FOSAMAX PLUS D

Warnings and Precautions, Atypical Fractures Including Femoral Fractures ( 5.5 ) 2/2026

1 INDICATIONS AND USAGE FOSAMAX PLUS D is a combination of a bisphosphonate and vitamin D indicated for: Treatment of osteoporosis in postmenopausal women ( 1.1 ) Treatment to increase bone mass in men with osteoporosis ( 1.2 ) Limitations of use : FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency. ( 1.3 ) Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use. ( 1.3 ) 1.1 Treatment of Osteoporosis in Postmenopausal Women FOSAMAX ® PLUS D is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, FOSAMAX PLUS D increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1) .] 1.2 Treatment to Increase Bone Mass in Men with Osteoporosis FOSAMAX PLUS D is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.2) ] . 1.3 Important Limitations of Use FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency. The optimal duration of use has not been determined. The safety and effectiveness of FOSAMAX PLUS D 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 70 mg alendronate/2800 international units vitamin D 3 or 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. ( 2.1 , 2.2 ) Instruct patients to: ( 2.3 ) 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 FOSAMAX PLUS D and until after food. 2.1 Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is one 70 mg alendronate/2800 international units vitamin D 3 or one 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. For most osteoporotic women, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D 3 ) once weekly. 2.2 Treatment to Increase Bone Mass in Men with Osteoporosis The recommended dosage is one 70 mg alendronate/2800 international units vitamin D 3 or one 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. For most osteoporotic men, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D 3 ) once weekly. 2.3 Important Administration Instructions Instruct patients to do the following: Take FOSAMAX PLUS D at least one-half hour before the first food, beverage, or medication of the day with plain water only [see Patient Counseling Information (17) ] . Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate [see Drug Interactions (7.1) ] . Waiting less than 30 minutes, or taking FOSAMAX PLUS D with food, beverages (other than plain water) or other medications will lessen the effect of alendronate by decreasing its absorption into the body. Take FOSAMAX PLUS D upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, a FOSAMAX PLUS D 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. FOSAMAX PLUS D 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) ] . 2.4 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 additional 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. The recommended intake of vitamin D is 400-800 international units daily. FOSAMAX PLUS D 70 mg/2800 international units and 70 mg/5600 international units are intended to provide seven days' worth of 400 and 800 international units daily vitamin D in a single, once-weekly dose, respectively. 2.5 Administration Instructions for Missed Doses If a once-weekly dose of FOSAMAX PLUS D is missed, instruct patients to take one tablet on the morning after they remember. They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.

3 DOSAGE FORMS AND STRENGTHS 70 mg/2800 international units tablets are white to off-white, modified capsule-shaped tablets with code 710 on one side and an outline of a bone image on the other. 70 mg/5600 international units tablets are white to off-white, modified rectangle-shaped tablets with code 270 on one side and an outline of a bone image on the other. Tablets: 70 mg/2800 international units and 70 mg/5600 international units ( 3 )

4 CONTRAINDICATIONS FOSAMAX PLUS D is contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1) ] Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2.3) , Warnings and Precautions (5.1) ] 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 ( 2.3 , 4 , 5.1 ) Hypocalcemia ( 4 , 5.2 ) Hypersensitivity to any component of this product ( 4 , 6.2 )

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ] Mineral Metabolism [see Warnings and Precautions (5.2) ] Musculoskeletal Pain [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.5) ] Renal Impairment [see Warnings and Precautions (5.6) ] Most common adverse reactions (greater than or equal to 3%) for alendronate are: abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. FOSAMAX Treatment of Osteoporosis in Postmenopausal Women FOSAMAX Daily The safety of FOSAMAX in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational; n=994); Study 3 was the three-year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027); and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to FOSAMAX. 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 FOSAMAX group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the FOSAMAX 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 FOSAMAX 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 FOSAMAX or placebo are presented in Table 1. Table 1: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients United States/Multinational Studies Fracture Intervention Trial FOSAMAX 10 mg/day for three years % (n=196) Placebo % (n=397) FOSAMAX 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years % (n=3236) Placebo % (n=3223) Gastrointestinal abdominal pain nausea dyspepsia constipation diarrhea flatulence acid regurgitation esophageal ulcer vomiting dysphagia abdominal distention gastritis 6.6 3.6 3.6 3.1 3.1 2.6 2.0 1.5 1.0 1.0 1.0 0.5 4.8 4.0 3.5 1.8 1.8 0.5 4.3 0.0 1.5 0.0 0.8 1.3 1.5 1.1 1.1 0.0 0.6 0.2 1.1 0.1 0.2 0.1 0.0 0.6 1.5 1.5 1.2 0.2 0.3 0.3 0.9 0.1 0.3 0.1 0.0 0.7 Musculoskeletal musculoskeletal (bone, muscle or joint) pain muscle cramp 4.1 0.0 2.5 1.0 0.4 0.2 0.3 0.1 Nervous System/Psychiatric headache dizziness 2.6 0.0 1.5 1.0 0.2 0.0 0.2 0.1 Special Senses taste perversion 0.5 1.0 0.1 0.0 Rash and erythema have occurred. Gastrointestinal Adverse …

7 DRUG INTERACTIONS Calcium supplements/antacids or oral medications containing multivalent cations interfere with absorption of alendronate. ( 2.3 , 7.1 ) Use caution when co-prescribing aspirin/nonsteroidal anti-inflammatory drugs that may worsen gastrointestinal irritation. ( 7.2 , 7.3 ) Some drugs may impair the absorption or increase the catabolism of cholecalciferol (vitamin D 3 ). Additional vitamin D supplementation should be considered. ( 7.4 , 7.5 , 12.3 ) 7.1 Calcium Supplements/Antacids Co-administration of FOSAMAX PLUS D and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate. Therefore, instruct patients to wait at least one-half hour after taking FOSAMAX PLUS D 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 FOSAMAX greater than 10 mg and aspirin-containing products. 7.3 Nonsteroidal Anti-Inflammatory Drugs FOSAMAX PLUS D 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 FOSAMAX 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 FOSAMAX PLUS D. 7.4 Drugs that May Impair the Absorption of Cholecalciferol Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Additional vitamin D supplementation should be considered [see Clinical Pharmacology (12.3) ] . 7.5 Drugs that May Increase the Catabolism of Cholecalciferol Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D. Additional vitamin D supplementation should be considered [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue when pregnancy is recognized. ( 8.1 ) FOSAMAX PLUS D is not indicated for use in pediatric patients. ( 8.4 ) FOSAMAX PLUS D is not recommended in patients with severe renal impairment (creatinine clearance less than 35 mL/min). ( 5.6 , 8.6 ) 8.1 Pregnancy Risk Summary Available data on the use of FOSAMAX plus vitamin D use in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue FOSAMAX PLUS D when pregnancy is recognized. Alendronate Sodium 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. Cholecalciferol No data are available for cholecalciferol (vitamin D 3 ) in animals. However, administration of high doses of vitamin D 2 to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of high doses of vitamin D 2 to pregnant rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally. (See Data .) The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Alendronate Sodium 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 d …

12.1 Mechanism of Action Alendronate Sodium 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. Cholecalciferol Vitamin D 3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D 3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D 3 . In the absence of adequate sunlight exposure, vitamin D 3 is an essential dietary nutrient. Vitamin D 3 in skin and dietary vitamin D 3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D 3 in the liver. Conversion to the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D 3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D 3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption. Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.

11 DESCRIPTION FOSAMAX PLUS D contains alendronate sodium, a bisphosphonate, and cholecalciferol (vitamin D 3 ). 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 empirical 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. Cholecalciferol (vitamin D 3 ) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25 dihydroxyvitamin D 3 ). The chemical name of cholecalciferol is (3β,5 Z ,7 E )-9,10-secocholesta-5,7,10(19)-trien-3-ol. The empirical formula of cholecalciferol is C 27 H 44 O and its molecular weight is 384.6. The structural formula is: Cholecalciferol is a white, crystalline, odorless powder. Cholecalciferol is practically insoluble in water, freely soluble in usual organic solvents, and slightly soluble in vegetable oils. FOSAMAX PLUS D for oral administration contains 91.37 mg of alendronate monosodium salt trihydrate, the molar equivalent of 70 mg of free acid, and 70 or 140 mcg of cholecalciferol, equivalent to 2800 or 5600 international units vitamin D, respectively. Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal silicon dioxide, magnesium stearate, butylated hydroxytoluene, modified food starch, and sodium aluminum silicate. image of alendronate sodium structural formula image of cholecalciferol structural formula

10 OVERDOSAGE Alendronate Sodium Significant lethality after single oral doses with alendronate 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. 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. Cholecalciferol Significant lethality occurred in mice treated with a single high oral dose of calcitriol (4 mg/kg), the hormonal metabolite of cholecalciferol. There is limited information regarding doses of cholecalciferol associated with acute toxicity, although intermittent (yearly or twice yearly) single doses of ergocalciferol (vitamin D 2 ) as high as 600,000 international units have been given without reports of toxicity. Signs and symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness, and lethargy. Serum and urine calcium levels should be monitored in patients with suspected vitamin D toxicity. Standard therapy includes restriction of dietary calcium, hydration, and systemic glucocorticoids in patients with severe hypercalcemia. Dialysis to remove vitamin D would not be beneficial.

16 HOW SUPPLIED/STORAGE AND HANDLING FOSAMAX PLUS D 70 mg/2800 international units are white to off-white, modified capsule-shaped tablets with code 710 on one side and an outline of a bone image on the other. They are supplied as follows: NDC 78206-137-01 unit of use blister packages of 4. FOSAMAX PLUS D 70 mg/5600 international units are white to off-white, modified rectangle-shaped tablets with code 270 on one side and an outline of a bone image on the other. They are supplied as follows: NDC 78206-136-01 unit of use blister packages of 4 Storage Store at 68°F to 77°F (20°C to 25°C), excursions between 59°F to 86°F (15°C to 30°C). are allowed. [See USP Controlled Room Temperature.] Protect from moisture and light. Store tablets in the original blister package until use.