Binosto

alendronate sodium · Tablet, Effervescent · Oral

Uses

1 INDICATIONS AND USAGE BINOSTO is a bisphosphonate indicated for: Treatment of osteoporosis in postmenopausal women ( 1.1 ) Treatment to increase bone mass in men with osteoporosis ( 1.2 ) 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 ( 1.3 ) 1.1 Treatment of Osteoporosis in Postmenopausal Women BINOSTO effervescent tablet 70 mg is indicated for the treatment of osteoporosis in postmenopausal women. For the treatment of osteoporosis, alendronate sodium increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1) .] 1.2 Treatment to Increase Bone Mass in Men With Osteoporosis BINOSTO is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.2) ] . 1.3 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of BINOSTO for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Dosage and administration

70 mg BINOSTO effervescent tablet once weekly. ( 2.1 , 2.2 ) Instruct patients to: ( 2.3 ) 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. 2.1 Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is one 70 mg effervescent tablet once weekly. 2.2 Treatment to Increase Bone Mass in Men With Osteoporosis The recommended dosage is one 70 mg effervescent tablet once weekly. 2.3 Important Administration Instructions Instruct patients to do the following to assure adequate drug absorption and to decrease the risk of esophageal adverse reactions: Take BINOSTO upon arising for the day and at least 30 minutes before the first food, beverage, or medication of the day. Patients should not swallow the undissolved effervescent tablet, should not chew the effervescent tablet or allow the effervescent tablet to dissolve in their mouths because of the risk for oropharyngeal irritation [see Warnings and Precautions (5.1) ]. Dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water). Wait at least 5 minutes after the effervescence stops and then stir the buffered solution for approximately 10 seconds and ingest. Avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day. Do not take BINOSTO at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse reactions [see Warnings and Precautions (5.1) ] . 2.4 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.2) ] . 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. 2.5 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.

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS BINOSTO effervescent tablets are round, flat-faced, white to off-white tablets, 25 mm in diameter, with beveled edges, with "M" debossed on one side, containing 91.37 mg of alendronate sodium, which is equivalent to 70 mg of free alendronic acid. After dissolution the solution has a pH of 4.8-5.4. Effervescent tablets, 70 mg ( 3 )

Contraindications

4 CONTRAINDICATIONS BINOSTO is contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1) ] Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2.3) ; Warnings and Precautions (5.1) ] Do not administer BINOSTO to patients at increased risk of aspiration Hypocalcemia [see Warnings and Precautions (5.2) ] Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see Adverse Reactions (6.2) ] . Abnormalities of the esophagus which delay emptying such as stricture or achalasia ( 4 , 5.1 ) Inability to stand/sit upright for at least 30 minutes ( 4 , 5.1 ) Increased risk of aspiration. ( 4 ) Hypocalcemia ( 4 , 5.2 ) Hypersensitivity to any component of this product ( 4 , 6.2 )

Warnings and precautions

Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. ( 5.1 ) Hypocalcemia can worsen and must be corrected prior to use. ( 5.2 ) Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop. ( 5.3 ) Osteonecrosis of the Jaw has been reported. ( 5.4 ) Atypical Fractures Including Femoral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. ( 5.5 ) Sodium Content: Each tablet contains 603 mg sodium, equivalent to 1532 mg NaCl. Use caution in patients on sodium restriction. ( 5.7 ) 5.1 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). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BINOSTO and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration (2.3) ] . In patients who cannot comply with dosing instructions due to mental disability, therapy with BINOSTO should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions (6.2) ] . 5.2 Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with BINOSTO [see Contraindications (4) ]. 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. Presumably due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Patients should receive adequate calcium and vitamin D intake. 5.3 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 [see Adverse Reactions (6.2) ] . 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. In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups. 5.4 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. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. 5.5 Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including alendronate sodium, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area.

Side effects

The following clinically significant adverse drug reactions are described elsewhere in the labeling: Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ] Mineral Metabolism [see Warnings and Precautions (5.2) ] Musculoskeletal Pain [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.5) ] Renal Impairment [see Warnings and Precautions (5.6) ] Patients sensitive to High Sodium Intake [see Warnings and Precautions (5.7) ] The most common adverse reactions (incidence greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Radius Health, Inc. at 1-855-672-3487 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium 10 mg daily in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n=994); Study 3 was the three year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027) and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 IU Vitamin D per day. Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate group. The incidence of serious adverse events was 30.7% in the placebo group and 30.9% in the alendronate group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate or placebo are presented in Table 1. Table 1 Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients United States/Multinational Studies Fracture Intervention Trial Alendronate Sodium 10 mg/day for three years Placebo Alendronate Sodium 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years Placebo % (N = 196) % (N = 397) % (N = 3236) % (N = 3223) Gastrointestinal Abdominal pain 6.6 4.8 1.5 1.5 Nausea 3.6 4.0 1.1 1.5 Dyspepsia 3.6 3.5 1.1 1.2 Constipation 3.1 1.8 0.0 0.2 Diarrhea 3.1 1.8 0.6 0.3 Flatulence 2.6 0.5 0.2 0.3 Acid regurgitation 2.0 4.3 1.1 0.9 Esophageal ulcer 1.5 0.0 0.1 0.1 Vomiting 1.0 1.5 0.2 0.3 Dysphagia 1.0 0.0 0.1 0.1 Abdominal distention 1.0 0.8 0.0 0.0 Gastritis 0.5 1.3 0.6 0.7 Musculoskeletal Musculoskeletal (bone, muscle or joint) pain 4.1 2.5 0.4 0.3 Muscle cramp 0.0 1.0 0.2 0.1 Nervous system/psychiatric Headache 2.6 1.5 0.2 0.2 Dizziness 0.0 1.0 0.0 0.1 Special senses Taste perversion 0.5 1.0 0.1 0.0 Rarely, rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated with alendronate sodium (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49-54% had a history of gastrointestinal disorders at baseline and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies [ see Warnings and Precautions (5.1) ]. Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups. Weekly Dosing The safety of alendronate sodium 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing alendronate 70 mg once weekly and alendronate 10 mg daily. The overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2.

Drug interactions

Calcium supplements, antacids or oral medications containing multivalent cations interfere with absorption of alendronate. ( 7.1 ) Use caution when co-prescribing aspirin/nonsteroidal anti- inflammatory drugs that may worsen gastrointestinal irritation. ( 7.2 , 7.3 ) 7.1 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. 7.2 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. 7.3 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. 7.4 Levothyroxine The bioavailability of alendronate was slightly decreased when BINOSTO and levothyroxine were co-administered to healthy subjects [see Clinical Pharmacology (12.3) ] .

Use in specific populations

Pregnancy: Discontinue when pregnancy is recognized. ( 8.1 ) BINOSTO is not indicated for use in pediatric patients. ( 8.4 ) BINOSTO is not recommended in patients with renal impairment (creatinine clearance less than 35 mL/min). ( 5.6 , 8.6 ) 8.1 Pregnancy Risk Summary Available data on the use of BINOSTO in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue BINOSTO when pregnancy is recognized. In animal reproduction studies, daily oral administration of alendronate to rats from before mating through the end of gestation or lactation showed decreased postimplantation survival and decreased pup body weight gain starting at doses equivalent to less than half of the highest recommended 40 mg clinical daily dose (based on body surface area, mg/m 2 ). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 3 times the 40 mg clinical daily dose. No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at doses equivalent to approximately 10 times the 40 mg clinical daily dose. Delayed or failed delivery of offspring, protracted parturition, and late pregnancy maternal and fetal deaths due to maternal hypocalcemia occurred in rats at oral doses as low as one tenth the 40 mg clinical daily dose (See Data ). Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at 2 mg/kg/day and decreased body weight gain starting at 1 mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m 2 . Incidence of incomplete fetal ossification in vertebral, skull, and sternebral bones were increased in rats dosed orally during organogenesis starting at 10 mg/kg/day (approximately 3 times the 40 mg clinical daily dose). No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at up to 35 mg/kg/day (equivalent to approximately 10 times the 40 mg clinical daily dose). Both total and ionized calcium decreased in pregnant rats dosed orally with 15 mg/kg/day alendronate (approximately 4 times the 40 mg clinical daily dose) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia was observed when rats were treated from before mating through gestation starting at 0.5 mg/kg/day (approximately one tenth the 40 mg clinical daily dose). Maternotoxicity (late pregnancy deaths) also occurred in female rats treated orally with 15 mg/kg/day (approximately 4 times the 40 mg clinical daily dose) for varying gestational time periods. These maternal deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation in the drinking water or by subcutaneous minipump to rats dosed orally with 15 mg/kg/day alendronate could not ameliorate the hypocalcemia or prevent the dystocia-related maternal and neonatal deaths. However, intravenous calcium supplementation prevented maternal, but not neonatal deaths. 8.2 Lactation Risk Summary It is not known whether alendronate is present in human breast milk, affects human milk production, or has effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BINOSTO and any potential adverse effects on the breastfed child from BINOSTO or from the underlying maternal condition. 8.4 Pediatric Use BINOSTO is not indicated for use in pediatric patients. The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight less than 40 kg) or 10 mg alendronate sodium daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebo- treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate-treated patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects.

Pregnancy

8.1 Pregnancy Risk Summary Available data on the use of BINOSTO in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue BINOSTO when pregnancy is recognized. In animal reproduction studies, daily oral administration of alendronate to rats from before mating through the end of gestation or lactation showed decreased postimplantation survival and decreased pup body weight gain starting at doses equivalent to less than half of the highest recommended 40 mg clinical daily dose (based on body surface area, mg/m 2 ). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 3 times the 40 mg clinical daily dose. No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at doses equivalent to approximately 10 times the 40 mg clinical daily dose. Delayed or failed delivery of offspring, protracted parturition, and late pregnancy maternal and fetal deaths due to maternal hypocalcemia occurred in rats at oral doses as low as one tenth the 40 mg clinical daily dose (See Data ). Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at 2 mg/kg/day and decreased body weight gain starting at 1 mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m 2 . Incidence of incomplete fetal ossification in vertebral, skull, and sternebral bones were increased in rats dosed orally during organogenesis starting at 10 mg/kg/day (approximately 3 times the 40 mg clinical daily dose). No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at up to 35 mg/kg/day (equivalent to approximately 10 times the 40 mg clinical daily dose). Both total and ionized calcium decreased in pregnant rats dosed orally with 15 mg/kg/day alendronate (approximately 4 times the 40 mg clinical daily dose) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia was observed when rats were treated from before mating through gestation starting at 0.5 mg/kg/day (approximately one tenth the 40 mg clinical daily dose). Maternotoxicity (late pregnancy deaths) also occurred in female rats treated orally with 15 mg/kg/day (approximately 4 times the 40 mg clinical daily dose) for varying gestational time periods. These maternal deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation in the drinking water or by subcutaneous minipump to rats dosed orally with 15 mg/kg/day alendronate could not ameliorate the hypocalcemia or prevent the dystocia-related maternal and neonatal deaths. However, intravenous calcium supplementation prevented maternal, but not neonatal deaths.

Pediatric use

8.4 Pediatric Use BINOSTO is not indicated for use in pediatric patients. The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight less than 40 kg) or 10 mg alendronate sodium daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebo- treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate-treated patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults. The overall safety profile of alendronate sodium in osteogenesis imperfecta patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in osteogenesis imperfecta patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo. In a pharmacokinetic study, 6 of 24 pediatric osteogenesis imperfecta patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium. [See Adverse Reactions (6.2) .]

Geriatric use

8.5 Geriatric Use Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women and osteoporosis studies in men, [see Clinical Studies (14.1) , (14.2) ] , 45% and 54%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Overdosage

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m 2 ) and 966 mg/kg (2898 mg/m 2 ), 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/m 2 ). 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.

Description

(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 C 4 H 12 NNaO 7 P 2 ∙ 3H 2 O and its molecular weight is 325.12. The structural formula of alendronate sodium is 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. 70 mg of BINOSTO effervescent tablet contains 603 mg of sodium and 17 mg of phosphorus. Once the effervescent tablet is dissolved in water, the alendronate sodium is present in a citrate-buffered solution of pH 4.8 to 5.4. Chemical Structure

Mechanism of action

12.1 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 [ 3 H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [ 3 H]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.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING BINOSTO effervescent tablets are round, flat faced, white to off-white tablets with beveled edges and "M" debossed on one side. BINOSTO effervescent tablets, 70 mg are provided in blisters made of aluminum foil composite, as follows: NDC 70539-400-04 carton containing 4 units of use blisters 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.

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.

Patient information

See FDA-approved patient labeling (Medication Guide) . Instruct patients to read the Medication Guide before starting therapy with BINOSTO and to reread it each time the prescription is renewed. 17.1 Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist. 17.2 Dosing Instructions Instruct patients that it is necessary to follow all dosing instructions for BINOSTO: BINOSTO should only be taken upon arising for the day and must be taken at least 30 minutes before the first food, beverage, or medication of the day. Instruct patients not to attempt to swallow, chew, or suck on the tablet because of a potential for oropharyngeal ulceration. Instruct patients to dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water). Instruct patients to wait at least 5 minutes after the effervescence stops and then stir the solution for approximately 10 seconds and then consume the contents. Instruct patients to avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day. Instruct patients not to take BINOSTO at bedtime or before arising for the day. Instruct patients that waiting less than 30 minutes, or taking BINOSTO with food, beverages (other than plain water) or other medications will lessen the effect of BINOSTO by decreasing its absorption into the body [see Drug Interactions (7.1) ] . Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of BINOSTO [see Clinical Pharmacology (12.3) ]. Inform patients that failure to follow these instructions may increase their risk of esophageal problems. [see Warnings and Precautions (5.1) ] . Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking BINOSTO and consult their physician. [see Warnings and Precautions (5.1) ]. Instruct patients that if they miss a dose of once weekly BINOSTO, they should 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. 17.3 Patients on Sodium Restriction Inform patients who are prescribed sodium restricted diets that BINOSTO contains 603 mg of sodium which is equivalent to approximately 1532 mg NaCl per tablet.

Label text from the FDA structured product label by Radius Health, Inc. (revised Feb 6, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Alendronate Sodium in 1 product

Binosto NDC products (1)

NDC	Strength & form	Labeler	Type
70539-400	Alendronate Sodium 91.37 mg/1 Tablet, Effervescent	Radius Health, Inc.	NDA

Frequently asked questions

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Who makes Binosto?

Binosto is listed by 1 labeler in the FDA NDC directory, including Radius Health, Inc..