Drug: Binosto

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. 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. Once the effervescent tablet is dissolved in water, the alendronate sodium is present in a citrate-buffered solution. Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

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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 theInvestigators and Reported in Greater Than or Equal to 1% of Patients
  United States/ Multinational Studies Fracture Intervention Trial Alendronate Sodium* %
(N=196) Placebo %
(N=397) Alendronate Sodium** %
(N=3236) Placebo %
(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 * 10 mg/day for three years
** 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years 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]. 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. Table 2 : Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by theInvestigators and Reported in Greater Than or Equal to 1% of Patients
  Once Weekly Alendronate Sodium 70 mg %
(N=519) Once Daily Alendronate Sodium 10 mg %
(N=370) Gastrointestinal   Abdominal pain 3.7 3.0   Dyspepsia 2.7 2.2   Acid regurgitation 1.9 2.4   Nausea 1.9 2.4   Abdominal distention 1.0 1.4   Constipation 0.8 1.6   Flatulence 0.4 1.6   Gastritis 0.2 1.1   Gastric ulcer 0.0 1.1 Musculoskeletal   Musculoskeletal (bone, muscle, joint) pain 2.9 3.2   Muscle cramp 0.2 1.1 Osteoporosis in Men In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate sodium 10 mg/day and a one-year study of once weekly alendronate sodium 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either alendronate or placebo are presented in the following table. Table 3 : Osteoporosis Studies in Men Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients
  Two-Year Study One-Year Study Once Daily Alendronate Sodium 10 mg %
(N=146) Placebo %
(N=95) Once Weekly Alendronate Sodium 70 mg %
(N=109) Placebo %
(N=58) Gastrointestinal   Acid regurgitation 4.1 3.2 0.0 0.0   Flatulence 4.1 1.1 0.0 0.0   Gastroesophageal reflux disease 0.7 3.2 2.8 0.0   Dyspepsia 3.4 0.0 2.8 1.7   Diarrhea 1.4 1.1 2.8 0.0   Abdominal pain 2.1 1.1 0.9 3.4   Nausea 2.1 0.0 0.0 0.0 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of alendronate sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema. Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported [see DOSAGE AND ADMINISTRATION; WARNINGS AND PRECAUTIONS]. Dental: Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see WARNINGS AND PRECAUTIONS]. Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe and incapacitating [see WARNINGS AND PRECAUTIONS]; joint swelling; low-energy femoral shaft and subtrochanteric fractures [see WARNINGS AND PRECAUTIONS]. Nervous system: dizziness and vertigo. Pulmonary: asthma exacerbations Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Special Senses: uveitis, scleritis or episcleritis. Read the Binosto (alendronate sodium effervescent tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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Treatment Of Osteoporosis In Postmenopausal Women The recommended dosage is one 70 mg effervescent tablet once weekly. Treatment To Increase Bone Mass In Men With Osteoporosis The recommended dosage is one 70 mg effervescent tablet once weekly. Important Administration Instructions Instruct patients to do the following to assure adequate drug absorption and to decrease the risk of esophageal adverse reactions: 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].
  • Take BINOSTO upon arising for the day and at least 30 minutes before the first food, beverage, or medication of the day.
  • 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 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].
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]. 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.

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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 [see CLINICAL PHARMACOLOGY]. Read the Binosto Drug Interactions Center for a complete guide to possible interactions Learn More »

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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] 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]. 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 reevaluated periodically.

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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]
  • Inability to stand or sit upright for at least 30 minutes [see DOSAGE AND ADMINISTRATION; WARNINGS AND PRECAUTIONS]
Do not administer BINOSTO to patients at increased risk of aspiration
  • Hypocalcemia [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see ADVERSE REACTIONS].
Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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.

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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. 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 0178-0101-02 carton containing 4 units of use blisters
NDC 0178-0101-03 carton containing 12 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. Manufactured for: Mission Pharmacal Company San Antonio, TX 78230 1355. Issued: February 2015 Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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]. 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]. Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with BINOSTO [see CONTRAINDICATIONS]. 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. 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]. 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. 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), 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. 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. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. 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 [see PATIENT INFORMATION]. Patient Counseling 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. 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. 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]. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of BINOSTO [see CLINICAL PHARMACOLOGY].
  • Inform patients that failure to follow these instructions may increase their risk of esophageal problems. [see WARNINGS AND PRECAUTIONS].
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]. 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. Patients On Sodium Restriction Inform patients who are prescribed sodium restricted diets that BINOSTO contains 650 mg of sodium which is equivalent to approximately 1650 mg NaCl per tablet. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.12 to 1.2 times a maximum recommended daily dose of 40 mg, based on surface area, mg/m². The relevance of this finding to humans is unknown. Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 0.26 and 1 times a 40 mg human daily dose based on surface area, mg/m². The relevance of this finding to humans is unknown. Alendronate sodium was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results. Alendronate sodium had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (1.3 times a 40 mg human daily dose based on surface area, mg/m² ). 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. 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 hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical 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. Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose. Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; intravenous calcium supplementation prevented maternal, but not fetal deaths. Exposure multiples based on surface area, mg/m² , were calculated using a 40-mg human daily dose. Animal dose ranged between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits. 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. 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 alendronatetreated 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] 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], 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. 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 [see CLINICAL PHARMACOLOGY]. 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 [see CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

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