ADVERSE REACTIONS SECTION.


6 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. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact ASCEND Therapeutics at 1-877-204-1013 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical TrialsExperience. Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in clinical practice.The safety of BINOSTO (alendronate sodium) effervescenttablet 70 mg is based on clinical trial data of alendronate sodium10 mg daily and alendronate sodium 70 mg weekly.. Treatment of Osteoporosis in Postmenopausal Women. Daily DosingThe safety of alendronate sodium 10 mg daily in the treatmentof postmenopausal osteoporosis was assessed in four clinical trialsthat enrolled 7453 women aged 44-84 years. Study and Study wereidentically designed, three-year, placebo-controlled, double-blind,multicenter studies (United States and Multinational n=994); Study3 was the three year vertebral fracture cohort of the Fracture InterventionTrial [FIT] (n=2027) and Study was the four-year clinical fracturecohort of FIT (n=4432). Overall, 3620 patients were exposed to placeboand 3432 patients exposed to alendronate. Patients with pre-existinggastrointestinal disease and concomitant use of non-steroidal anti-inflammatorydrugs were included in these clinical trials. In Study and Study2 all women received 500 mg elemental calcium as carbonate. In Study3 and Study all women with dietary calcium intake less than 1000mg per day received 500 mg calcium and 250 IU Vitamin per day. Among patients treated with alendronate10 mg or placebo in Study and Study 2, and all patients in Study3 and Study 4, the incidence of all-cause mortality was 1.8% in theplacebo group and 1.8% in the alendronate group. The incidence ofserious adverse events was 30.7% in the placebo group and 30.9% inthe alendronate group. The percentage of patients who discontinuedthe study due to any clinical adverse event was 9.5% in the placebogroup and 8.9% in the alendronate group. Adverse reactions from thesestudies considered by the investigators as possibly, probably, ordefinitely drug related in greater than or equal to 1% of patientstreated with either alendronate or placebo are presented in Table1.Table Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely DrugRelated by the Investigators and Reported in Greater Than or Equalto 1% of Patients 10 mg/day for three years mg/dayfor years and 10 mg/day for either or additional years UnitedStates/Multinational StudiesFractureIntervention TrialAlendronate Sodium (N=196) Placebo (N=397) Alendronate Sodium (N=3236) Placebo (N=3223) Gastrointestinal Abdominal pain6.64.81.51.5 Nausea3.64.01.11.5 Dyspepsia3.63.51.11.2 Constipation3.11.80.00.2 Diarrhea3.11.80.60.3 Flatulence2.60.50.20.3 Acid regurgitation2.04.31.10.9 Esophageal ulcer1.50.00.10.1 Vomiting1.01.50.20.3 Dysphagia1.00.00.10.1 Abdominal distention1.00.80.00.0 Gastritis0.51.30.60.7Musculoskeletal Musculoskeletal (bone, muscle or joint)pain4.12.50.40.3 Muscle cramp0.01.00.20.1Nervous system/psychiatric Headache2.61.50.20.2 Dizziness0.01.00.00.1Special senses Taste perversion0.51.00.10.0Rarely, rash and erythema have occurred.Gastrointestinal Adverse Reactions: One patient treated with alendronate sodium (10 mg/day), who hada history of peptic ulcer disease and gastrectomy and who was takingconcomitant aspirin developed an anastomotic ulcer with mild hemorrhage,which was considered drug related. Aspirin and alendronate sodiumwere discontinued and the patient recovered. In the Study and Study2 populations, 49-54% had history of gastrointestinal disordersat baseline and 54-89% used nonsteroidal anti-inflammatory drugs oraspirin at some time during the studies see Warnings andPrecautions 5.1) ]. Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild,and transient decreases in serum calcium and phosphate were observedin approximately 18% and 10%, respectively, of patients taking alendronateversus 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 (0.65mM) were similar in both treatment groups. Weekly DosingThesafety of alendronate sodium 70 mg once weekly for the treatment ofpostmenopausal osteoporosis was assessed in one-year, double-blind,multicenter study comparing alendronate 70 mg once weekly and alendronate10 mg daily. The overall safety and tolerability profiles of onceweekly 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 OsteoporosisTreatment Studies in Postmenopausal Women Adverse ReactionsConsidered Possibly, Probably, or Definitely Drug Related by the Investigatorsand 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 pain3.73.0 Dyspepsia2.72.2 Acid regurgitation1.92.4 Nausea1.92.4 Abdominal distention1.01.4 Constipation0.81.6 Flatulence0.41.6 Gastritis0.21.1 Gastric ulcer0.01.1Musculoskeletal Musculoskeletal (bone, muscle, joint) pain2.93.2 Muscle cramp0.21.1Osteoporosis in MenIn two placebo-controlled, double-blind, multicenterstudies in men (a two-year study of alendronate sodium 10 mg/day anda one-year study of once weekly alendronate sodium 70 mg) the ratesof discontinuation of therapy due to any clinical adverse event were2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% foronce weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactionsconsidered by the investigators as possibly, probably, or definitelydrug related in greater than or equal to 2% of patients treated witheither alendronate or placebo are presented in the following table. Table OsteoporosisStudies in Men Adverse Reactions Considered Possibly, Probably,or Definitely Drug Related by the Investigators and Reported in GreaterThan or Equal to 2% of Patients Two-YearStudyOne-YearStudyOnce Daily Alendronate Sodium 10 mg (N=146) Placebo (N=95) Once Weekly Alendronate Sodium 70 mg (N=109) Placebo (N=58) Gastrointestinal Acid regurgitation4.13.20.00.0 Flatulence4.11.10.00.0 Gastroesophageal reflux disease0.73.22.80.0 Dyspepsia3.40.02.81.7 Diarrhea1.41.12.80.0 Abdominal pain2.11.10.93.4 Nausea2.10.00.00.0. 6.2 Post-Marketing Experience. The following adverse reactions have been identifiedduring post-approval use of alendronate sodium. Because these reactionsare reported voluntarily from population of uncertain size, it isnot always possible to reliably estimate their frequency or establisha causal relationship to drug exposure.Body as Whole: hypersensitivityreactions including urticaria and angioedema. Transient symptoms ofmyalgia, malaise, asthenia and fever have been reported with alendronate,typically in association with initiation of treatment. Symptomatichypocalcemia has occurred, generally in association with predisposingconditions. Peripheral edema. Gastrointestinal: esophagitis, esophageal erosions,esophageal ulcers, esophageal stricture or perforation, and oropharyngealulceration. Gastric or duodenal ulcers, some severe and with complicationshave also been reported [see Dosage and Administration 2.3); Warnings and Precautions 5.1)] Dental: Localized osteonecrosis of the jaw, generally associatedwith tooth extraction and/or local infection with delayed healing,has been reported [see Warnings and Precautions 5.4)] Musculoskeletal: bone, joint, and/or muscle pain,occasionally severe and incapacitating [see Warnings and Precautions( 5.3)] joint swelling; low-energyfemoral shaft and subtrochanteric fractures [see Warningsand Precautions 5.5)] Nervous system: dizzinessand vertigo. Pulmonary: acute asthma exacerbations. Skin: rash (occasionally with photosensitivity),pruritus, alopecia, severe skin reactions, including Stevens-Johnsonsyndrome and toxic epidermal necrolysis. Special Senses: uveitis, scleritisor episcleritis. Cholesteatoma of the external auditory canal (focalosteonecrosis).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICALPHARMACOLOGY. 12.1 Mechanism of Action. Animal studies have indicated the following mode of action. At thecellular level, alendronate shows preferential localization to sitesof bone resorption, specifically under osteoclasts. The osteoclastsadhere normally to the bone surface but lack the ruffled border thatis indicative of active resorption. Alendronate does not interferewith osteoclast recruitment or attachment, but it does inhibit osteoclastactivity. Studies in mice on the localization of radioactive 3H]alendronate in bone showed about 10-fold higheruptake on osteoclast surfaces than on osteoblast surfaces. Bones examined6 and 49 days after 3H]alendronate administrationin rats and mice, respectively, showed that normal bone was formedon top of the alendronate, which was incorporated inside the matrix.While incorporated in bone matrix, alendronate is not pharmacologicallyactive. Thus, alendronate must be continuously administered to suppressosteoclasts on newly formed resorption surfaces. Histomorphometryin baboons and rats showed that alendronate treatment reduces boneturnover (i.e., the number of sites at which bone is remodeled). Inaddition, bone formation exceeds bone resorption at these remodelingsites, leading to progressive gains in bone mass. 12.2 Pharmacodynamics. Alendronate is bisphosphonate that binds to bone hydroxyapatiteand specifically inhibits the activity of osteoclasts, the bone-resorbingcells. Alendronate reduces bone resorption with no direct effect onbone formation, although the latter process is ultimately reducedbecause bone resorption and formation are coupled during bone turnover.. Osteoporosis in Postmenopausal Women. Osteoporosis is characterized by low bonemass that leads to an increased risk of fracture. The diagnosis canbe confirmed by the finding of low bone mass, evidence of fractureon x-ray, history of osteoporotic fracture, or height loss or kyphosis,indicative of vertebral (spinal) fracture. Osteoporosis occurs inboth males and females but is most common among women following themenopause, when bone turnover increases and the rate of bone resorptionexceeds that of bone formation. These changes result in progressivebone loss and lead to osteoporosis in significant proportion ofwomen over age 50. Fractures, usually of the spine, hip, and wrist,are the common consequences. From age 50 to age 90, the risk of hipfracture in white women increases 50-fold and the risk of vertebralfracture 15- to 30-fold. It is estimated that approximately 40% of50-year-old women will sustain one or more osteoporosis-related fracturesof the spine, hip, or wrist during their remaining lifetimes. Hipfractures, in particular, are associated with substantial morbidity,disability, and mortality.Dailyoral doses of alendronate sodium (5, 20, and 40 mg for six weeks)in postmenopausal women produced biochemical changes indicative ofdose-dependent inhibition of bone resorption, including decreasesin urinary calcium and urinary markers of bone collagen degradation(such as deoxypyridinoline and cross-linked N-telopeptides of typeI collagen). These biochemical changes tended to return toward baselinevalues as early as weeks following the discontinuation of therapywith alendronate and did not differ from placebo after months.Long-term treatment of osteoporosis withalendronate sodium 10 mg/day (for up to five years) reduced urinaryexcretion of markers of bone resorption, deoxypyridinoline and cross-linkedN-telopeptides of type collagen, by approximately 50% and 70%, respectively,to reach levels similar to those seen in healthy premenopausal women.Similar decreases were seen in patients in osteoporosis preventionstudies who received alendronate sodium mg/day. The decrease inthe rate of bone resorption indicated by these markers was evidentas early as month and at to months reached plateau that wasmaintained for the entire duration of treatment with alendronate sodium.In osteoporosis treatment studies alendronate sodium 10 mg/day decreasedthe markers of bone formation, osteocalcin and bone specific alkalinephosphatase by approximately 50%, and total serum alkaline phosphataseby approximately 25 to 30% to reach plateau after to 12 months.In osteoporosis prevention studies alendronate sodium mg/day decreasedosteocalcin and total serum alkaline phosphatase by approximately40% and 15%, respectively. Similar reductions in the rate of boneturnover were observed in postmenopausal women during one-year studieswith once weekly alendronate sodium 70 mg for the treatment of osteoporosisand once weekly alendronate sodium 35 mg for the prevention of osteoporosis.These data indicate that the rate of bone turnover reached new steadystate, despite the progressive increase in the total amount of alendronatedeposited within bone.As resultof inhibition of bone resorption, asymptomatic reductions in serumcalcium and phosphate concentrations were also observed followingtreatment with alendronate sodium. In the long-term studies, reductionsfrom baseline in serum calcium (approximately 2%) and phosphate (approximately4 to 6%) were evident the first month after the initiation of alendronatesodium 10 mg. No further decreases in serum calcium were observedfor the five-year duration of treatment; however, serum phosphatereturned toward prestudy levels during years three through five. Similarreductions were observed with alendronate sodium mg/day. In one-yearstudies with once weekly alendronate sodium 35 and 70 mg, similarreductions were observed at and 12 months. The reduction in serumphosphate may reflect not only the positive bone mineral balance dueto alendronate sodium but also decrease in renal phosphate reabsorption.. Osteoporosis in Men. Treatment of men with osteoporosis with alendronatesodium 10 mg/day for two years reduced urinary excretion of cross-linkedN-telopeptides of type collagen by approximately 60% and bone-specificalkaline phosphatase by approximately 40%. Similar reductions wereobserved in one-year study in men with osteoporosis receiving onceweekly alendronate sodium 70 mg.. 12.3 Pharmacokinetics. Absorption. Relative to an intravenous (IV) reference dose, the mean oral bioavailabilityof alendronate in women was 0.64% for doses ranging from to 70 mgwhen administered after an overnight fast and two hours before standardizedbreakfast. Oral bioavailability of the 10 mg tablet in men (0.59%)was similar to that in women when administered after an overnightfast and hours before breakfast.BINOSTO 70 mg effervescent tablet and alendronate sodium 70 mg tabletare bioequivalent.A study evaluatingthe effect of food on the bioavailability of BINOSTO was performedin 119 healthy women. Bioavailability was decreased (by approximately50%) when 70 mg alendronate sodium was administered 15 minutes beforea standardized breakfast, when compared to dosing hours before eating.In studies of treatment and preventionof osteoporosis, alendronate was effective when administered at least30 minutes before breakfast.Bioavailability was negligible whether alendronate sodium was administeredwith or up to hours after standardized breakfast. Concomitantadministration of alendronate with coffee or orange juice reducedbioavailability by approximately 60%.. Distribution. Preclinical studies (in male rats) show that alendronatesodium transiently distributes to soft tissues following mg/kg IVadministration but is then rapidly redistributed to bone or excretedin the urine. The mean steady-state volume of distribution, exclusiveof bone, is at least 28 in humans. Concentrations of drug in plasmafollowing therapeutic oral doses are too low (less than ng/mL) foranalytical detection. Protein binding in human plasma is approximately78%.. Metabolism. There is no evidence that alendronate sodium is metabolizedin animals or humans.. Excretion. Following single IV dose of 14C]alendronate, approximately 50% of the radioactivity was excretedin the urine within 72 hours and little or no radioactivity was recoveredin the feces. Following single 10 mg IV dose, the renal clearanceof alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]),and systemic clearance did not exceed 200 mL/min. Plasma concentrationsfell by more than 95% within hours following IV administration.The terminal half-life in humans is estimated to exceed 10 years,probably reflecting release of alendronate from the skeleton. Basedon the above, it is estimated that after 10 years of oral treatmentwith alendronate sodium (10 mg daily) the amount of alendronate releaseddaily from the skeleton is approximately 25% of that absorbed fromthe gastrointestinal tract. Specific Populations. Gender: Bioavailability and the fractionof an intravenous dose excreted in urine were similar in men and women. . Geriatric: Bioavailabilityand disposition (urinary excretion) were similar in elderly and youngerpatients. No dosage adjustment is necessary in elderly patients. Race: Pharmacokineticdifferences due to race have not been studied. . Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasingamounts of drug are present in plasma, kidney, spleen, and tibia.In healthy controls, drug that is not deposited in bone is rapidlyexcreted in the urine. No evidence of saturation of bone uptake wasfound after weeks dosing with cumulative intravenous doses of 35 mg/kgin young male rats. Although no formal renal impairment pharmacokineticstudy has been conducted in patients, it is likely that, as in animals,elimination of alendronate via the kidney will be reduced in patientswith impaired renal function. Therefore, somewhat greater accumulationof alendronate in bone might be expected in patients with impairedrenal function. No dosage adjustmentis necessary for patients with creatinine clearance 35 to 60 mL/min.BINOSTO is not recommended for patients with creatinine clearanceless than 35 mL/min due to lack of experience with alendronate inrenal failure.Hepatic Impairment: As there is evidence that alendronateis not metabolized or exreted in the bile, no studies were conductedin patients with hepatic impairment. No dosage adjustment is necessary. Drug Interactions. Ranitidine: Intravenous ranitidine wasshown to double the bioavailability of oral alendronate. The clinicalsignificance of this increased bioavailability and whether similarincreases will occur in patients given oral 2-antagonists is unknown. Prednisone: In healthy subjects, oral prednisone (20 mg threetimes daily for five days) did not produce clinically meaningfulchange in the oral bioavailability of alendronate (a mean increaseranging from 20 to 44%). Calcium and Multivalent Cations: Products containing calciumand other multivalent cations are likely to interfere with absorptionof alendronate. Levothyroxine: The geometric mean AUC (0-) and max of alendronate decreased by 7% (pointestimate: 0.93; 90% CI: 0.79-1.08) and 9% (point estimate: 0.91; 90%CI: 0.77-1.08), respectively, when single dose of BINOSTO (70 mgalendronate) and 600 mcg levothyroxine were given concomitantly to29 healthy male and female subjects.

CLINICAL STUDIES SECTION.


14 CLINICALSTUDIES. 14.1 Treatment of Osteoporosis in Postmenopausal Women. BINOSTO (alendronate sodium) effervescenttablet 70 mg is bioequivalent to alendronate sodium tablet 70 mg.The fracture reduction efficacy and bone mineral density changes attributedto BINOSTO are based on clinical trial data of alendronate sodium10 mg daily and alendronate sodium 70 mg weekly.. Daily Dosing. The efficacy of alendronate sodium 10 mg daily wasassessed in four clinical trials. Study 1, three-year, multicenterdouble-blind, placebo-controlled, US clinical study enrolled 478 patientswith BMD T-score at or below minus 2.5 with or without prior vertebralfracture; Study 2, three-year, multicenter double blind placebocontrolled Multinational clinical study enrolled 516 patients witha BMD T-score at or below minus 2.5 with or without prior vertebralfracture; Study 3, the Three-Year Study of the Fracture InterventionTrial (FIT) study which enrolled 2027 postmenopausal patients withat least one baseline vertebral fracture; and Study 4, the Four-YearStudy of FIT: study which enrolled 4432 postmenopausal patientswith low bone mass but without baseline vertebral fracture.. Effect on Fracture Incidence. To assess the effects of alendronate sodiumon the incidence of vertebral fractures (detected by digitized radiography;approximately one third of these were clinically symptomatic), theU.S. and Multinational studies were combined in an analysis that comparedplacebo to the pooled dosage groups of alendronate sodium (5 or 10 mgfor three years or 20 mg for two years followed by mg for one year).There was statistically significant reduction in the proportionof patients treated with alendronate experiencing one or more newvertebral fractures relative to those treated with placebo (3.2% vs.6.2%; 48% relative risk reduction). reduction in the total numberof new vertebral fractures (4.2 vs. 11.3 per 100 patients) was alsoobserved. In the pooled analysis, patients who received alendronatehad loss in stature that was statistically significantly less thanwas observed in those who received placebo (-3.0 mm vs. -4.6 mm).The Fracture Intervention Trial (FIT)consisted of two studies in postmenopausal women: the Three-Year Studyof patients who had at least one baseline radiographic vertebral fractureand the Four-Year Study of patients with low bone mass but withouta baseline vertebral fracture. In both studies of FIT, 96% of randomizedpatients completed the studies (i.e., had closeout visit at thescheduled end of the study); approximately 80% of patients were stilltaking study medication upon completion.. Fracture Intervention Trial: Three-Year Study (patients withat least one baseline radiographic vertebral fracture). This randomized, double-blind, placebo-controlled,2027-patient study (alendronate, n=1022; placebo, n=1005) demonstratedthat treatment with alendronate sodium resulted in statistically significantreductions in fracture incidence at three years as shown in Table4.Table Effect of Alendronate Sodium on Fracture Incidencein the Three-Year Study of FIT (Patients With Vertebral Fracture atBaseline)Number evaluable for vertebral fractures: alendronate,n=984; placebo, n=966 +p<0.001, p=0.007, p<0.01, p<0.05 Percent of PatientsAlendronate Sodium (N=1022) Placebo (N=1005) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk Patients with: Vertebral fractures (diagnosed by X-ray) >=1 new vertebral fracture7.915.07.147 >=2 new vertebral fractures0.54.94.490 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture13.818.14.326 >=1 clinical (symptomatic) vertebral fracture2.35.02.754 Hip fracture1.12.21.151 Wrist (forearm) fracture2.24.11.948 Furthermore, in this populationof patients with baseline vertebral fracture, treatment with alendronatesodium significantly reduced the incidence of hospitalizations (25.0%vs. 30.7%).In the Three-YearStudy of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patientson placebo and 11 (1.1%) of 1022 patients on alendronate sodium, p=0.047.Figure displays the cumulative incidence of hip fractures in thisstudy.. Figure 3 yr study. Fracture Intervention Trial: Four-Year Study (patients withlow bone mass but without baseline radiographic vertebral fracture). This randomized, double-blind,placebo-controlled, 4432-patient study (alendronate, n=2214; placebo,n=2218) further investigated the reduction in fracture incidence dueto alendronate sodium. The intent of the study was to recruit womenwith osteoporosis, defined as baseline femoral neck BMD at leasttwo standard deviations below the mean for young adult women. However,due to subsequent revisions to the normative values for femoral neckBMD, 31% of patients were found not to meet this entry criterion andthus this study included both osteoporotic and non-osteoporotic women.The results are shown in Table for the patients with osteoporosis.Table Effect of Alendronate on Fracture Incidence in OsteoporoticPatients in the Four-Year Study of FIT (Patients Without VertebralFracture at Baseline)Baseline femoral neck BMD at least SD below themean for young adult women +Number evaluable for vertebral fractures: alendronate, n=1426; placebo,n=1428 p<0.001, p=0.035, p=0.01 Not significant. This study was notpowered to detect differences at these sites. Percent ofPatientsAlendronate Sodium (n=1545) Placebo (n=1521) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk (%) Patients with: Vertebral fractures (diagnosed by X-ray)+ >=1 new vertebral fracture2.54.82.348 >=2 new vertebral fractures0.10.60.578 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture12.916.23.322 >=1 clinical (symptomatic) vertebral fracture1.01.60.641 (NS) Hip fracture1.01.40.429 (NS) Wrist (forearm) fracture3.93.8-0.1NS Fracture Results Across Studies. In the Three-Year Study of FIT, alendronatesodium reduced the percentage of women experiencing at least one newradiographic vertebral fracture from 15.0% to 7.9% (47% relative riskreduction, p<0.001); in the Four-Year Study of FIT, the percentagewas reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001);and in the combined U.S./Multinational studies, from 6.2% to 3.2%(48% relative risk reduction, p=0.034).Alendronate sodium reduced the percentage of womenexperiencing multiple (two or more) new vertebral fractures from 4.2%to 0.6% (87% relative risk reduction, p<0.001) in the combinedU.S./Multinational studies and from 4.9% to 0.5% (90% relative riskreduction, p<0.001) in the Three-Year Study of FIT. In the Four-YearStudy of FIT, alendronate sodium reduced the percentage of osteoporoticwomen experiencing multiple vertebral fractures from 0.6% to 0.1%(78% relative risk reduction, p=0.035).Thus, alendronate sodium reduced the incidence of radiographicvertebral fractures in osteoporotic women whether or not they hada previous radiographic vertebral fracture.. Effect on Bone Mineral Density. The bone mineral density efficacy of alendronatesodium 10 mg once daily in postmenopausal women, 44 to 84 years ofage, with osteoporosis (lumbar spine bone mineral density [BMD] ofat least standard deviations below the premenopausal mean) was demonstratedin double-blind, placebo-controlled clinical studies of or yearsduration.Figure shows themean increases in BMD of the lumbar spine, femoral neck, and trochanterin patients receiving alendronate sodium 10 mg/day relative to placebo-treatedpatients at three years for each of these studies.At years significant increases in BMD, relative bothto baseline and placebo, were seen at each measurement site in eachstudy in patients who received alendronate 10 mg/day. Total body BMDalso increased significantly in each study, suggesting that the increasesin bone mass of the spine and hip did not occur at the expense ofother skeletal sites. Increases in BMD were evident as early as 3months and continued throughout the years of treatment. See figures below for lumbar spine results.) In the 2-yearextension of these studies, treatment of 147 patients with alendronatesodium 10 mg/day resulted in continued increases in BMD at the lumbarspine and trochanter (absolute additional increases between years3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoralneck, forearm and total body were maintained. Alendronate sodium wassimilarly effective regardless of age, race, baseline rate of boneturnover, and baseline BMD in the range studied (at least standarddeviations below the premenopausal mean). In patients with postmenopausal osteoporosis treatedwith alendronate sodium 10 mg/day for one or two years, the effectsof treatment withdrawal were assessed. Following discontinuation,there were no further increases in bone mass and the rates of boneloss were similar to those of the placebo groups.. Figure Osteoporosis. Figure Osteoporosis. Bone Histology. Bone histology in 270 postmenopausal patients withosteoporosis treated with alendronate sodium at doses ranging from1 to 20 mg/day for one, two, or three years revealed normal mineralizationand structure, as well as the expected decrease in bone turnover relativeto placebo. These data, together with the normal bone histology andincreased bone strength observed in rats and baboons exposed to long-termalendronate treatment, support the conclusion that bone formed duringtherapy with alendronate sodium is of normal quality.. Effect on height. Alendronate sodium, over three- or four-year period,was associated with statistically significant reductions in loss ofheight vs. placebo in patients with and without baseline radiographicvertebral fractures. At the end of the FIT studies the between-treatmentgroup differences were 3.2 mm in the Three-Year Study and 1.3 mm inthe Four-Year Study.. Weekly dosing. The therapeutic equivalence of once weekly alendronatesodium 70 mg (n=519) and alendronate sodium 10 mg daily (n=370) wasdemonstrated in one-year, double-blind, multicenter study of postmenopausalwomen with osteoporosis. In the primary analysis of completers, themean increases from baseline in lumbar spine BMD at year were 5.1%(4.8, 5.4%; 95% CI) in the 70 mg once-weekly group (n=440) and 5.4%(5.0, 5.8%; 95% CI) in the 10 mg daily group (n=330). The treatmentgroups were also similar with regard to BMD increases at other skeletalsites. The results of the intention-to-treat analysis were consistentwith the primary analysis of completers.. 14.2 Treatment to Increase Bone Mass in Men with Osteoporosis. The efficacy of alendronate sodium in menwith hypogonadal or idiopathic osteoporosis was demonstrated in twoclinical studies.. Daily Dosing. two-year, double-blind, placebo-controlled, multicenterstudy of alendronate sodium 10 mg once daily enrolled total of 241men between the ages of 31 and 87 (mean, 63). All patients in thetrial had either: 1) BMD T-score less than or equal to -2 at thefemoral neck and less than or equal to -1 at the lumbar spine, or2) baseline osteoporotic fracture and BMD T-score less than orequal to -1 at the femoral neck. At two years, the mean increasesrelative to placebo in BMD in men receiving alendronate sodium 10mg/day were significant at the following sites: lumbar spine, 5.3%;femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatmentwith alendronate sodium also reduced height loss (alendronate, -0.6mm vs. placebo, -2.4 mm).. Weekly dosing. one-year, double-blind, placebo-controlled, multicenterstudy of once weekly alendronate sodium 70 mg enrolled total of167 men between the ages of 38 and 91 (mean, 66). Patients in thestudy had either: 1) BMD T-score less than or equal to -2 at thefemoral neck and less than or equal to -1 at the lumbar spine, 2)a BMD T-score less than or equal to -2 at the lumbar spine and lessthan or equal to -1 at the femoral neck, or 3) baseline osteoporoticfracture and BMD T-score less than or equal to -1 at the femoralneck. At one year, the mean increases relative to placebo in BMD inmen receiving alendronate sodium 70 mg once weekly were significantat the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter,2.0%; and total body, 1.2%. These increases in BMD were similar tothose seen at one year in the alendronate sodium 10 mg once-dailystudy.In both studies, BMD responseswere similar regardless of age (greater than or equal to 65 yearsvs. less than 65 years), gonadal function (baseline testosterone lessthan ng/dL vs. greater than or equal to ng/dL), or baseline BMD(femoral neck and lumbar spine T-score less than or equal to -2.5vs. greater than -2.5).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. BINOSTO is contraindicated inpatients with the following conditions:Abnormalities of the esophagus which delay esophageal emptyingsuch 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); Warningsand Precautions 5.1)] Do not administer BINOSTOto patients at increased risk of aspirationHypocalcemia [see Warnings and Precautions 5.2)] Hypersensitivity to any component of this product. Hypersensitivityreactions including urticaria and angioedema have been reported [see Adverse Reactions 6.2)] . Abnormalities of the esophagus which delay esophageal emptyingsuch 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); Warningsand Precautions 5.1)] Hypocalcemia [see Warnings and Precautions 5.2)] Hypersensitivity to any component of this product. Hypersensitivityreactions including urticaria and angioedema have been reported [see Adverse Reactions 6.2)] . Abnormalities of the esophagus which delay emptying suchas 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) Abnormalities of the esophagus which delay emptying suchas 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).

DESCRIPTION SECTION.


11 DESCRIPTION. BINOSTO (alendronate sodium) is bisphosphonate that acts as 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 4H 12NNaO 7P o 3H 2O and its molecular weight is 325.12. The structural formula of alendronate sodium isAlendronate sodium is 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 citrate-buffered solution of pH 4.8 to 5.4.. alendronate sodium 11 description.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGEAND 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 glassof plain room temperature water (4 oz). Wait at least minutes afterthe effervescence stops, stir the solution for approximately 10 secondsand 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 BINOSTOand until after the first food of the day. 70 mg BINOSTO effervescent tablet once weekly. 2.1, 2.2) Instruct patients to: 2.3) Dissolve one tablet of BINOSTO in approximately half glassof plain room temperature water (4 oz). Wait at least minutes afterthe effervescence stops, stir the solution for approximately 10 secondsand 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 BINOSTOand until after the first food of the day. Dissolve one tablet of BINOSTO in approximately half glassof plain room temperature water (4 oz). Wait at least minutes afterthe effervescence stops, stir the solution for approximately 10 secondsand 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 BINOSTOand until after the first food of the day.. 2.1 Treatment of Osteoporosis in Postmenopausal Women. The recommended dosage is one 70 mg effervescenttablet once weekly.. 2.2 Treatment to Increase Bone Mass in Men With Osteoporosis. The recommended dosage is one 70 mg effervescenttablet 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:i. Take BINOSTO upon arising for the day and at least 30 minutes before the first food, beverage, or medication of the day.o 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 ounces room temperature plain water only (not mineral water or flavored water).ii. Wait at least minutes after the effervescence stops and then stir the buffered solution for approximately 10 seconds and ingest.iii. Avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day.iv. 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 Supplementation. Instruct patients to take supplemental calciumand vitamin if dietary intake is inadequate [see Warningsand Precautions 5.2)] Patientsat increased risk for vitamin insufficiency (e.g., over the ageof 70 years, nursing home-bound, or chronically ill) may need vitaminD supplementation. Patients with gastrointestinal malabsorption syndromesmay require higher doses of vitamin supplementation and measurementof 25-hydroxyvitamin should be considered. 2.5 Administration Instructions for Missed Doses. If the once-weekly dose is missed, instructpatients to take one dose on the morning after they remember. Theyshould not take doses on the same day but should return to takingone dose once week, as originally scheduled on their chosen day.

DOSAGE FORMS & STRENGTHS SECTION.


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 pH of 4.8-5.4.. Effervescent tablets, 70 mg 3).

DRUG INTERACTIONS SECTION.


7 DRUGINTERACTIONS. Calcium supplements, antacids or oral medications containingmultivalent cations interfere with absorption of alendronate. 7.1) Use caution when co-prescribing aspirin/nonsteroidal anti-inflammatorydrugs that may worsen gastrointestinal irritation. 7.2, 7.3) Calcium supplements, antacids or oral medications containingmultivalent cations interfere with absorption of alendronate. 7.1) Use caution when co-prescribing aspirin/nonsteroidal anti-inflammatorydrugs 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 willinterfere with absorption of BINOSTO. Therefore, instruct patientsto wait at least one-half hour after taking BINOSTO before takingany other oral medications.. 7.2 Aspirin. In clinical studies, the incidence of uppergastrointestinal adverse events was increased in patients receivingconcomitant therapy with daily doses of alendronate sodium greaterthan 10 mg and aspirin-containing products.. 7.3 Nonsteroidal Anti-InflammatoryDrugs (NSAIDs). BINOSTOmay be administered to patients taking NSAIDs. In 3-year, controlled,clinical study (n=2027) during which majority of patients receivedconcomitant NSAIDs, the incidence of upper gastrointestinal adverseevents was similar in patients taking alendronate sodium or 10 mg/daycompared to those taking placebo. However, since NSAID use is associatedwith gastrointestinal irritation, caution should be used during concomitantuse with BINOSTO.. 7.4 Levothyroxine. The bioavailability of alendronate was slightlydecreased when BINOSTO and levothyroxine were co-administered to healthysubjects [see Clinical Pharmacology 12.3)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGEAND 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 17139-400-04 carton containing units of use blistersStore at 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F), [See USP Controlled Room Temperature.] Protect from moisture. Store tablets in original blister package until use.

INDICATIONS & USAGE SECTION.


1 INDICATIONSAND USAGE. BINOSTO is 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 durationof use has not been determined. For patients at low-risk for fracture,consider drug discontinuation after to years of use. 1.3) Treatment of osteoporosis in postmenopausal women 1.1) Treatment to increase bone mass in men with osteoporosis( 1.2) 1.1 Treatment of Osteoporosisin Postmenopausal Women. BINOSTO effervescent tablet 70 mg is indicated for the treatmentof osteoporosis in postmenopausal women. For the treatment of osteoporosis,alendronate sodium increases bone mass and reduces the incidence offractures, including those of the hip and spine (vertebral compressionfractures). [See Clinical Studies 14.1).] 1.2 Treatment to IncreaseBone Mass in Men With Osteoporosis. BINOSTO is indicated for treatment to increase bonemass in men with osteoporosis [see Clinical Studies 14.2)] . 1.3 Important Limitationsof Use. The optimal durationof use has not been determined. The safety and effectiveness of BINOSTOfor the treatment of osteoporosis are based on clinical data of fouryears duration. All patients on bisphosphonate therapy should havethe need for continued therapy re-evaluated on periodic basis. Patientsat low-risk for fracture should be considered for drug discontinuationafter to years of use. Patients who discontinue therapy shouldhave their risk for fracture re-evaluated periodically.

INFORMATION FOR PATIENTS SECTION.


17 PATIENTCOUNSELING INFORMATION. See FDA-approved patient labeling (Medication Guide). Instructpatients to read the Medication Guide before starting therapy withBINOSTO and to reread it each time the prescription is renewed. 17.1 Osteoporosis Recommendations,Including Calcium and Vitamin Supplementation. Instruct patients to take supplementalcalcium and vitamin D, if daily dietary intake is inadequate. Weight-bearingexercise should be considered along with the modification of certainbehavioral factors, such as cigarette smoking and/or excessive alcoholconsumption, 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 attempt to swallow, chew, or suck on the tablet because of potential for oropharyngeal ulceration.Instruct patients to dissolve the effervescent tablet in ounces room temperature plain water only (not mineral water or flavored water).Instruct patients to wait at least 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 dose of once weekly BINOSTO, they should take one dose on the morning after they remember. They should not take doses on the same day but should return to taking one dose once week, as originally scheduled on their chosen day.. 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 attempt to swallow, chew, or suck on the tablet because of potential for oropharyngeal ulceration.. Instruct patients to dissolve the effervescent tablet in ounces room temperature plain water only (not mineral water or flavored water).. Instruct patients to wait at least 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)] .. 17.3 Patients on SodiumRestriction. 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.Manufactured for: ASCEND Therapeutics, Herndon,VA 20170.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICALTOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Harderian gland (a retro-orbital glandnot present in humans) adenomas were increased in high-dose femalemice (p=0.003) in 92-week oral carcinogenicity study at doses ofalendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and mg/kg/day(females). These doses are equivalent to 0.12 to 1.2 times maximumrecommended daily dose of 40 mg, based on surface area, mg/m 2. The relevance of this finding to humans is unknown. Parafollicular cell (thyroid) adenomaswere increased in high-dose male rats (p=0.003) in 2-year oral carcinogenicitystudy at doses of and 3.75 mg/kg body weight. These doses are equivalentto 0.26 and times 40 mg human daily dose based on surface area,mg/m 2. The relevance of this finding tohumans is unknown. Alendronatesodium was not genotoxic in the in vitro microbial mutagenesis assaywith and without metabolic activation, in an in vitro mammalian cellmutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes,and in an in vivo chromosomal aberration assay in mice. In an in vitrochromosomal aberration assay in Chinese hamster ovary cells, however,alendronate gave equivocal results.Alendronate sodium had no effect on fertility (male or female) inrats at oral doses up to mg/kg/day (1.3 times 40 mg human dailydose based on surface area, mg/m 2). 13.2 Animal Toxicology and/or Pharmacology. The relative inhibitory activities on bone resorptionand mineralization of alendronate and etidronate were compared inthe Schenk assay, which is based on histological examination of theepiphyses of growing rats. In this assay, the lowest dose of alendronatethat interfered with bone mineralization (leading to osteomalacia)was 6000-fold the antiresorptive dose. The corresponding ratio foretidronate was one to one. These data suggest that alendronate administeredin therapeutic doses is highly unlikely to induce osteomalacia.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Significant lethality after single oral doseswas 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, 626and 1280 mg/kg, respectively. There was no lethality in dogs at oraldoses up to 200 mg/kg (4000 mg/m 2). No specific information is available onthe treatment of overdosage with BINOSTO. Hypocalcemia, hypophosphatemia,and upper gastrointestinal adverse events, such as upset stomach,heartburn, esophagitis, gastritis, or ulcer, may result from oraloverdosage. Milk or antacids should be given to bind alendronate.Due to the risk of esophageal irritation, vomiting should not be inducedand the patient should remain fully upright.Dialysis would not be beneficial.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Binosto (R) 70 mg Carton Effervescent Tablets NDC 17139-400-04. Binosto 70mg Carton Tablets.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Absorption. Relative to an intravenous (IV) reference dose, the mean oral bioavailabilityof alendronate in women was 0.64% for doses ranging from to 70 mgwhen administered after an overnight fast and two hours before standardizedbreakfast. Oral bioavailability of the 10 mg tablet in men (0.59%)was similar to that in women when administered after an overnightfast and hours before breakfast.BINOSTO 70 mg effervescent tablet and alendronate sodium 70 mg tabletare bioequivalent.A study evaluatingthe effect of food on the bioavailability of BINOSTO was performedin 119 healthy women. Bioavailability was decreased (by approximately50%) when 70 mg alendronate sodium was administered 15 minutes beforea standardized breakfast, when compared to dosing hours before eating.In studies of treatment and preventionof osteoporosis, alendronate was effective when administered at least30 minutes before breakfast.Bioavailability was negligible whether alendronate sodium was administeredwith or up to hours after standardized breakfast. Concomitantadministration of alendronate with coffee or orange juice reducedbioavailability by approximately 60%.. Distribution. Preclinical studies (in male rats) show that alendronatesodium transiently distributes to soft tissues following mg/kg IVadministration but is then rapidly redistributed to bone or excretedin the urine. The mean steady-state volume of distribution, exclusiveof bone, is at least 28 in humans. Concentrations of drug in plasmafollowing therapeutic oral doses are too low (less than ng/mL) foranalytical detection. Protein binding in human plasma is approximately78%.. Metabolism. There is no evidence that alendronate sodium is metabolizedin animals or humans.. Excretion. Following single IV dose of 14C]alendronate, approximately 50% of the radioactivity was excretedin the urine within 72 hours and little or no radioactivity was recoveredin the feces. Following single 10 mg IV dose, the renal clearanceof alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]),and systemic clearance did not exceed 200 mL/min. Plasma concentrationsfell by more than 95% within hours following IV administration.The terminal half-life in humans is estimated to exceed 10 years,probably reflecting release of alendronate from the skeleton. Basedon the above, it is estimated that after 10 years of oral treatmentwith alendronate sodium (10 mg daily) the amount of alendronate releaseddaily from the skeleton is approximately 25% of that absorbed fromthe gastrointestinal tract. Specific Populations. Gender: Bioavailability and the fractionof an intravenous dose excreted in urine were similar in men and women. . Geriatric: Bioavailabilityand disposition (urinary excretion) were similar in elderly and youngerpatients. No dosage adjustment is necessary in elderly patients. Race: Pharmacokineticdifferences due to race have not been studied. . Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasingamounts of drug are present in plasma, kidney, spleen, and tibia.In healthy controls, drug that is not deposited in bone is rapidlyexcreted in the urine. No evidence of saturation of bone uptake wasfound after weeks dosing with cumulative intravenous doses of 35 mg/kgin young male rats. Although no formal renal impairment pharmacokineticstudy has been conducted in patients, it is likely that, as in animals,elimination of alendronate via the kidney will be reduced in patientswith impaired renal function. Therefore, somewhat greater accumulationof alendronate in bone might be expected in patients with impairedrenal function. No dosage adjustmentis necessary for patients with creatinine clearance 35 to 60 mL/min.BINOSTO is not recommended for patients with creatinine clearanceless than 35 mL/min due to lack of experience with alendronate inrenal failure.Hepatic Impairment: As there is evidence that alendronateis not metabolized or exreted in the bile, no studies were conductedin patients with hepatic impairment. No dosage adjustment is necessary. Drug Interactions. Ranitidine: Intravenous ranitidine wasshown to double the bioavailability of oral alendronate. The clinicalsignificance of this increased bioavailability and whether similarincreases will occur in patients given oral 2-antagonists is unknown. Prednisone: In healthy subjects, oral prednisone (20 mg threetimes daily for five days) did not produce clinically meaningfulchange in the oral bioavailability of alendronate (a mean increaseranging from 20 to 44%). Calcium and Multivalent Cations: Products containing calciumand other multivalent cations are likely to interfere with absorptionof alendronate. Levothyroxine: The geometric mean AUC (0-) and max of alendronate decreased by 7% (pointestimate: 0.93; 90% CI: 0.79-1.08) and 9% (point estimate: 0.91; 90%CI: 0.77-1.08), respectively, when single dose of BINOSTO (70 mgalendronate) and 600 mcg levothyroxine were given concomitantly to29 healthy male and female subjects.

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryAvailable data on the use of BINOSTO in pregnant women are insufficient to inform 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/m2). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 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 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 potential risk of fetal harm, predominantly skeletal, if woman becomes pregnant after completing 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 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 4% and 15 20%, respectively.DataAnimal DataReproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at mg/kg/day and decreased body weight gain starting at mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m2. 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 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 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 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.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration (2.3) 06/2020Warnings and Precautions (5.7) 06/2020. Dosage and Administration (2.3) 06/2020. Warnings and Precautions (5.7) 06/2020.

SPL MEDGUIDE SECTION.


Medication Guide BINOSTO (R) (BIN -oss-tow (alendronate sodium) Effervescent Tablets Read the Medication Guide that comes with BINOSTO (R) before you start taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment.What is the most important information should know about BINOSTO Effervescent TabletBINOSTO Effervescent Tablet can cause serious side effects, including:Esophagus problemsLow calcium levels in your blood (hypocalcemia)Bone, joint, or muscle painSevere jaw bone problems (osteonecrosis)Unusual thigh bone fracturesEsophagus problems. Some people who take BINOSTO may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed. It is important that you take BINOSTO exactly as prescribed to help lower your chance of getting esophagus problems. (See the section How should take BINOSTO) Stop taking BINOSTO and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow. Low calcium levels in your blood (hypocalcemia).BINOSTO may lower the calcium levels in your blood. If you have low blood calcium before you start taking BINOSTO, it may get worse during treatment. Your low blood calcium must be treated before you take BINOSTO. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as: Spasms, twitches, or cramps in your muscles Numbness or tingling in your fingers, toes, or around your mouth Your doctor may prescribe calcium and vitamin to help prevent low calcium levels in your blood, while you take BINOSTO. Take calcium and vitamin as your doctor tells you to.Bone, joint, or muscle pain.Some people who take BINOSTO develop severe bone, joint, or muscle pain.Severe jaw bone problems (osteonecrosis).Severe jaw bone problems may happen when you take BINOSTO. Your doctor should examine your mouth before you start BINOSTO. Your doctor may tell you to see your dentist before you start BINOSTO. It is important for you to practice good mouth care during treatment with BINOSTO.Unusual thigh bone fractures.Some people have developed unusual fractures in their thigh bone. Symptoms of fracture may include new or unusual pain in your hip, groin, or thigh.Call your doctor right away if you have any of these side effects.What is BINOSTO Effervescent TabletBINOSTO is prescription medicine used to:Treat thinning of your bones (osteoporosis) in women after menopause. BINOSTO helps reduce the chance of having hip or spinal fracture (break).Increase bone mass in men who have osteoporosis.It is not known how long BINOSTO works for the treatment of osteoporosis. You should see your doctor regularly to determine if BINOSTO is still right for you.BINOSTO is not for use in children.Who should not take BINOSTO Effervescent TabletDo not take BINOSTO if you:Have certain problems with your esophagus, the tube that connects your mouth with your stomachCannot stand or sit upright for at least 30 minutesHave trouble swallowing liquidsHave low levels of calcium in your bloodAre allergic to BINOSTO or any of its ingredients. See the end of this leaflet for complete list of ingredients in BINOSTO.What should tell my doctor before taking BINOSTO Effervescent TabletBefore you start taking BINOSTO, tell your doctor about all of your medical conditions, including if you:Have problems with swallowingHave stomach or digestive problemsHave low blood calciumPlan to have dental surgery or teeth removedHave kidney problemsHave been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)Have been told to lower your salt intakeAre pregnant, planning to become pregnant or suspect that you are pregnant. If you become pregnant while taking BINOSTO, stop taking it and contact your doctor. It is not known if BINOSTO can harm your unborn baby.Are breastfeeding or plan to breastfeed. It is not known if BINOSTO passes into your milk and may harm your baby.Tell your doctor about all medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.Especially tell your doctor if you take:calciumantacidsaspirinNonsteroidal Anti-Inflammatory (NSAID) medicinesKnow the medicines you take. Keep list of them and show it to your doctor and pharmacist each time you get new medicine.How should take BINOSTO Effervescent TabletTake BINOSTO exactly as your doctor tells you.BINOSTO is taken time each week. Choose the day of the week that best fits your schedule, then take BINOSTO on the same day every week.BINOSTO works only if you take it on an empty stomach.Take BINOSTO after you get up for the day and 30 minutes before taking your first food, drink, or other medicine.Take BINOSTO while you are sitting or standing.Do not swallow, chew or suck on BINOSTO tablet.Do not dissolve BINOSTO in:mineral or flavored watercoffeeteasodajuiceYou must dissolve your BINOSTO effervescent tablet in plain water at room temperature before you take it. To prepare your BINOSTO liquid medicine:Step 1. Place the BINOSTO tablet in about half glass (4 ounces) of plain water. The water should not be cold or hot, and should be at room temperature. Step 2. Wait at least minutes after the bubbling (effervescence) stops for the BINOSTO tablet to completely dissolve in the water. Step 3. Stir the liquid medicine for about 10 seconds. Step 4. Drink all of the BINOSTO liquid medicine in the glass.After you take BINOSTO, wait at least 30 minutes before you:lie down. You may sit, stand or walk, and do normal activities like reading.take your first food or drink, except for plain water.take other medicines, including antacids, calcium, and other supplements and vitamins.Do not lie down until after you eat your first food of the day.If you miss dose of BINOSTO, do not take it later in the day. Take your missed dose on the next morning after you remember and then return to your normal schedule. Do not take doses on the same day.If you think you took more than your prescribed dose of BINOSTO, drink full glass of milk and call your doctor right away. Do not try to vomit. Do not lie down.What should avoid while taking BINOSTO Effervescent TabletBINOSTO contains high amount of salt in each tablet. Avoid eating foods with high amount of salt if your doctor has told you to limit how much salt you eat.What are the possible side effects of BINOSTO Effervescent TabletBINOSTO may cause serious side effects.See What is the most important information should know about BINOSTO The most common side effects of BINOSTO are:Stomach area (abdominal) painHeartburnConstipationDiarrheaUpset stomachPain in your bones, joints, or musclesNauseaYou may get allergic reactions, such as hives, swelling of your face, lips, tongue, or throat.Tell your doctor about any side effect that bothers you or that does not go away.These are not all the side effects with BINOSTO. Ask your doctor or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store BINOSTO Effervescent TabletStore BINOSTO at room temperature between 68F to 77F (20C to 25C).Keep BINOSTO tablets in their original blister pack until you use them.Protect BINOSTO from moisture.Keep BINOSTO and all medicines out of the reach of children.General information about the safe and effective use of BINOSTO Effervescent TabletMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use BINOSTO for condition for which it was not prescribed. Do not give BINOSTO to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about BINOSTO. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about BINOSTO that is written for health professionals.For more information, go to BINOSTO.com, or call 1-877-204-1013.What are the ingredients in BINOSTO Effervescent TabletActive ingredient: alendronate sodium Inactive ingredients: monosodium citrate anhydrous, citric acid anhydrous, sodium hydrogen carbonate, sodium carbonate anhydrous, strawberry flavor, acesulfame potassium, and sucralose.This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured for: ASCEND TherapeuticsHerndon, VA 20170Issued: October 2020. Esophagus problems. Low calcium levels in your blood (hypocalcemia). Bone, joint, or muscle pain. Severe jaw bone problems (osteonecrosis). Unusual thigh bone fractures. Esophagus problems. Some people who take BINOSTO may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed. It is important that you take BINOSTO exactly as prescribed to help lower your chance of getting esophagus problems. (See the section How should take BINOSTO) Stop taking BINOSTO and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow. Low calcium levels in your blood (hypocalcemia).BINOSTO may lower the calcium levels in your blood. If you have low blood calcium before you start taking BINOSTO, it may get worse during treatment. Your low blood calcium must be treated before you take BINOSTO. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as: Spasms, twitches, or cramps in your muscles Numbness or tingling in your fingers, toes, or around your mouth Your doctor may prescribe calcium and vitamin to help prevent low calcium levels in your blood, while you take BINOSTO. Take calcium and vitamin as your doctor tells you to.. Bone, joint, or muscle pain.Some people who take BINOSTO develop severe bone, joint, or muscle pain.. Severe jaw bone problems (osteonecrosis).Severe jaw bone problems may happen when you take BINOSTO. Your doctor should examine your mouth before you start BINOSTO. Your doctor may tell you to see your dentist before you start BINOSTO. It is important for you to practice good mouth care during treatment with BINOSTO.. Unusual thigh bone fractures.Some people have developed unusual fractures in their thigh bone. Symptoms of fracture may include new or unusual pain in your hip, groin, or thigh.. Treat thinning of your bones (osteoporosis) in women after menopause. BINOSTO helps reduce the chance of having hip or spinal fracture (break).. Increase bone mass in men who have osteoporosis.. Have certain problems with your esophagus, the tube that connects your mouth with your stomach. Cannot stand or sit upright for at least 30 minutes. Have trouble swallowing liquids. Have low levels of calcium in your blood. Are allergic to BINOSTO or any of its ingredients. See the end of this leaflet for complete list of ingredients in BINOSTO.. Have problems with swallowing. Have stomach or digestive problems. Have low blood calcium. Plan to have dental surgery or teeth removed. Have kidney problems. Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome). Have been told to lower your salt intake. Are pregnant, planning to become pregnant or suspect that you are pregnant. If you become pregnant while taking BINOSTO, stop taking it and contact your doctor. It is not known if BINOSTO can harm your unborn baby.. Are breastfeeding or plan to breastfeed. It is not known if BINOSTO passes into your milk and may harm your baby.. calcium. antacids. aspirin. Nonsteroidal Anti-Inflammatory (NSAID) medicines. Take BINOSTO exactly as your doctor tells you.. BINOSTO is taken time each week. Choose the day of the week that best fits your schedule, then take BINOSTO on the same day every week.. BINOSTO works only if you take it on an empty stomach.. Take BINOSTO after you get up for the day and 30 minutes before taking your first food, drink, or other medicine.. Take BINOSTO while you are sitting or standing.. Do not swallow, chew or suck on BINOSTO tablet.. Do not dissolve BINOSTO in:mineral or flavored watercoffeeteasodajuice. mineral or flavored water. coffee. tea. soda. juice. You must dissolve your BINOSTO effervescent tablet in plain water at room temperature before you take it. To prepare your BINOSTO liquid medicine:Step 1. Place the BINOSTO tablet in about half glass (4 ounces) of plain water. The water should not be cold or hot, and should be at room temperature. Step 2. Wait at least minutes after the bubbling (effervescence) stops for the BINOSTO tablet to completely dissolve in the water. Step 3. Stir the liquid medicine for about 10 seconds. Step 4. Drink all of the BINOSTO liquid medicine in the glass.. lie down. You may sit, stand or walk, and do normal activities like reading.. take your first food or drink, except for plain water.. take other medicines, including antacids, calcium, and other supplements and vitamins.. If you miss dose of BINOSTO, do not take it later in the day. Take your missed dose on the next morning after you remember and then return to your normal schedule. Do not take doses on the same day.. If you think you took more than your prescribed dose of BINOSTO, drink full glass of milk and call your doctor right away. Do not try to vomit. Do not lie down.. See What is the most important information should know about BINOSTO Stomach area (abdominal) pain. Heartburn. Constipation. Diarrhea. Upset stomach. Pain in your bones, joints, or muscles. Nausea. Store BINOSTO at room temperature between 68F to 77F (20C to 25C).. Keep BINOSTO tablets in their original blister pack until you use them.. Protect BINOSTO from moisture.

SPL UNCLASSIFIED SECTION.


7.4 Levothyroxine. The bioavailability of alendronate was slightlydecreased when BINOSTO and levothyroxine were co-administered to healthysubjects [see Clinical Pharmacology 12.3)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USEIN 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). 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 SummaryAvailable data on the use of BINOSTO in pregnant women are insufficient to inform 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/m2). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 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 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 potential risk of fetal harm, predominantly skeletal, if woman becomes pregnant after completing 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 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 4% and 15 20%, respectively.DataAnimal DataReproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at mg/kg/day and decreased body weight gain starting at mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m2. 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 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 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 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 SummaryIt 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 mothers 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 pediatricpatients.The safety and efficacyof alendronate sodium were examined in randomized, double-blind,placebo-controlled two-year study of 139 pediatric patients, aged4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-ninepatients were randomized to mg alendronate sodium daily (weightless than 40 kg) or 10 mg alendronate sodium daily (weight greaterthan or equal to 40 kg) and 30 patients to placebo. The mean baselinelumbar spine BMD Z-score of the patients was -4.5. The mean changein lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in thealendronate-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 sustaineda radiologically-confirmed fracture by Month 12 of the study had delayedfracture healing (callus remodeling) or fracture non-union when assessedradiographically at Month 24 compared with 9% of the placebo-treatedpatients. In alendronate-treated patients, bone histomorphometry dataobtained at Month 24 demonstrated decreased bone turnover and delayedmineralization time; however, there were no mineralization defects.There were no statistically significant differences between the alendronatesodium and placebo groups in reduction of bone pain. The oral bioavailabilityin children was similar to that observed in adults.The overall safety profile of alendronate sodium inosteogenesis imperfecta patients treated for up to 24 months was generallysimilar to that of adults with osteoporosis treated with alendronatesodium. However, there was an increased occurrence of vomiting inosteogenesis imperfecta patients treated with alendronate sodium comparedto placebo. During the 24-month treatment period, vomiting was observedin 32 of 109 (29.4%) patients treated with alendronate sodium and3 of 30 (10%) patients treated with placebo.In pharmacokinetic study, of 24 pediatric osteogenesisimperfecta patients who received single oral dose of alendronatesodium 35 or 70 mg developed fever, flu-like symptoms, and/or mildlymphocytopenia within 24 to 48 hours after administration. Theseevents, lasting no more than to days and responding to acetaminophen,are consistent with an acute-phase response that has been reportedin patients receiving bisphosphonates, including alendronate sodium. [See Adverse Reactions 6.2).] 8.5 Geriatric Use. Of the patients receiving alendronate sodiumin the Fracture Intervention Trial (FIT), 71% (n=2302) were greaterthan or equal to 65 years of age and 17% (n=550) were greater thanor equal to 75 years of age. Of the patients receiving alendronatesodium in the United States and Multinational osteoporosis treatmentstudies in women and osteoporosis studies in men, [see ClinicalStudies 14.1), 14.2)] 45% and 54%, respectively, were 65 years of age or over.No overall differences in efficacy or safety were observed betweenthese patients and younger patients, but greater sensitivity of someolder individuals cannot be ruled out. 8.6 Renal Impairment. BINOSTO is not recommended for patientswith creatinine clearance less than 35 mL/min Nodosage adjustment is necessary in patients with creatinine clearancevalues between 35-60 mL/min [see Clinical Pharmacology 12.3)] . 8.7 Hepatic Impairment. As there is evidence that alendronate isnot metabolized or excreted in the bile, no studies were conductedin patients with hepatic impairment. No dosage adjustment is necessary [see Clinical Pharmacology 12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 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 Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out femoral fracture. 5.5)Sodium Content: Each tablet contains 603 mg sodium, equivalent to 1532 mg NaCl. Use caution in patients on sodium restriction. 5.7). 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 Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out femoral fracture. 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 administeredorally, may cause local irritation of the upper gastrointestinal mucosa.Because of these possible irritant effects and potential for worseningof the underlying disease, caution should be used when BINOSTO isgiven to patients with active upper gastrointestinal problems (suchas known Barretts esophagus, dysphagia, other esophageal diseases,gastritis, duodenitis, or ulcers).Esophageal adverse experiences, such as esophagitis, esophageal ulcersand esophageal erosions, occasionally with bleeding and rarely followedby esophageal stricture or perforation, have been reported in patientsreceiving treatment with oral bisphosphonates including alendronatesodium. In some cases these have been severe and required hospitalization.Physicians should therefore be alert to any signs or symptoms signalinga possible esophageal reaction and patients should be instructed todiscontinue BINOSTO and seek medical attention if they develop dysphagia,odynophagia, retrosternal pain or new or worsening heartburn.The risk of severe esophageal adverse experiencesappears to be greater in patients who lie down after taking oral bisphosphonatesincluding alendronate sodium, and/or who continue to take oral bisphosphonatesincluding alendronate sodium after developing symptoms suggestiveof esophageal irritation. Therefore, it is very important that thefull 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 mentaldisability, therapy with BINOSTO should be used under appropriatesupervision. There have been post-marketingreports of gastric and duodenal ulcers with oral bisphosphonate use,some severe and with complications, although no increased risk wasobserved 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)]. Otherdisorders affecting mineral metabolism (such as vitamin deficiency)should also be effectively treated. In patients with these conditions,serum calcium and symptoms of hypocalcemia should be monitored duringtherapy with BINOSTO. Presumablydue to the effects of BINOSTO on increasing bone mineral, small, asymptomaticdecreases in serum calcium and phosphate may occur. Patients shouldreceive adequate calcium and vitamin intake.. 5.3 Musculoskeletal Pain. In post-marketing experience, severe and occasionally incapacitatingbone, joint, and/or muscle pain has been reported in patients takingbisphosphonates that are approved for the treatment of osteoporosis [see Adverse Reactions 6.2)] .This category of drugs includes BINOSTO. Most of the patients werepostmenopausal women. The time to onset of symptoms varied from oneday to several months after starting the drug. Discontinue use ifsevere symptoms develop. Most patients had relief of symptoms afterstopping. subset had recurrence of symptoms when rechallenged withthe same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronatesodium, the percentages of patients with these symptoms were similarin 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 Subtrochanteric and Diaphyseal Femoral Fractures. Atypical, low-energy, or low trauma fracturesof the femoral shaft have been reported in bisphosphonate-treatedpatients. These fractures can occur anywhere in the femoral shaftfrom just below the lesser trochanter to above the supracondylar flareand are transverse or short oblique in orientation without evidenceof comminution. Causality has not been established as these fracturesalso occur in osteoporotic patients who have not been treated withbisphosphonates.Atypical femurfractures most commonly occur with minimal or no trauma to the affectedarea. They may be bilateral and many patients report prodromal painin the affected area, usually presenting as dull, aching thigh pain,weeks to months before complete fracture occurs. number of reportsnote that patients were also receiving treatment with glucocorticoids(e.g., prednisone) at the time of fracture.Any patient with history of bisphosphonate exposurewho presents with thigh or groin pain should be suspected of havingan atypical fracture and should be evaluated to rule out an incompletefemur fracture. Patients presenting with an atypical fracture shouldalso be assessed for symptoms and signs of fracture in the contralaterallimb. Interruption of bisphosphonate therapy should be considered,pending risk/benefit assessment, on an individual basis.. 5.6 Renal Impairment. BINOSTO is not recommended for patients with creatinine clearance<35 mL/min.. 5.7 Patients Sensitive to High Sodium Intake. Each BINOSTO effervescent tablet contains 603 mg of sodium, equivalent to approximately 1532 mg of salt (NaCl). Use caution in patients who must restrict their sodium intake, including some patients with history of heart failure, hypertension, or other cardiovascular diseases [see Patient Counseling Information 17.3)].