

Anticonvulsants, cimetidine, and thiazide diuretics may accelerate the catabolism of vitamin D.

Storage Conditions

Store in a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life is 18 months.

Dispensing Status

Prescription only.

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.