1.1 Treatment of Osteoporosis in Postmenopausal Women

Alendronate sodium tablets, USP are indicated for the treatment of osteoporosisin postmenopausal women. In postmenopausal women, alendronate sodium tablets,USP increase bone mass and reduces the incidence of fractures, including thoseof the hip and spine (vertebral compression fractures). [SeeClinical Studies (14.1).]

1.2 Prevention of Osteoporosis in Postmenopausal Women

Alendronate sodium tablets, USP are indicated for the prevention ofpostmenopausal osteoporosis [see ClinicalStudies (14.2)].

1.3 Treatment to Increase Bone Mass in Men with Osteoporosis

Alendronate sodium tablets, USP are indicated for treatment to increase bonemass in men with osteoporosis [see ClinicalStudies (14.3)].

1.4 Treatment of Glucocorticoid-Induced Osteoporosis

Alendronate sodium tablets, USP are indicated for the treatmentof glucocorticoid-induced osteoporosis in men and women receivingglucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisoneand who have low bone mineral density [see Clinical Studies (14.4)].

1.5 Treatment of Paget's Disease of Bone

Alendronate sodium tablets, USP are indicated for the treatmentof Paget’s disease of bone in men and women. Treatment is indicated in patientswith Paget's disease of bone who have alkaline phosphatase at least two timesthe upper limit of normal, or those who are symptomatic, or those at risk forfuture complications from their disease. [See Clinical Studies (14.5).]

1.6 Important Limitations of Use

The safety and effectiveness of alendronate sodium tablets, USP for thetreatment of osteoporosis are based on clinical data of four years duration. Theoptimal duration of use has not been determined. All patients on bisphosphonatetherapy should have the need for continued therapy re-evaluated on a periodicbasis.

2.1 Treatment of Osteoporosis in Postmenopausal Women

The recommended dosage is:
• one 10 mg (alendronate) tabletonce daily
or
• one 70 mg (alendronate) tablet once weekly

2.2 Prevention of Osteoporosis in Postmenopausal Women

The recommended dosage is:
• one 35 mg (alendronate) tablet onceweekly
or
• one 5 mg (alendronate) tablet once daily

2.3 Treatment to Increase Bone Mass in Men with Osteoporosis

The recommended dosage is:
• one 70 mg (alendronate)tablet once weekly
or
• one 10 mg (alendronate) tablet once daily 

2.4 Treatment of Glucocorticoid-Induced Osteoporosis

The recommended dosage is one 5 mg (alendronate) tablet oncedaily, except for postmenopausal women not receiving estrogen, for whom therecommended dosage is one 10 mg (alendronate) tablet once daily.

2.5 Treatment of Paget's Disease of Bone

The recommended treatment regimen is 40 mg once a day for six months.
Re-treatment of Paget’s Disease
 Re-treatment withalendronate sodium tablets may be considered, following a six-monthpost-treatment evaluation period in patients who have relapsed, based onincreases in serum alkaline phosphatase, which should be measured periodically.Re-treatment may also be considered in those who failed to normalize their serumalkaline phosphatase. 

2.6 Dosing Instructions

Alendronate sodium tablets must be taken at least one-half hourbefore the first food, beverage, or medication of the day with plain water only[see Patient Counseling Information(17.2)]. Other beverages (including mineral water), food, and somemedications are likely to reduce the absorption of alendronate sodium tablet[see Drug Interactions (7.1)].Waiting less than 30 minutes, or taking alendronate sodium tablets with food,beverages (other than plain water) or other medications will lessen the effectof alendronate sodium tablets by decreasing its absorption into thebody.
Alendronate sodium tablets should only be taken upon arising for theday. To facilitate delivery to the stomach and thus reduce the potential foresophageal irritation, an alendronate sodium tablet should be swallowed with afull glass of water (6-8 oz). Patients should not lie down for at least 30minutes and until after their first food of theday. Alendronate sodium tablets should not be taken at bedtime or before arisingfor the day. Failure to follow these instructions may increase the risk ofesophageal adverse experiences [see Warnings and Precautions (5.1) and PatientCounseling Information (17.2)].

2.7 Recommendations for Calcium and Vitamin D Supplementation

Patients should receive supplemental calcium if dietary intake isinadequate [see Warnings and Precautions(5.2)]. Patients at increased risk for vitamin D insufficiency (e.g.,over the age of 70 years, nursing home-bound, or chronically ill) may needvitamin D supplementation. Patients with gastrointestinal malabsorptionsyndromes may require higher doses of vitamin D supplementation and measurementof 25-hydroxyvitamin D should be considered.
Patients treated withglucocorticoids should receive adequate amounts of calcium and vitamin D.

2.8 Dosing in Severe Renal Impairment

Alendronate sodium tablets is not recommended for patients withcreatinine clearance <35 mL/min due to lack of experience in this population[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].

5.1 Upper Gastrointestinal Adverse Reactions

Alendronate sodium, like other bisphosphonates administered orally, may causelocal irritation of the upper gastrointestinal mucosa. Because of these possibleirritant effects and a potential for worsening of the underlying disease,caution should be used when alendronate sodium is given to patients with activeupper gastrointestinal problems (such as known Barrett's esophagus, dysphagia,other esophageal diseases, gastritis, duodenitis, or ulcers).
Esophagealadverse experiences, such as esophagitis, esophageal ulcers and esophagealerosions, occasionally with bleeding and rarely followed by esophageal strictureor perforation, have been reported in patients receiving treatment with oralbisphosphonates including alendronate sodium. In some cases these have beensevere and required hospitalization. Physicians should therefore be alert to anysigns or symptoms signaling a possible esophageal reaction and patients shouldbe instructed to discontinue alendronate sodium and seek medical attention ifthey develop dysphagia, odynophagia, retrosternal pain or new or worseningheartburn.
The risk of severe esophageal adverse experiences appears to begreater in patients who lie down after taking oral bisphosphonates includingalendronate sodium and/or who fail to swallow oral bisphosphonates includingalendronate sodium with the recommended full glass (6-8 oz) of water, and/or whocontinue to take oral bisphosphonates including alendronate sodium afterdeveloping symptoms suggestive of esophageal irritation. Therefore, it is veryimportant that the full dosing instructions are provided to, and understood by,the patient [see Dosage and Administration(2.6)]. In patients who cannot comply with dosing instructions due tomental disability, therapy with alendronate sodium should be used underappropriate supervision.
There have been post-marketing reports of gastricand duodenal ulcers with oral bisphosphonate use, some severe and withcomplications, although no increased risk was observed in controlled clinicaltrials [see Adverse Reactions(6.2)].

5.2 Mineral Metabolism

Hypocalcemia must be corrected before initiating therapy withalendronate sodium [see Contraindications(4)]. Other disorders affecting mineral metabolism (such as vitamin Ddeficiency) should also be effectively treated. In patients with theseconditions, serum calcium and symptoms of hypocalcemia should be monitoredduring therapy with alendronate sodium.
Presumably due to the effects ofalendronate sodium on increasing bone mineral, small, asymptomatic decreases inserum calcium and phosphate may occur, especially in patients with Paget’sdisease, in whom the pretreatment rate of bone turnover may be greatly elevated,and in patients receiving glucocorticoids, in whom calcium absorption may bedecreased.
Ensuring adequate calcium and vitamin D intake is especiallyimportant in patients with Paget’s disease of bone and in patients receivingglucocorticoids.

5.3 Musculoskeletal Pain

In post-marketing experience, severe and occasionallyincapacitating bone, joint, and/or muscle pain has been reported in patientstaking bisphosphonates that are approved for the prevention and treatment ofosteoporosis [see Adverse Reactions(6.2)]. This category of drugs includes alendronate. Most of thepatients were postmenopausal women. The time to onset of symptoms varied fromone day to several months after starting the drug. Discontinue use if severesymptoms develop. Most patients had relief of symptoms after stopping. A subsethad recurrence of symptoms when rechallenged with the same drug or anotherbisphosphonate.
In placebo-controlled clinical studies of alendronate sodium,the percentages of patients with these symptoms were similar in the alendronatesodium and placebo groups.

5.4 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, isgenerally associated with tooth extraction and/or local infection with delayedhealing, and has been reported in patients taking bisphosphonates, includingalendronate sodium. Known risk factors for osteonecrosis of the jaw includeinvasive dental procedures (e.g., tooth extraction, dental implants, boneysurgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy,corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontaland/or other pre-existing dental disease, anemia, coagulopathy, infection,ill-fitting dentures).
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 themanagement plan of each patient based on individual benefit/risk assessment.
Patients who develop osteonecrosis of the jaw while on bisphosphonatetherapy should receive care by an oral surgeon. In these patients, extensivedental surgery to treat ONJ may exacerbate the condition. Discontinuation ofbisphosphonate therapy should be considered based on individual benefit/riskassessment

5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Atypical, low-energy, or low trauma fractures of the femoralshaft have been reported in bisphosphonate-treated patients. These fractures canoccur anywhere in the femoral shaft from just below the lesser trochanter toabove the supracondylar flare and are transverse or short oblique in orientationwithout evidence of comminution. Causality has not been established as thesefractures also occur in osteoporotic patients who have not been treated withbisphosphonates.
Atypical femur fractures most commonly occur with minimal orno trauma to the affected area. They may be bilateral and many patients reportprodromal pain in the affected area, usually presenting as dull, aching thighpain, weeks to months before a complete fracture occurs. A number of reportsnote that patients were also receiving treatment with glucocorticoids (e.g.prednisone) at the time of fracture.
Any patient with a history ofbisphosphonate exposure who presents with thigh or groin pain should besuspected of having an atypical fracture and should be evaluated to rule out anincomplete femur fracture. Patients presenting with an atypical fracture shouldalso be assessed for symptoms and signs of fracture in the contralateral limb.Interruption of bisphosphonate therapy should be considered, pending arisk/benefit assessment, on an individual basis.

5.6 Renal Impairment

Alendronate sodium is not recommended for patients with creatinine clearance<35 mL/min[see Dosage andAdministration (2.8)].

5.7 Glucocorticoid-Induced Osteoporosis

The risk versus benefit of alendronate sodium for treatment atdaily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalenthas not been established [see Indicationsand Usage (1.4)]. Before initiating treatment, the gonadal hormonalstatus of both men and women should be ascertained and appropriate replacementconsidered.
A bone mineral density measurement should be made at theinitiation of therapy and repeated after 6 to 12 months of combined alendronatesodium and glucocorticoid treatment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect therates observed in practice.
Treatment of Osteoporosis inPostmenopausal Women
Daily Dosing
Thesafety of alendronate sodium in the treatment of postmenopausal osteoporosis wasassessed 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); Study3 was the three year vertebral fracture cohort of the Fracture InterventionTrial [FIT] (n=2027) and Study 4 was the four-year clinical fracture cohort ofFIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patientsexposed to alendronate sodium. Patients with pre-existing gastrointestinaldisease and concomitant use of non-steroidal anti-inflammatory drugs wereincluded in these clinical trials. In Study 1 and Study 2 all women received 500mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietarycalcium intake less than 1000 mg per day received 500 mg calcium and 250 IUVitamin D per day.
Among patients treated with alendronate 10 mg or placeboin Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidenceof all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronatesodium group. The incidence of serious adverse event was 30.7% in the placebogroup and 30.9% in the alendronate sodium group. The percentage of patients whodiscontinued the study due to any clinical adverse event was 9.5% in the placebogroup and 8.9% in the alendronate sodium group. Adverse reactions from thesestudies considered by the investigators as possibly, probably, or definitelydrug related in ≥1% of patients treated with either alendronate sodium orplacebo are presented in Table 1.

Rarely, rash and erythema have occurred.
Gastrointestinal Adverse Reactions: One patient treatedwith alendronate (10 mg/day), who had a history of peptic ulcer disease andgastrectomy and who was taking concomitant aspirin, developed an anastomoticulcer with mild hemorrhage, which was considered drug related. Aspirin andalendronate sodium were discontinued and the patient recovered. In the Study 1and Study 2 populations, 49-54% had a history of gastrointestinal disorders atbaseline and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at sometime during the studies. [See Warnings andPrecautions (5.1).]
Laboratory TestFindings: In double-blind, multicenter, controlled studies, asymptomatic,mild, and transient decreases in serum calcium and phosphate were observed inapproximately 18% and 10%, respectively, of patients taking alendronate sodiumversus approximately 12% and 3% of those taking placebo. However, the incidencesof decreases in serum calcium to <8.0 mg/dL (2.0 mM) and serum phosphate to≤2.0 mg/dL (0.65 mM) were similar in both treatment groups.

Weekly Dosing
The safety of alendronate 70 mgonce weekly for the treatment of postmenopausal osteoporosis was assessed in aone-year, double-blind, multicenter study comparing alendronate 70 mg onceweekly and alendronate 10 mg daily. The overall safety and tolerability profilesof once weekly alendronate 70 mg and alendronate 10 mg daily were similar. Theadverse reactions considered by the investigators as possibly, probably, ordefinitely drug related in ≥1% of patients in either treatment group arepresented in Table 2.

Prevention of Osteoporosis in PostmenopausalWomen
Daily Dosing
The safety ofalendronate 5 mg/day in postmenopausal women 40-60 years of age has beenevaluated in three double-blind, placebo-controlled studies involving over 1,400patients randomized to receive alendronate sodium for either two or three years.In these studies the overall safety profiles of alendronate 5 mg/day and placebowere similar. Discontinuation of therapy due to any clinical adverse eventoccurred in 7.5% of 642 patients treated with alendronate 5 mg/day and 5.7% of648 patients treated with placebo.

Weekly Dosing
The safety of alendronate 35 mgonce weekly compared to alendronate 5 mg daily was evaluated in a one-year,double-blind, multicenter study of 723 patients. The overall safety andtolerability profiles of once weekly alendronate 35 mg and alendronate 5 mgdaily were similar.
The adverse reactions from these studies considered bythe investigators as possibly, probably, or definitely drug related in ≥1% ofpatients treated with either once weekly alendronate 35 mg, alendronate 5 mg/dayor placebo are presented in Table 3.

Concomitant Use with Estrogen/Hormone ReplacementTherapy
In two studies (of one and two years’ duration) ofpostmenopausal osteoporotic women (total: n=853), the safety and tolerabilityprofile of combined treatment with alendronate 10 mg once daily and estrogen ±progestin (n=354) was consistent with those of the individualtreatments.
Osteoporosis in Men

In two placebo-controlled, double-blind, multicenter studies in men (a two-yearstudy of alendronate 10 mg/day and a one-year study of once weekly alendronate70 mg) the rates of discontinuation of therapy due to any clinical adverse eventwere 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for onceweekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions consideredby the investigators as possibly, probably, or definitely drug related in ≥2% ofpatients treated with either alendronate or placebo are presented in Table4.

Glucocorticoid-Induced Osteoporosis
In two,one-year, placebo-controlled, double-blind, multicenter studies in patientsreceiving glucocorticoid treatment, the overall safety and tolerability profilesof alendronate 5 and 10 mg/day were generally similar to that of placebo. Theadverse reactions considered by the investigators as possibly, probably, ordefinitely drug related in ≥1% of patients treated with  eitheralendronate 5 or 10 mg/day or placebo are presented in Table 5.

The overall safety and tolerability profile in the glucocorticoid-inducedosteoporosis population that continued therapy for the second year of thestudies (alendronate sodium: n=147) was consistent with that observed in thefirst year.
Paget's Disease of Bone
In clinical studies(osteoporosis and Paget's disease), adverse events reported in 175 patientstaking alendronate 40 mg/day for 3-12 months were similar to those inpostmenopausal women treated with alendronate 10 mg/day. However, there was anapparent increased incidence of upper gastrointestinal adverse reactions inpatients taking alendronate 40 mg/day (17.7% alendronate sodium vs. 10.2%placebo). One case of esophagitis and two cases of gastritis resulted indiscontinuation of treatment.
Additionally, musculoskeletal (bone, muscle orjoint) pain, which has been described in patients with Paget's disease treatedwith other bisphosphonates, was considered by the investigators as possibly,probably, or definitely drug related in approximately 6% of patients treatedwith alendronate 40 mg/day versus approximately 1% of patients treated withplacebo, but rarely resulted in discontinuation of therapy. Discontinuation oftherapy due to any clinical adverse events occurred in 6.4% of patients withPaget's disease treated with alendronate 40 mg/day and 2.4% of patients treatedwith placebo.

6.2 Post-Marketing Experience

The following adverse reactions have been identified duringpost-approval use of alendronate. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible toreliably estimate their frequency or establish a causal relationship to drugexposure.
Body as a Whole: hypersensitivityreactions including urticaria and rarely angioedema. Transient symptoms ofmyalgia, malaise, asthenia and rarely, fever have been reported withalendronate, typically in association with initiation of treatment. Rarely,symptomatic hypocalcemia has occurred, generally in association withpredisposing conditions. Rarely, peripheral edema.
Gastrointestinal: esophagitis, esophageal erosions,esophageal ulcers, rarely esophageal stricture or perforation, and oropharyngealulceration. Gastric or duodenal ulcers, some severe and with complications, havealso been reported [see Dosage andAdministration (2); Warnings and Precautions(5.1)].
Localized osteonecrosis of the jaw, generally associatedwith tooth extraction and/or local infection with delayed healing, has beenreported rarely [see Warnings andPrecautions (5.4)].
Musculoskeletal:bone, joint, and/or muscle pain, occasionally severe, and rarely incapacitating[see Warnings and Precautions(5.3)]; joint swelling; low-energy femoral shaft and subtrochantericfractures [see Warnings and Precautions(5.5)].
Nervous System: dizziness andvertigo.
Skin: rash (occasionally withphotosensitivity), pruritus, alopecia, rarely severe skin reactions, includingStevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses: rarely uveitis, scleritis orepiscleritis.

7.1 Calcium Supplements/Antacids

Co-administration of alendronate sodium and calcium, antacids, or oralmedications containing multivalent cations will interfere with absorption ofalendronate sodium. Therefore, patients must wait at least one-half hour aftertaking alendronate sodium before taking any other oral medications.

7.2 Aspirin

In clinical studies, the incidence of upper gastrointestinaladverse events was increased in patients receiving concomitant therapy withdaily doses of alendronate greater than 10 mg and aspirin-containingproducts.

7.3 Nonsteroidal Anti-Inflammatory Drugs

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

8.1 Pregnancy

Pregnancy Category C:
There are no studies inpregnant women. Alendronate sodium should be used during pregnancy only if thepotential benefit justifies the potential risk to the mother andfetus.
Bisphosphonates are incorporated into the bone matrix, from which theyare gradually released over a period of years. The amount of bisphosphonateincorporated into adult bone, and hence, the amount available for release backinto the systemic circulation, is directly related to the dose and duration ofbisphosphonate use. There are no data on fetal risk in humans. However, there isa theoretical risk of fetal harm, predominantly skeletal, if a woman becomespregnant after completing a course of bisphosphonate therapy. The impact ofvariables such as time between cessation of bisphosphonate therapy toconception, the particular bisphosphonate used, and the route of administration(intravenous versus oral) on the risk has not been studied.
Reproductionstudies in rats showed decreased postimplantation survival and decreased bodyweight gain in normal pups at doses less than half of the recommended clinicaldose. Sites of incomplete fetal ossification were statistically significantlyincreased in rats beginning at approximately 3 times the clinical dose invertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. Nosimilar fetal effects were seen when pregnant rabbits were treated with dosesapproximately 10 times the clinical dose.
Both total and ionized calciumdecreased in pregnant rats at approximately 4 times the clinical dose resultingin delays and failures of delivery. Protracted parturition due to maternalhypocalcemia occurred in rats at doses as low as one tenth the clinical dosewhen rats were treated from before mating through gestation. Maternotoxicity(late pregnancy deaths) also occurred in the female rats treated atapproximately 4 times the clinical dose for varying periods of time ranging fromtreatment only during pre-mating to treatment only during early, middle, or lategestation; these deaths were lessened but not eliminated by cessation oftreatment. Calcium supplementation either in the drinking water or by minipumpcould not ameliorate the hypocalcemia or prevent maternal and neonatal deathsdue to delays in delivery; intravenous calcium supplementation preventedmaternal, 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 inrabbits.

8.3 Nursing Mothers

It is not known whether alendronate is excreted in human milk. Becausemany drugs are excreted in human milk, caution should be exercised whenalendronate sodium is administered to nursing women.

8.4 Pediatric Use

Alendronate is not indicated for use in pediatric patients.
The safetyand 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 wererandomized to 5 mg alendronate daily (weight <40 kg) or 10 mg alendronatedaily (weight ≥40 kg) and 30 patients to placebo. The mean baseline lumbar spineBMD Z-score of the patients was -4.5. The mean change in lumbar spine BMDZ-score from baseline to Month 24 was 1.3 in the alendronate sodium-treatedpatients and 0.1 in the placebo-treated patients. Treatment with alendronatesodium did not reduce the risk of fracture. Sixteen percent of the alendronatesodium patients who sustained a radiologically-confirmed fracture by Month 12 ofthe study had delayed fracture healing (callus remodeling) or fracture non-unionwhen assessed radiographically at Month 24 compared with 9% of theplacebo-treated patients. In alendronate sodium-treated patients, bonehistomorphometry data obtained at Month 24 demonstrated decreased bone turnoverand delayed mineralization 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 bioavailability inchildren was similar to that observed in adults.
The overall safety profileof alendronate sodium in OI patients treated for up to 24 months was generallysimilar to that of adults with osteoporosis treated with alendronate sodium.However, there was an increased occurrence of vomiting in OI patients treatedwith alendronate sodium compared to placebo. During the 24-month treatmentperiod, vomiting was observed in 32 of 109 (29.4%) patients treated withalendronate sodium and 3 of 30 (10%) patients treated with placebo.
In apharmacokinetic study, 6 of 24 pediatric OI patients who received a single oraldose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms,and/or mild lymphocytopenia within 24 to 48 hours after administration. Theseevents, lasting no more than 2 to 3 days and responding to acetaminophen, areconsistent with an acute-phase response that has been reported in patientsreceiving bisphosphonates, including alendronate sodium. [See Adverse Reactions (6.2).]

8.5 Geriatric Use

Of the patients receiving alendronate sodium in the Fracture Intervention Trial(FIT), 71% (n=2302) were ≥65 years of age and 17% (n=550) were ≥75 years of age.Of the patients receiving alendronate sodium in the United States andMultinational osteoporosis treatment studies in women, osteoporosis studies inmen, glucocorticoid-induced osteoporosis studies, and Paget’s disease studies[see Clinical Studies (14.1), (14.3), (14.4), (14.5)], 45%, 54%, 37%, and 70%, respectively, were 65years of age or over. No overall differences in efficacy or safety were observedbetween these patients and younger patients, but greater sensitivity of someolder individuals cannot be ruled out.

8.6 Renal Impairment

Alendronate sodium is not recommended for patients withcreatinine clearance <35 mL/min. No dosage adjustment is necessary inpatients with creatinine clearance values between 35-60 mL/min[see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

As there is evidence that alendronate is not metabolized or excreted in thebile, no studies were conducted in patients with hepatic impairment. No dosageadjustment is necessary [see ClinicalPharmacology (12.3)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Alendronate is a bisphosphonate that binds to bone hydroxyapatite andspecifically inhibits the activity of osteoclasts, the bone-resorbing cells.Alendronate reduces bone resorption with no direct effect on bone formation,although the latter process is ultimately reduced because bone resorption andformation are coupled during bone turnover.
Osteoporosisin Postmenopausal Women
Osteoporosis is characterized by low bone massthat leads to an increased risk of fracture. The diagnosis can be confirmed bythe finding of low bone mass, evidence of fracture on x-ray, a history ofosteoporotic fracture, or height loss or kyphosis, indicative of vertebral(spinal) fracture. Osteoporosis occurs in both males and females but is mostcommon among women following the menopause, when bone turnover increases and therate of bone resorption exceeds that of bone formation. These changes result inprogressive bone loss and lead to osteoporosis in a significant proportion ofwomen over age 50. Fractures, usually of the spine, hip, and wrist, are thecommon consequences. From age 50 to age 90, the risk of hip fracture in whitewomen increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It isestimated that approximately 40% of 50-year-old women will sustain one or moreosteoporosis-related fractures of the spine, hip, or wrist during theirremaining lifetimes. Hip fractures, in particular, are associated withsubstantial morbidity, disability, and mortality. Daily oral doses ofalendronate (5, 20, and 40 mg for six weeks) in postmenopausal women producedbiochemical changes indicative of dose-dependent inhibition of bone resorption,including decreases in urinary calcium and urinary markers of bone collagendegradation (such as deoxypyridinoline and cross-linked N-telopeptides of type Icollagen). These biochemical changes tended to return toward baseline values asearly as 3 weeks following the discontinuation of therapy with alendronate anddid not differ from placebo after 7 months.
Long-term treatment ofosteoporosis with alendronate 10 mg/day (for up to five years) reduced urinaryexcretion of markers of bone resorption, deoxypyridinoline and cross-linkedN-telopeptides of type l collagen, by approximately 50% and 70%, respectively,to reach levels similar to those seen in healthy premenopausal women. Similardecreases were seen in patients in osteoporosis prevention studies who receivedalendronate 5 mg/day. The decrease in the rate of bone resorption indicated bythese markers was evident as early as one month and at three to six monthsreached a plateau that was maintained for the entire duration of treatment withalendronate sodium. In osteoporosis treatment studies alendronate 10 mg/daydecreased the markers of bone formation, osteocalcin and bone specific alkalinephosphatase by approximately 50%, and total serum alkaline phosphatase byapproximately 25 to 30% to reach a plateau after 6 to 12 months. In osteoporosisprevention studies alendronate 5 mg/day decreased osteocalcin and total serumalkaline phosphatase by approximately 40% and 15%, respectively. Similarreductions in the rate of bone turnover were observed in postmenopausal womenduring one-year studies with once weekly alendronate 70 mg for the treatment ofosteoporosis and once weekly alendronate 35 mg for the prevention ofosteoporosis. These data indicate that the rate of bone turnover reached a newsteady-state, despite the progressive increase in the total amount ofalendronate deposited within bone.
As a result of inhibition of boneresorption, asymptomatic reductions in serum calcium and phosphateconcentrations were also observed following treatment with alendronate sodium.In the long-term studies, reductions from baseline in serum calcium(approximately 2%) and phosphate (approximately 4 to 6%) were evident the firstmonth after the initiation of alendronate 10 mg. No further decreases in serumcalcium were observed for the five-year duration of treatment; however, serumphosphate returned toward prestudy levels during years three through five.Similar reductions were observed with alendronate 5 mg/day. In one-year studieswith once weekly alendronate 35 and 70 mg, similar reductions were observed at 6and 12 months. The reduction in serum phosphate may reflect not only thepositive bone mineral balance due to alendronate sodium but also a decrease inrenal phosphate reabsorption.
Osteoporosis inMen
Treatment of men with osteoporosis with alendronate 10 mg/day fortwo years reduced urinary excretion of cross-linked N-telopeptides of type Icollagen by approximately 60% and bone-specific alkaline phosphatase byapproximately 40%. Similar reductions were observed in a one-year study in menwith osteoporosis receiving once weekly alendronate 70 mg.
Glucocorticoid-Induced Osteoporosis
Sustained use ofglucocorticoids is commonly associated with development of osteoporosis andresulting fractures (especially vertebral, hip, and rib). It occurs both inmales and females of all ages. Osteoporosis occurs as a result of inhibited boneformation and increased bone resorption resulting in net bone loss. Alendronatedecreases bone resorption without directly inhibiting bone formation.
Inclinical studies of up to two years’ duration, alendronate 5 and 10 mg/dayreduced cross-linked N-telopeptides of type I collagen (a marker of boneresorption) by approximately 60% and reduced bone-specific alkaline phosphataseand total serum alkaline phosphatase (markers of bone formation) byapproximately 15 to 30% and 8 to 18%, respectively. As a result of inhibition ofbone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases inserum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to8%).
Paget's Disease of Bone
Paget’s disease ofbone is a chronic, focal skeletal disorder characterized by greatly increasedand disorderly bone remodeling. Excessive osteoclastic bone resorption isfollowed by osteoblastic new bone formation, leading to the replacement of thenormal bone architecture by disorganized, enlarged, and weakened bonestructure.
Clinical manifestations of Paget’s disease range from no symptomsto severe morbidity due to bone pain, bone deformity, pathological fractures,and neurological and other complications. Serum alkaline phosphatase, the mostfrequently used biochemical index of disease activity, provides an objectivemeasure of disease severity and response to therapy.
Alendronate sodiumdecreases the rate of bone resorption directly, which leads to an indirectdecrease in bone formation. In clinical trials, alendronate sodium 40 mg oncedaily for six months produced significant decreases in serum alkalinephosphatase as well as in urinary markers of bone collagen degradation. As aresult of the inhibition of bone resorption, alendronate sodium inducedgenerally mild, transient, and asymptomatic decreases in serum calcium andphosphate.

12.3 Pharmacokinetics

Absorption
Relative to an intravenous referencedose, the mean oral bioavailability of alendronate in women was 0.64% for dosesranging from 5 to 70 mg when administered after an overnight fast and two hoursbefore a standardized breakfast. Oral bioavailability of the 10 mg tablet in men(0.59%) was similar to that in women when administered after an overnight fastand 2 hours before breakfast. Alendronate sodium 70 mg oral solution andalendronate sodium 70 mg tablet are equally bioavailable.
A study examiningthe effect of timing of a meal on the bioavailability of alendronate wasperformed in 49 postmenopausal women. Bioavailability was decreased (byapproximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hourbefore a standardized breakfast, when compared to dosing 2 hours before eating.In studies of treatment and prevention of osteoporosis, alendronate waseffective when administered at least 30 minutes beforebreakfast.
Bioavailability was negligible whether alendronate wasadministered with or up to two hours after a standardized breakfast. Concomitantadministration of alendronate with coffee or orange juice reducedbioavailability by approximately 60%.
Distribution
Preclinical studies (in male rats) showthat alendronate transiently distributes to soft tissues following 1 mg/kgintravenous administration but is then rapidly redistributed to bone or excretedin the urine. The mean steady-state volume of distribution, exclusive of bone,is at least 28 L in humans. Concentrations of drug in plasma followingtherapeutic oral doses are too low (less than 5 ng/mL) for analytical detection.Protein binding in human plasma is approximately 78%.
Metabolism
There is no evidence that alendronate ismetabolized in animals or humans.
Excretion
Following a single intravenous dose of [14C]alendronate, approximately 50% of the radioactivity wasexcreted in the urine within 72 hours and little or no radioactivity wasrecovered in the feces. Following a single 10 mg intravenous dose, the renalclearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]),and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell bymore than 95% within 6 hours following intravenous administration. The terminalhalf-life in humans is estimated to exceed 10 years, probably reflecting releaseof alendronate from the skeleton. Based on the above, it is estimated that after10 years of oral treatment with alendronate (10 mg daily) the amount ofalendronate released daily from the skeleton is approximately 25% of thatabsorbed from the gastrointestinal tract.
SpecificPopulations
Gender: Bioavailability and thefraction of an intravenous dose excreted in urine were similar in men andwomen.
Geriatric: Bioavailability and disposition(urinary excretion) were similar in elderly and younger patients. No dosageadjustment is necessary in elderly patients.
Race:Pharmacokinetic differences due to race have not been studied.
Renal Impairment: Preclinical studies show that, in ratswith kidney failure, increasing amounts of drug are present in plasma, kidney,spleen, and tibia. In healthy controls, drug that is not deposited in bone israpidly excreted in the urine. No evidence of saturation of bone uptake wasfound after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg inyoung male rats. Although no formal renal impairment pharmacokinetic study hasbeen conducted in patients, it is likely that, as in animals, elimination ofalendronate via the kidney will be reduced in patients with impaired renalfunction. Therefore, somewhat greater accumulation of alendronate in bone mightbe expected in patients with impaired renal function.
No dosage adjustment isnecessary for patients with creatinine clearance 35 to 60 mL/min. Alendronatesodium is not recommended for patients with creatinine clearance <35 mL/mindue to lack of experience with alendronate in renal failure.
Hepatic Impairment: As there is evidence that alendronateis not metabolized or excreted in the bile, no studies were conducted inpatients with hepatic impairment. No dosage adjustment is necessary.
Drug Interactions
Intravenous ranitidine was shown todouble the bioavailability of oral alendronate. The clinical significance ofthis increased bioavailability and whether similar increases will occur inpatients given oral H2-antagonists is unknown.
Inhealthy subjects, oral prednisone (20 mg three times daily for five days) didnot produce a clinically meaningful change in the oral bioavailability ofalendronate (a mean increase ranging from 20 to 44%).
Products containingcalcium and other multivalent cations are likely to interfere with absorption ofalendronate.

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Harderian gland (a retro-orbital gland not present in humans) adenomas wereincreased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicitystudy at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5mg/kg/day (females). These doses are equivalent to approximately 0.1 to 1 timesa maximum recommended daily dose of 40 mg (Paget’s disease) based on surfacearea, mg/m2. The relevance of this finding to humans isunknown.
Parafollicular cell (thyroid) adenomas were increased in high-dosemale rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and3.75 mg/kg body weight. These doses are equivalent to approximately 0.3 and 1times a 40 mg human daily dose based on surface area, mg/m2. The relevance of this finding to humans isunknown.
Alendronate was not genotoxic in the invitro microbial mutagenesis assay with and without metabolic activation,in an in vitro mammalian cell mutagenesis assay, inan in vitro alkaline elution assay in rathepatocytes, and in an in vivo chromosomal aberrationassay in mice. In an in vitro chromosomal aberrationassay in Chinese hamster ovary cells, however, alendronate gave equivocalresults.
Alendronate had no effect on fertility (male or female) in rats atoral doses up to 5 mg/kg/day (approximately 1 times a 40 mg human daily dosebased on surface area, mg/m2).

13.2 Animal Pharmacology & OR Toxicology

The relative inhibitory activities on bone resorption andmineralization of alendronate and etidronate were compared in the Schenk assay,which is based on histological examination of the epiphyses of growing rats. Inthis assay, the lowest dose of alendronate that interfered with bonemineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose.The corresponding ratio for etidronate was one to one. These data suggest thatalendronate administered in therapeutic doses is highly unlikely to induceosteomalacia.

14.1 Treatment of Osteoporosis in Postmenopausal Women

Daily Dosing
The efficacy ofalendronate 10 mg daily was assessed in four clinical trials. Study 1, athree-year, multicenter double-blind, placebo-controlled, US clinical studyenrolled 478 patients with a BMD T-score at or below minus 2.5 with or without aprior vertebral fracture; Study 2, a three-year, multicenter double blindplacebo controlled Multinational clinical study enrolled 516 patients with a BMDT-score at or below minus 2.5 with or without a prior vertebral fracture; Study3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study whichenrolled 2027 postmenopausal patients with at least one baseline vertebralfracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432postmenopausal patients with low bone mass but without a baseline vertebralfracture.
Effect on Fracture Incidence
Toassess the effects of alendronate sodium on the incidence of vertebral fractures(detected by digitized radiography; approximately one third of these wereclinically symptomatic), the U.S. and Multinational studies were combined in ananalysis that compared placebo to the pooled dosage groups of alendronate (5 or10 mg for three years or 20 mg for two years followed by 5 mg for one year).There was a statistically significant reduction in the proportion of patientstreated with alendronate sodium experiencing one or more new vertebral fracturesrelative to those treated with placebo (3.2% vs. 6.2%; a 48% relative riskreduction). A reduction in the total number of new vertebral fractures (4.2 vs.11.3 per 100 patients) was also observed. In the pooled analysis, patients whoreceived alendronate sodium had a loss in stature that was statisticallysignificantly less than was observed in those who received placebo (-3.0 mm vs.-4.6 mm).
The Fracture Intervention Trial (FIT) consisted of two studies inpostmenopausal women: the Three-Year Study of patients who had at least onebaseline radiographic vertebral fracture and the Four-Year Study of patientswith low bone mass but without a baseline vertebral fracture. In both studies ofFIT, 96% of randomized patients completed the studies (i.e., had a closeoutvisit at the scheduled end of the study); approximately 80% of patients werestill taking study medication upon completion.
FractureIntervention Trial: Three-Year Study (patients with at least one baselineradiographic vertebral fracture)
This randomized, double-blind,placebo-controlled, 2027-patient study (alendronate sodium, n=1022; placebo,n=1005) demonstrated that treatment with alendronate sodium resulted instatistically significant reductions in fracture incidence at three years asshown in Table 6.

Furthermore, in this population of patients with baseline vertebral fracture,treatment with alendronate sodium significantly reduced the incidence ofhospitalizations (25.0% vs. 30.7%).
In the Three-Year Study of FIT, fracturesof the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of1022 patients on alendronate sodium, p=0.047. Figure 1 displays the cumulativeincidence of hip fractures in this study.

Fracture Intervention Trial: Four-Year Study (patientswith low bone mass but without a baseline radiographic vertebralfracture)
This randomized, double-blind, placebo-controlled,4432-patient study (alendronate sodium, n=2214; placebo, n=2218) furtherinvestigated the reduction in fracture incidence due to alendronate sodium. Theintent of the study was to recruit women with osteoporosis, defined as abaseline femoral neck BMD at least two standard deviations below the mean foryoung adult women. However, due to subsequent revisions to the normative valuesfor femoral neck BMD, 31% of patients were found not to meet this entrycriterion and thus this study included both osteoporotic and non-osteoporoticwomen. The results are shown in Table 7 for the patients withosteoporosis.

Fracture Results Across Studies
In theThree-Year Study of FIT, alendronate sodium reduced the percentage of womenexperiencing at least one new radiographic vertebral fracture from 15.0% to 7.9%(47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, thepercentage was 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% relativerisk 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 combined U.S./Multinationalstudies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in theThree-Year Study of FIT. In the Four-Year Study of FIT, alendronate sodiumreduced the percentage of osteoporotic women experiencing multiple vertebralfractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).
Thus,alendronate sodium reduced the incidence of radiographic vertebral fractures inosteoporotic women whether or not they had a previous radiographic vertebralfracture.
Effect on Bone Mineral Density
Thebone mineral density efficacy of alendronate 10 mg once daily in postmenopausalwomen, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineraldensity [BMD] of at least 2 standard deviations below the premenopausal mean)was demonstrated in four double-blind, placebo-controlled clinical studies oftwo or three years’ duration.
Figure 2 shows the mean increases in BMD of thelumbar spine, femoral neck, and trochanter in patients receiving alendronate 10mg/day relative to placebo-treated patients at three years for each of thesestudies.

At three years significant increases in BMD, relative both to baseline andplacebo, were seen at each measurement site in each study in patients whoreceived alendronate 10 mg/day. Total body BMD also increased significantly ineach study, suggesting that the increases in bone mass of the spine and hip didnot occur at the expense of other skeletal sites. Increases in BMD were evidentas early as three months and continued throughout the three years of treatment.(See Figure 3 for lumbar spine results.) In the two-year extension of thesestudies, treatment of 147 patients with alendronate 10 mg/day resulted incontinued increases in BMD at the lumbar spine and trochanter (absoluteadditional increases between years 3 and 5: lumbar spine, 0.94%; trochanter,0.88%). BMD at the femoral neck, forearm and total body were maintained.Alendronate sodium was similarly effective regardless of age, race, baselinerate of bone turnover, and baseline BMD in the range studied (at least 2standard deviations below the premenopausal mean).

In patients with postmenopausal osteoporosis treated with alendronate 10mg/day for one or two years, the effects of treatment withdrawal were assessed.Following discontinuation, there were no further increases in bone mass and therates of bone loss were similar to those of the placebo groups.
Bone Histology
Bone histology in 270 postmenopausalpatients with osteoporosis treated with alendronate sodium at doses ranging from1 to 20 mg/day for one, two, or three years revealed normal mineralization andstructure, as well as the expected decrease in bone turnover relative toplacebo. These data, together with the normal bone histology and increased bonestrength observed in rats and baboons exposed to long-term alendronatetreatment, support the conclusion that bone formed during therapy withalendronate sodium is of normal quality.
Effect on Height
Alendronate sodium, over athree- or four-year period, was associated with statistically significantreductions in loss of height vs. placebo in patients with and without baselineradiographic vertebral fractures. At the end of the FIT studies thebetween-treatment group differences were 3.2 mm in the Three-Year Study and 1.3mm in the Four-Year Study.
Weekly Dosing
Thetherapeutic equivalence of once weekly alendronate 70 mg (n=519) and alendronate10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenterstudy of postmenopausal women with osteoporosis. In the primary analysis ofcompleters, the mean increases from baseline in lumbar spine BMD at one yearwere 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 two treatment groupswere also similar with regard to BMD increases at other skeletal sites. Theresults of the intention-to-treat analysis were consistent with the primaryanalysis of completers.
Concomitant Use withEstrogen/Hormone Replacement Therapy (HRT)
The effects on BMD oftreatment with alendronate 10 mg once daily and conjugated estrogen (0.625mg/day) either alone or in combination were assessed in a two-year,double-blind, placebo-controlled study of hysterectomized postmenopausalosteoporotic women (n=425). At two years, the increases in lumbar spine BMD frombaseline were significantly greater with the combination (8.3%) than with eitherestrogen or alendronate sodium alone (both 6.0%).
The effects on BMD whenalendronate sodium was added to stable doses (for at least one year) of HRT(estrogen ± progestin) were assessed in a one-year, double-blind,placebo-controlled study in postmenopausal osteoporotic women (n=428). Theaddition of alendronate 10 mg once daily to HRT produced, at one year,significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone(1.1%).
In these studies, significant increases or favorable trends in BMDfor combined therapy compared with HRT alone were seen at the total hip, femoralneck, and trochanter. No significant effect was seen for total bodyBMD.
Histomorphometric studies of transiliac biopsies in 92 subjects showednormal bone architecture. Compared to placebo there was a 98% suppression ofbone turnover (as assessed by mineralizing surface) after 18 months of combinedtreatment with alendronate sodium and HRT, 94% on alendronate sodium alone, and78% on HRT alone. The long-term effects of combined alendronate sodium and HRTon fracture occurrence and fracture healing have not been studied.

14.2 Prevention of Osteoporosis in Postmenopausal Women

Daily Dosing
Prevention of boneloss was demonstrated in two double-blind, placebo-controlled studies ofpostmenopausal women 40-60 years of age. One thousand six hundred nine patients(alendronate 5 mg/day; n=498) who were at least six months postmenopausal wereentered into a two-year study without regard to their baseline BMD. In the otherstudy, 447 patients (alendronate 5 mg/day; n=88), who were between six monthsand three years postmenopause, were treated for up to three years. In theplacebo-treated patients BMD losses of approximately 1% per year were seen atthe spine, hip (femoral neck and trochanter) and total body. In contrast,alendronate 5 mg/day prevented bone loss in the majority of patients and inducedsignificant increases in mean bone mass at each of these sites (see Figure 4).In addition, alendronate 5 mg/day reduced the rate of bone loss at the forearmby approximately half relative to placebo. Alendronate 5 mg/day was similarlyeffective in this population regardless of age, time since menopause, race andbaseline rate of bone turnover.

Bone Histology
Bone histology was normal in the 28patientsbiopsied at the end of three years who received alendronate at doses ofup to 10 mg/day.
Weekly Dosing
Thetherapeutic equivalence of once weekly alendronate 35 mg (n=362) and alendronate5 mg daily (n=361) was demonstrated in a one-year, double-blind, multicenterstudy of postmenopausal women without osteoporosis. In the primary analysis ofcompleters, the mean increases from baseline in lumbar spine BMD at one yearwere 2.9% (2.6, 3.2%; 95% CI) in the 35-mg once-weekly group (n=307) and 3.2%(2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). The two treatment groupswere also similar with regard to BMD increases at other skeletal sites. Theresults of the intention-to-treat analysis were consistent with the primaryanalysis of completers.

14.3 Treatment to Increase Bone Mass in Men with Osteoporosis

The efficacy of alendronate sodium in men with hypogonadal oridiopathic osteoporosis was demonstrated in two clinical studies.
Daily Dosing
A two-year, double-blind,placebo-controlled, multicenter study of alendronate 10 mg once daily enrolled atotal of 241 men between the ages of 31 and 87 (mean, 63). All patients in thetrial had either a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbarspine, or a baseline osteoporotic fracture and a BMD T-score ≤-1 at the femoralneck. At two years, the mean increases relative to placebo in BMD in menreceiving alendronate 10 mg/day were significant at the following sites: lumbarspine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%.Treatment with alendronate sodium also reduced height loss (alendronate sodium,-0.6 mm vs. placebo, -2.4 mm).
WeeklyDosing
A one-year, double-blind, placebo-controlled, multicenter studyof once weekly alendronate 70 mg enrolled a total of 167 men between the ages of38 and 91 (mean, 66). Patients in the study had either a BMD T-score ≤-2 at thefemoral neck and ≤-1 at the lumbar spine, or a BMD T-score ≤-2 at the lumbarspine and ≤-1 at the femoral neck, or a baseline osteoporotic fracture and a BMDT-score ≤-1 at the femoral neck. At one year, the mean increases relative toplacebo in BMD in men receiving alendronate 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 to those seen atone year in the 10 mg once-daily study.
In both studies, BMD responses weresimilar regardless of age (≥65 years vs. <65 years), gonadal function(baseline testosterone <9 ng/dL vs. ≥9 ng/dL), or baseline BMD (femoral neckand lumbar spine T-score ≤-2.5 vs. >-2.5).

14.4 Treatment of Glucocorticoid-Induced Osteoporosis

The efficacy of alendronate 5 and 10 mg once daily in men andwomen receiving glucocorticoids (at least 7.5 mg/day of prednisone orequivalent) was demonstrated in two, one-year, double-blind, randomized,placebo-controlled, multicenter studies of virtually identical design, oneperformed in the United States and the other in 15 different countries(Multinational [which also included alendronate 2.5 mg/day]). These studiesenrolled 232 and 328 patients, respectively, between the ages of 17 and 83 witha variety of glucocorticoid-requiring diseases. Patients received supplementalcalcium and vitamin D. Figure 5 shows the mean increases relative to placebo inBMD of the lumbar spine, femoral neck, and trochanter in patients receivingalendronate 5 mg/day for each study.

After one year, significant increases relative to placebo in BMD were seen inthe combined studies at each of these sites in patients who received alendronate5 mg/day. In the placebo-treated patients, a significant decrease in BMDoccurred at the femoral neck (-1.2%), and smaller decreases were seen at thelumbar spine and trochanter. Total body BMD was maintained with alendronate 5mg/day. The increases in BMD with alendronate 10 mg/day were similar to thosewith alendronate 5 mg/day in all patients except for postmenopausal women notreceiving estrogen therapy. In these women, the increases (relative to placebo)with alendronate 10 mg/day were greater than those with alendronate 5 mg/day atthe lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not atother sites. Alendronate sodium was effective regardless of dose or duration ofglucocorticoid use. In addition, alendronate sodium was similarly effectiveregardless of age (<65 vs. ≥65 years), race (Caucasian vs. other races),gender, underlying disease, baseline BMD, baseline bone turnover, and use with avariety of common medications.
Bone histology was normal in the 49 patientsbiopsied at the end of one year who received alendronate at doses of up to 10mg/day.
Of the original 560 patients in these studies, 208 patients whoremained on at least 7.5 mg/day of prednisone or equivalent continued into aone-year double-blind extension. After two years of treatment, spine BMDincreased by 3.7% and 5.0% relative to placebo with alendronate 5 and 10 mg/day,respectively. Significant increases in BMD (relative to placebo) were alsoobserved at the femoral neck, trochanter, and total body.
After one year,2.3% of patients treated with alendronate 5 or 10 mg/day (pooled) vs. 3.7% ofthose treated with placebo experienced a new vertebral fracture (notsignificant). However, in the population studied for two years, treatment withalendronate (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for oneyear followed by 10 mg for one year) significantly reduced the incidence ofpatients with a new vertebral fracture (alendronate sodium 0.7% vs. placebo6.8%).

14.5 Treatment of Paget's Disease of Bone

The efficacy of alendronate 40 mg once daily for six months wasdemonstrated in two double-blind clinical studies of male and female patientswith moderate to severe Paget’s disease (alkaline phosphatase at least twice theupper limit of normal): a placebo-controlled, multinational study and a U.S.comparative study with etidronate disodium 400 mg/day. Figure 6 shows the meanpercent changes from baseline in serum alkaline phosphatase for up to six monthsof randomized treatment.

At six months the suppression in alkaline phosphatase in patients treated withalendronate sodium was significantly greater than that achieved with etidronateand contrasted with the complete lack of response in placebo-treated patients.Response (defined as either normalization of serum alkaline phosphatase ordecrease from baseline ≥60%) occurred in approximately 85% of patients treatedwith alendronate sodium in the combined studies vs. 30% in the etidronate groupand 0% in the placebo group. Alendronate sodium was similarly effectiveregardless of age, gender, race, prior use of other bisphosphonates, or baselinealkaline phosphatase within the range studied (at least twice the upper limit ofnormal).
Bone histology was evaluated in 33 patients with Paget’s diseasetreated with alendronate 40 mg/day for 6 months. As in patients treated forosteoporosis [see Clinical Studies(14.1)], alendronate sodium did not impair mineralization, and theexpected decrease in the rate of bone turnover was observed. Normal lamellarbone was produced during treatment with alendronate sodium, even wherepreexisting bone was woven and disorganized. Overall, bone histology datasupport the conclusion that bone formed during treatment with alendronate sodiumis of normal quality.

17.1 Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation

Patients should be instructed to take supplemental calcium and vitamin D, ifdaily dietary intake is inadequate. Weight-bearing exercise should be consideredalong with the modification of certain behavioral factors, such as cigarettesmoking and/or excessive alcohol consumption, if these factors exist.

17.2 Dosing Instructions

Patients should be instructed that the expected benefits ofalendronate sodium may only be obtained when it is taken with plain water thefirst thing upon arising for the day at least 30 minutes before the first food,beverage, or medication of the day. Even dosing with orange juice or coffee hasbeen shown to markedly reduce the absorption of alendronate sodium [see Clinical Pharmacology(12.3)].

Patients should not chew or suck on the tablet because of a potential fororopharyngeal ulceration. To facilitate delivery to the stomach and thus reducethe potential for esophageal irritation, patients should be instructed toswallow each tablet of alendronate sodium with a full glass of water (6-8oz).

Patients should be instructed not to lie down for at least 30 minutes anduntil after their first food of the day.

Patients should be specifically instructed not to take alendronate sodium atbedtime or before arising for the day. Patients should be informed that failureto follow these instructions may increase their risk of esophageal problems.

Patients should be instructed that if they develop symptoms of esophagealdisease (such as difficulty or pain upon swallowing, retrosternal pain or new orworsening heartburn) they should stop taking alendronate sodium and consulttheir physician.

Patients should be instructed that if they miss a dose of once weeklyalendronate sodium, they should take one dose on the morning after theyremember. They should not take two doses on the same day but should return totaking one dose once a week, as originally scheduled on their chosenday.

June 27, 2012

LBL035

Manufacturedby:
AustarPharma, LLC,18 Mayfield Avenue
Edison, NJ 08837
For AscendLaboratories, LLC
Montvale, NJ 07645, USA