Osterepar (Tablets) Instructions for Use

Marketing Authorization Holder

Polpharma Pharmaceutical Works, Sa (Poland)

Contact Information

AKRIKHIN AO (Russia)

ATC Code

M05BA04 (Alendronic acid)

Active Substance

Alendronic acid (Rec.INN registered by WHO)

Dosage Form

Osterepar

Tablets 70 mg: 4 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, oblong, biconvex.

Excipients: lactose monohydrate – 128.64 mg, microcrystalline cellulose – 65 mg, croscarmellose sodium – 15 mg, magnesium stearate – 3 mg, colloidal anhydrous silicon dioxide – 2 mg.

4 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Bone resorption inhibitor. Bisphosphonate

Pharmacotherapeutic Group

Bone resorption inhibitor – bisphosphonate

Pharmacological Action

Inhibitor of bone resorption. It belongs to the group of bisphosphonates, which, localizing in areas of active bone resorption, under osteoclasts, inhibit the process of bone tissue resorption caused by osteoclasts, without having a direct effect on the process of new bone tissue formation. Since bone resorption and the appearance of new bone tissue are interrelated, bone formation is also reduced, but to a lesser extent than resorption, which leads to a progressive increase in bone mass. During treatment with alendronate, normal bone tissue is formed, into the matrix of which alendronate is incorporated, remaining pharmacologically inactive. In therapeutic doses, alendronate does not cause osteomalacia.

Pharmacokinetics

Absorption

After oral administration in doses of 5-70 mg on an empty stomach, no later than 2 hours before a standard breakfast, the bioavailability of alendronate is 0.64% in women and 0.6% in men.

When alendronate is taken on an empty stomach 1-1.5 hours before a standard breakfast, bioavailability decreases by approximately 40%.

In patients with osteoporosis, the drug Osterepar^® is effective when taken on an empty stomach no later than 30 minutes before the first meal or liquid.

The bioavailability of alendronate is negligible when it is administered simultaneously with food or within 2 hours after a meal. Concurrent administration with coffee or orange juice reduces the bioavailability of the drug by approximately 60%.

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

Distribution

The average V_d of alendronate at steady state (excluding bone tissue) is at least 28 L. When taken in therapeutic doses, the concentration of the drug in blood plasma is negligible (less than 5 ng/ml). The binding of alendronate to plasma proteins is approximately 78%.

Metabolism

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

Excretion

After a single intravenous administration of alendronate labeled with carbon atoms [¹⁴C], approximately 50% of the drug is excreted in the urine within 72 hours; excretion of the labeled drug 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. Six hours after intravenous administration, the concentration in blood plasma decreases by more than 95%. The terminal T_1/2 exceeds 10 years, reflecting the release of the drug from bone tissue. Alendronate does not impair the excretion of drugs through the acidic and basic transport systems of the kidneys.

Pharmacokinetics in special patient groups

The bioavailability of alendronic acid does not differ significantly between men and women.

The bioavailability and excretion of alendronic acid are similar in elderly and young patients.

Pharmacokinetic differences by race have not been studied.

In patients with impaired liver function, there is no need to adjust the dose of alendronic acid, since it is not metabolized and is not excreted in bile.

Indications

• Treatment of osteoporosis in postmenopausal women to prevent fractures, including hip fractures and vertebral compression fractures;
• Treatment of osteoporosis in men to prevent fractures.

ICD codes

Dosage Regimen

The drug is taken orally, without chewing, with drinking water, at least 30 minutes before the first meal, liquid, or other medications. Other beverages (including mineral water), food, and some medications may reduce the absorption of Osterepar^®.

To reduce the risk of esophageal irritation, Osterepar^® should be taken by following these rules

• Take in the morning immediately after getting out of bed;
• Take with a full glass of water to facilitate the passage of the tablet into the stomach;
• 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 Osterepar^®;
• The drug should not be taken at bedtime or before getting out of bed.

Patients should additionally take calcium and vitamin D supplements if the intake of these substances from food is insufficient.

Treatment of osteoporosis in postmenopausal women: recommended dose -1 tablet (70 mg) once a week.

Treatment of osteoporosis in men recommended dose -1 tablet (70 mg) once a week.

The optimal duration of use of the drug has not been established. The need to continue bisphosphonate therapy should be assessed regularly, especially after 5 or more years of use.

For elderly patients and patients with mild to moderate renal impairment (creatinine clearance from 35 to 60 ml/min), no dose adjustment is required. Osterepar^® is not recommended for patients with severe renal impairment (creatinine clearance less than 35 ml/min) due to lack of experience in these patients.

Due to the lack of clinical data, the drug is not prescribed to children.

Adverse Reactions

In a one-year study in women with postmenopausal osteoporosis, the overall safety profiles of alendronate 70 mg once weekly (n=519) and alendronate 10 mg/day (n=370) were generally similar.

In two three-year studies with virtually identical designs in postmenopausal women (alendronate 10 mg: n=196; placebo: n=397), the safety profiles of alendronate 10 mg/day and placebo were generally similar.

Adverse events described in these studies as possibly, probably, or definitely related to the drug are presented in the table below.

Adverse events were observed in >1% of patients in each treatment group in the one-year study. In >1% of patients taking alendronate 10 mg/day, adverse events were observed more frequently than in the placebo group in the three-year study.

The following adverse events have been reported during clinical studies and/or post-registration use. The frequency of adverse events 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, including isolated cases).

Immune system rare – hypersensitivity reactions, including urticaria, angioedema.

Metabolism rare – symptomatic hypocalcemia, often against a background of predisposing factors¹.

Nervous system common – headache, dizziness²; uncommon – taste perversion².

Eye disorders uncommon – inflammation of the eye (uveitis, scleritis, episcleritis).

Ear and labyrinth disorders common – systemic dizziness²; very rare – osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).

Gastrointestinal system common – abdominal pain, dyspepsia, constipation, diarrhea, flatulence, esophageal ulcer³, dysphagia³, abdominal distension, acid regurgitation; uncommon – nausea, vomiting, gastritis, esophagitis³, esophageal erosion, melena²; rare – esophageal stricture³, esophageal ulceration³, upper gastrointestinal adverse events (perforation, ulcers, bleeding).

Skin and subcutaneous tissue disorders common – pruritus², alopecia²; uncommon – skin rash, erythema; rare – skin rash with photosensitivity, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis⁴.

Musculoskeletal system very common – musculoskeletal pain (in bones, muscles, or joints), sometimes severe^1,2; common – joint swelling²; rare – localized osteonecrosis of the jaw, mainly associated with prior tooth extraction and/or local infection (including osteomyelitis), often with slow healing^1,4, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)⁵.

General disorders and administration site conditions common – asthenia², peripheral edema²; uncommon – transient symptoms as an acute phase reaction (myalgia, malaise and rarely – fever), usually associated with initiation of treatment².

¹ See section “Special Precautions”.

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

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

⁴ This adverse reaction was identified during post-registration surveillance.

⁵ Identified during post-registration use.

Contraindications

• Abnormalities of the esophagus and other factors that delay esophageal emptying (including achalasia, stricture);
• Inability of the patient to stand or sit upright for at least 30 minutes;
• Hypocalcemia;
• Severe hypoparathyroidism;
• Chronic renal failure (creatinine clearance less than 35 ml/min);
• Vitamin D deficiency;
• Severe disturbances of mineral metabolism;
• Pregnancy;
• Breastfeeding period;
• Childhood;
• Lactase deficiency, galactose intolerance, glucose-galactose malabsorption (the drug contains lactose);
• Hypersensitivity to the components of the drug.

With caution: active gastrointestinal diseases (dysphagia, esophageal disease, esophagitis, gastritis, duodenitis, gastric and duodenal ulcer); serious gastrointestinal diseases in the previous 12 months (e.g., peptic ulcer, gastrointestinal bleeding), surgery on the upper gastrointestinal tract, except for pyloroplasty; predisposition to hypocalcemia (hypothyroidism, calcium malabsorption); vitamin D deficiency.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the use of alendronic acid in pregnant women. However, there is a theoretical risk of negative effects on the fetus (especially on bone tissue) if pregnancy occurs after a course of bisphosphonate therapy. Animal studies have revealed impaired fetal bone formation with the use of high doses of alendronic acid, and dysfunctional labor associated with hypokalemia. The use of alendronic acid during pregnancy is contraindicated.

Breastfeeding period

There are no data on penetration into breast milk; taking alendronic acid during breastfeeding is contraindicated.

Use in Hepatic Impairment

In patients with impaired liver function, there is no need to adjust the dose of alendronic acid, since it is not metabolized and is not excreted in bile.

Use in Renal Impairment

The use of the drug is contraindicated in chronic renal failure (creatinine clearance less than 35 ml/min).

For patients with mild to moderate renal impairment (creatinine clearance from 35 to 60 ml/min), no dose adjustment is required.

Pediatric Use

Due to the lack of clinical data, the drug is not prescribed to children.

Geriatric Use

For elderly patients, no dose adjustment is required.

Special Precautions

Upper gastrointestinal adverse reactions

Alendronate can cause local irritation of the upper gastrointestinal mucosa. In this regard, caution should be exercised when prescribing alendronate to patients with diseases of the upper gastrointestinal tract, for example, with dysphagia, esophageal disease, gastritis, duodenitis, ulcer, serious gastrointestinal disease in the previous 12 months, for example, peptic ulcer, as well as with active gastrointestinal bleeding, surgical operation on the upper gastrointestinal tract, except for pyloroplasty (see section “Contraindications”). 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 esophageal adverse reactions (esophagitis, esophageal ulcer or erosion) have been reported during treatment with alendronate, sometimes severe and 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 (see section “Adverse Reactions”).

The risk of severe esophageal adverse events is higher in those patients who do not follow the recommendations for taking the drug and/or continue to take it when symptoms of esophageal irritation appear. It is especially important to give the patient instructions for taking the drug so that he understands that the risk of developing esophageal damage increases if these recommendations are not followed (see section “Dosage Regimen”).

Although extended clinical studies of alendronate did not show an increased risk of gastrointestinal adverse events, post-registration reports have described rare cases of gastric and duodenal ulcers, sometimes severe and complicated (see section “Adverse Reactions”).

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw, mainly associated with prior tooth extraction and/or local infection (including osteomyelitis), have been observed in cancer patients treated with intravenous bisphosphonates. Many of these patients also received chemotherapy and corticosteroids. Cases of osteonecrosis of the jaw have also been reported in patients with osteoporosis taking oral bisphosphonates.

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

• Bisphosphonate potency (highest for zoledronic acid), route of administration (see above) and cumulative dose;
• Cancer, chemotherapy, radiotherapy, use of corticosteroids, angiogenesis inhibitors, smoking;
• History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and poorly fitting dentures.

Before starting therapy with oral bisphosphonates, patients with an unsatisfactory dental status are recommended to undergo a dental examination and preventive treatment measures.

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

During bisphosphonate therapy, patients should be informed about the importance of proper oral hygiene, preventive check-ups, and should be warned about the need to report any oral symptoms, for example, tooth mobility, pain, or swelling.

Osteonecrosis of the External Auditory Canal

Cases of osteonecrosis of the external auditory canal have been reported during the use of bisphosphonates, mainly during long-term therapy. Possible risk factors for the development of osteonecrosis of the external auditory canal include the use of steroids and chemotherapy and/or local risk factors, such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients taking bisphosphonates who have ear disorders, such as pain, discharge, or chronic infection.

Musculoskeletal Pain

Cases of bone, joint, and/or muscle pain have been reported during the course of bisphosphonates. During post-marketing use, in rare cases, these symptoms were severe and/or disabling (see the “Adverse Reactions” section).

The time to onset of symptoms varied from one day to several months after starting treatment. In most patients, the symptoms resolved after discontinuation of treatment. In some of them, the symptoms recurred upon re-initiation of the same drug or another bisphosphonate.

Atypical Femoral Fractures

Cases of atypical subtrochanteric or diaphyseal femoral fractures have been reported during treatment with bisphosphonates, mainly in patients receiving 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 pain in the thigh or groin, often associated with imaging features of stress fractures, for several 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 have sustained a femoral shaft 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 benefit-risk assessment.

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

Skin Reactions

During post-marketing use, rare reports of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been received.

Missed Dose

Patients should be advised that if a once-weekly dose of Osterepar^® is missed, they should take one tablet on the morning after the day they remember. They should not take two tablets on the same day, but should then return to taking one tablet once a week on their originally chosen day of the week.

Renal Impairment

Osterepar^® is contraindicated in patients with renal impairment where creatinine clearance is less than 35 ml/min (see the “Contraindications” section).

Bone Metabolism and Mineral Metabolism

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

If hypocalcemia is present, the blood calcium level must be corrected before initiating treatment with alendronate (see the “Contraindications” section). Other disturbances of mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated before initiating therapy with alendronate. In patients with these disturbances, serum calcium levels and symptoms of hypocalcemia should be monitored during therapy with Osterepar^®.

Since alendronate incorporates into bone, a decrease in serum calcium and phosphate levels may occur, particularly in patients taking corticosteroids in whom calcium absorption may be decreased.

Usually, this decrease is small and asymptomatic. Nevertheless, rare instances of symptomatic hypocalcemia have occurred, sometimes severe, and in predisposed patients (e.g., hypoparathyroidism, vitamin D deficiency, and calcium malabsorption) (see the “Adverse Reactions” section).

Excipients

Osterepar^® contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effects on Ability to Drive and Use Machines

Studies on the effect of alendronic acid on the ability to drive and use machines have not been performed. However, given the possibility of adverse reactions (dizziness and others), caution is advised when driving vehicles, operating machinery, and patients should refrain from these activities if adverse effects occur.

Overdose

Symptoms abdominal pain, dyspeptic disorders, dysphagia, heartburn, esophagitis, gastritis; hypocalcemia and hypophosphatemia may develop.

Treatment symptomatic. Administration of milk or antacids to bind alendronate is indicated. Because of the risk of esophageal irritation, vomiting should not be induced, and the patient should remain upright.

Drug Interactions

Calcium, antacids, some oral medications, food, and beverages, including mineral water, affect the absorption of alendronate; medications should be taken no earlier than 1 hour after taking alendronate.

Ranitidine increases bioavailability (clinical significance unknown).

When Osterepar^® and hormone replacement therapy (estrogen ± progestin) are used concomitantly, the safety and tolerability of the combined therapy are consistent with those of the individual treatments. In clinical studies of Osterepar^® in men, postmenopausal women, and patients taking corticosteroids, no clinically significant drug interactions were identified regarding protein binding, renal excretion, or metabolism.

The incidence of upper gastrointestinal adverse events is increased when Osterepar^® at a dose greater than 10 mg/day is combined with drugs containing acetylsalicylic acid. However, this effect was not observed with the once-weekly 70 mg Osterepar^® dose.

Osterepar^® may be prescribed with caution (due to the risk of gastrointestinal bleeding) to patients taking NSAIDs; however, results from a clinical study did not show a clinically significant drug interaction or an increase in the frequency of adverse effects with concomitant use.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.