Alendronate

1 INDICATIONS AND USAGE Alendronate sodium is a bisphosphonate indicated for: Treatment and prevention of osteoporosis in postmenopausal women ( 1.1 , 1.2 ) Treatment to increase bone mass in men with osteoporosis ( 1.3 ) Treatment of glucocorticoid-induced osteoporosis ( 1.4 ) Treatment of Paget's disease of bone ( 1.5 ) Limitations of use: Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use. ( 1.6 ) 1.1 Treatment of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, alendronate sodium tablets, USP increase bone mass and reduce the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1) .] 1.2 Prevention of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the prevention of postmenopausal osteoporosis [see Clinical Studies (14.2) ] . 1.3 Treatment to Increase Bone Mass in Men with Osteoporosis Alendronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3) ] . 1.4 Treatment of Glucocorticoid-Induced Osteoporosis Alendronate sodium tablets, USP are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and 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 treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget's disease of bone who have alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease. [See Clinical Studies (14.5) .] 1.6 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of alendronate sodium tablets, USP for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2 DOSAGE AND ADMINISTRATION Treatment of osteoporosis in postmenopausal women and in men: 10 mg daily or 70 mg tablet once weekly. ( 2.1 , 2.3 ) Prevention of osteoporosis in postmenopausal women: 5 mg daily or 35 mg once weekly. ( 2.2 ) Glucocorticoid-induced osteoporosis: 5 mg daily; or 10 mg daily in postmenopausal women not receiving estrogen. ( 2.4 ) Paget's disease: 40 mg daily for six months. ( 2.5 ) Instruct patients to: ( 2.6 ) Swallow tablets whole with 6-8 ounces plain water at least 30 minutes before the first food, drink, or medication of the day. Not lie down for at least 30 minutes after taking alendronate sodium tablet and until after food. 2.1 Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is: ● one 70 mg (alendronate) tablet once weekly or ● one 10 mg (alendronate) tablet once daily 2.2 Prevention of Osteoporosis in Postmenopausal Women The recommended dosage is: ● one 35 mg (alendronate) tablet once weekly 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 tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg 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 with alendronate sodium tablets may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase. 2.6 Important Administration Instructions Instruct patients to do the following: Take alendronate sodium tablets at least one-half hour before 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 some medications are likely to reduce the absorption of alendronate sodium tablets [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 effect of alendronate sodium tablets by decreasing its absorption into the body. Take alendronate sodium tablets upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, an alendronate sodium tablet should be swallowed with a full glass of water (6-8 ounces). Patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate sodium tablets should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences [see Warnings and Precautions (5.1) and Patient Counseling Information (17.2) ] . 2.7 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium if dietary intake is inadequate [see Warnings and Precautions (5.2) ] . Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. 2.8 Administration Instructions for Missed Doses If a once-weekly dose of alendronate sodium tablet is missed, instruct patients to take one dose on the morning after they remember. They should not take two doses on th …

3 DOSAGE FORMS AND STRENGTHS 5 mg (alendronate) tablets are round, flat face beveled edged, white to off-white tablets; one side debossed "AP209", the other side blank. 10 mg (alendronate) tablets are modified oval, white to off-white tablets; one side debossed "AP208", the other side blank. 35 mg (alendronate) tablets are modified oval, white to off-white tablets; one side debossed "AP207", the other side blank. 70 mg (alendronate) tablets are modified oval, white to off-white tablets; one side debossed "AP205", the other side blank. Tablets: 5 mg, 10 mg, 35 mg and 70 mg ( 3 )

4 CONTRAINDICATIONS Alendronate sodium tablets are contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions ( 5.1 )] Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration ( 2.6 ); Warnings and Precautions ( 5.1 )] Hypocalcemia [see Warnings and Precautions ( 5.2 )] Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see Adverse Reactions ( 6.2 )]. Abnormalities of the esophagus which delay emptying such as stricture or achalasia ( 4 , 5.1 ) Inability to stand/sit upright for at least 30 minutes ( 2.6 , 4 , 5.1 ) Hypocalcemia ( 4 , 5.2 ) Hypersensitivity to any component of this product ( 4 , 6.2 )

6 ADVERSE REACTIONS Most common adverse reactions (greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44 to 84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n=994); Study 3 was the three-year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027) and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate sodium. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 international units Vitamin D per day. Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate sodium group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate sodium group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate sodium group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate sodium or placebo are presented in Table 1. Table 1: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patient United States/ Multinational Studies Fracture Intervention Trial Alendronate Sodium* % (n=196) Placebo % (n=397) Alendronate Sodium** % (n=3236) Placebo % (n=3223) Gastrointestinal abdominal pain 6.6 4.8 1.5 1.5 nausea 3.6 4 1.1 1.5 dyspepsia 3.6 3.5 1.1 1.2 constipation 3.1 1.8 0 0.2 diarrhea 3.1 1.8 0.6 0.3 flatulence 2.6 0.5 0.2 0.3 acid regurgitation 2 4.3 1.1 0.9 esophageal ulcer 1.5 0 0.1 0.1 vomiting 1 1.5 0.2 0.3 dysphagia 1 0 0.1 0.1 abdominal distention 1 0.8 0 0 gastritis 0.5 1.3 0.6 0.7 Musculoskeletal musculoskeletal (bone, muscle or joint) pain 4.1 0.4 0.3 muscle cramp 0 0.2 0.1 Nervous System/Psychiatric headache 2.6 0.2 0.2 dizziness 0 0 0.1 Special Sense taste perversion 0.5 0.1 0 *10 mg/day for three years **5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years Rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated with alendronate (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin, developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49 to 54% had a history of gastrointestinal disorders at baseline and 54 to 89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies. [ See Warnings …

7 DRUG INTERACTIONS Calcium supplements, antacids, or oral medications containing multivalent cations interfere with absorption of alendronate. ( 2.6 , 7.1 ) Use caution when co-prescribing aspirin/nonsteroidal anti-inflammatory drugs that may worsen gastrointestinal irritation. ( 7.2 , 7.3 ) 7.1 Calcium Supplements/Antacids Co-administration of alendronate sodium and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate sodium. Therefore, instruct patients to wait at least one-half hour after taking alendronate sodium before taking any other oral medications. 7.2 Aspirin In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate greater than 10 mg and aspirin-containing products. 7.3 Nonsteroidal Anti-Inflammatory Drugs Alendronate sodium may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate sodium.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue when pregnancy is recognized. ( 8.1 ) Alendronate sodium is not indicated for use in pediatric patients. ( 8.4 ) Alendronate sodium is not recommended in patients with renal impairment (creatinine clearance less than 35 mL/min). ( 5.6 , 8.6 ) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2020 8.1 Pregnancy Risk Summary Available data on the use of alendronate sodium in pregnant women are insufficient to inform a drug- associated risk of adverse maternal or fetal outcomes. Discontinue alendronate sodium when pregnancy is recognized. In animal reproduction studies, daily oral administration of alendronate to rats from before mating through the end of gestation or lactation showed decreased postimplantation survival and decreased pup body weight gain starting at doses equivalent to less than half of the highest recommended 40 mg clinical daily dose (based on body surface area, mg/m 2 ). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 3 times the 40 mg clinical daily dose. No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at doses equivalent to approximately 10 times the 40 mg clinical daily dose. Delayed or failed delivery of offspring, protracted parturition, and late pregnancy maternal and fetal deaths due to maternal hypocalcemia occurred in rats at oral doses as low as one tenth the 40 mg clinical daily dose (see Data ). Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at 2 mg/kg/day and decreased body weight gain starting at 1 mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m 2 . Incidence of incomplete fetal ossification in vertebral, skull, and sternebral bones were increased in rats dosed orally during organogenesis starting at 10 mg/kg/day (approximately 3 times the 40 mg clinical daily dose). No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at up to 35 mg/kg/day (equivalent to approximately 10 times the 40 mg clinical daily dose). Both total and ionized calcium decreased in pregnant rats dosed orally with 15 mg/kg/day alendronate (approximately 4 times the 40 mg clinical daily dose) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia was observed when rats were treated from before mating through gestation starting at 0.5 mg/kg/day (approximately one tenth the 40 mg clinical daily dose). Maternotoxicity (late pregnancy deaths) also occurred in female rats treated orally with 15 mg/kg/day (approximately 4 times the 40 mg clinical daily dose) for varying gestational ti …

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

11 DESCRIPTION Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate. The molecular formula of alendronate sodium is C 4 H 12 NNaO 7 P 2 •3H 2 O and its formula weight is 325.12. The structural formula is: Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Alendronate sodium tablets, USP for oral administration contain 6.53, 13.06, 45.69, or 91.37 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5 mg, 10 mg, 35 mg, and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, Croscarmellose sodium, and magnesium stearate. structure

10 OVERDOSAGE Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m 2 ) and 966 mg/kg (2898 mg/m 2 ), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m 2 ). No specific information is available on the treatment of overdosage with alendronate sodium. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright. Dialysis would not be beneficial.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Alendronate sodium tablets USP, 35 mg (alendronate), are modified oval, white to off-white tablets; one side debossed 'AP207', the other side blank. NDC 60723-207-31 blister packs of 4 with child resistant package. NDC 60723-207-32 unit-of-use packages of 12 with child resistant package. NDC 60723-207-33 unit dose packages of 20. This package not intended for household use. For institutional use only. Alendronate sodium tablets USP, 70 mg (alendronate), are modified oval, white to off-white tablets; one side debossed 'AP205', the other side blank. NDC 60723-205-31 blister packs of 4 with child resistant package. NDC 60723-205-32 unit-of-use packages of 12 with child resistant package. NDC 60723-205-33 unit dose packages of 20. This package not intended for household use. For institutional use only. Storage Store in a well-closed container at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature].

How Supplied Alendronate sodium tablets USP, 35 mg (alendronate), are modified oval, white to off-white tablets; one side debossed 'AP207', the other side blank. NDC 60723-207-31 blister packs of 4 with child resistant package. NDC 60723-207-32 unit-of-use packages of 12 with child resistant package. NDC 60723-207-33 unit dose packages of 20. This package not intended for household use. For institutional use only. Alendronate sodium tablets USP, 70 mg (alendronate), are modified oval, white to off-white tablets; one side debossed 'AP205', the other side blank. NDC 60723-205-31 blister packs of 4 with child resistant package. NDC 60723-205-32 unit-of-use packages of 12 with child resistant package. NDC 60723-205-33 unit dose packages of 20. This package not intended for household use. For institutional use only.