BINOSTO (alendronate sodium) effervescent tablets

BINOSTO (alendronate sodium) effervescent tablets

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BINOSTO (alendronate sodium) effervescent tablets

BINOSTO (alendronate sodium) is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate sodium is chemically described as (4 amino-1-hydroxybutylidene) bisphosphonic acid, monosodium salt, trihydrate. The molecular formula of alendronate sodium is C4H12NNaO7P2 • 3H2O and its molecular weight is 325.12.

Alendronate sodium is a white or almost white crystalline powder that is soluble in water, very slightly soluble in methanol, and practically insoluble in methylene chloride.

BINOSTO for oral administration is an effervescent tablet formulation that must be dissolved in water before use. Each individual tablet contains 91.37 mg of alendronate sodium, which is equivalent to 70 mg of free alendronic acid. Each tablet also contains the following inactive ingredients: monosodium citrate anhydrous, citric acid anhydrous, sodium hydrogen carbonate, and sodium carbonate anhydrous as buffering agents, strawberry flavor, acesulfame potassium, and sucralose.

Once the effervescent tablet is dissolved in water, the alendronate sodium is present in a citrate-buffered solution.

Indications and usage

BINOSTO is a bisphosphonate indicated for:

  • Treatment of osteoporosis in postmenopausal women
  • Treatment to increase bone mass in men with osteoporosis

Limitation of use: Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use

Mechanism of Action

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Dosage and administration

70 mg BINOSTO effervescent tablet once weekly. Instruct patients to:

  • Dissolve one tablet of BINOSTO in approximately half a glass of plain room temperature water (4 oz). Wait at least 5 minutes after the effervescence stops, stir the solution for approximately 10 seconds and consume contents.
  • Swallow solution at least 30 minutes before the first food, beverage, or medication of the day.
  • Avoid lying down for at least 30 minutes after taking BINOSTO and until after the first food of the day.

Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

Administration Instructions for Missed Doses

If the once-weekly dose is missed, instruct patients to take one dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.

Contraindications

  • Abnormalities of the esophagus which delay emptying such as stricture or achalasia
  • Inability to stand/sit upright for at least 30 minutes
  • Increased risk of aspiration.
  • Hypocalcemia
  • Hypersensitivity to any component of this product

Adverse reactions

The most common adverse reactions (incidence greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, and nausea.

Warnings and precautions

Upper Gastrointestinal Adverse Reactions: BINOSTO, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BINOSTO is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).

Mineral Metabolism: Hypocalcemia must be corrected before initiating therapy with BINOSTO. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with BINOSTO.

Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the treatment of osteoporosis. This category of drugs includes BINOSTO. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

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Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.

Renal Impairment: BINOSTO is not recommended for patients with creatinine clearance <35 mL/min.

Patients Sensitive to High Sodium Intake: Each BINOSTO effervescent tablet contains 650 mg of sodium, equivalent to approximately 1650 mg of salt (NaCl). Use caution in patients who must restrict their sodium intake, including some patients with a history of heart failure, hypertension, or other cardiovascular diseases

Drug interactions

Calcium Supplements/Antacids: Co-administration of BINOSTO and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of BINOSTO. Therefore, instruct patients to wait at least one-half hour after taking BINOSTO before taking any other oral medications.

Aspirin: In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): BINOSTO may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with BINOSTO.

Levothyroxine: The bioavailability of alendronate was slightly decreased when BINOSTO and levothyroxine were co-administered to healthy subjects

Use in specific populations

Pregnancy: Pregnancy Category C: There are no studies in pregnant women. BINOSTO should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers: It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BINOSTO is administered to nursing women.

Pediatric Use: BINOSTO is not indicated for use in pediatric patients.

Renal Impairment: BINOSTO is not recommended for patients with creatinine clearance less than 35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35-60 mL/min.

Hepatic Impairment: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary

Overdosage

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2 ) and 966 mg/kg (2898 mg/m2 ), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2 ).

No specific information is available on the treatment of overdosage with BINOSTO. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Dialysis would not be beneficial.

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F), [See USP Controlled Room Temperature.] Protect from moisture. Store tablets in original blister package until use.

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