Reclast contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is: Zoledronic acid monohydrate is a white crystalline powder. Its molecular formula is C 5 H 10 N 2 O 7 P 2 • H 2 O and a molar mass of 290.1 g/mol. Zoledronic acid monohydrate is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of the Reclast solution for infusion is approximately 6.0–7.0. Reclast Injection is available as a sterile solution in bottles for intravenous infusion. One bottle with 100 mL solution contains 5.330 mg of zoledronic acid monohydrate, equivalent to 5 mg zoledronic acid on an anhydrous basis. Inactive Ingredients : 4950 mg of mannitol, USP; and 30 mg of sodium citrate, USP. Zoledronic acid structural formula

Reclast is a bisphosphonate indicated for: • Treatment and prevention of postmenopausal osteoporosis • Treatment to increase bone mass in men with osteoporosis • Treatment and prevention of glucocorticoid-induced osteoporosis • Treatment of Paget’s disease of bone in men and women 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 1.1 Treatment of Osteoporosis in Postmenopausal Women Reclast is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, Reclast reduces the incidence of fractures (hip, vertebral, and non-vertebral osteoporosis-related fractures). In patients at high risk of fracture, defined as a recent low-trauma hip fracture, Reclast reduces the incidence of new clinical fractures

Prevention of Osteoporosis in Postmenopausal Women Reclast is indicated for prevention of osteoporosis in postmenopausal women

Osteoporosis in Men Reclast is indicated for treatment to increase bone mass in men with osteoporosis

Glucocorticoid-Induced Osteoporosis Reclast is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months

Paget's Disease of Bone Reclast is indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget’s disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease

Important Limitations of Use The safety and effectiveness of Reclast for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy reevaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture reevaluated periodically.

5 mg in a 100 mL ready to infuse solution. 5 mg in a 100 mL ready-to-infuse solution

Infusion given intravenously over no less than 15 minutes: • Treatment of postmenopausal osteoporosis; treatment to increase bone mass in men with osteoporosis: treatment and prevention of glucocorticoid-induced osteoporosis: 5 mg once a year • Prevention of postmenopausal osteoporosis: 5 mg once every 2 years • Treatment of Paget’s disease of bone: a single 5 mg infusion. Patients should receive 1500 mg elemental calcium and 800 international units vitamin D daily 2.1 Important Administration Instructions Reclast injection must be administered as an intravenous infusion over no less than 15 minutes. • Patients must be appropriately hydrated prior to administration of Reclast . • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • Intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line. • Administration of acetaminophen following Reclast administration may reduce the incidence of acute-phase reaction symptoms

Treatment of Osteoporosis in Postmenopausal Women The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes

Prevention of Osteoporosis in Postmenopausal Women The recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes

Osteoporosis in Men The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes

Treatment of Paget’s Disease of Bone The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate. Re-treatment of Paget’s Disease After a single treatment with Reclast in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with Reclast may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice

Laboratory Testing and Oral Examination Prior to Administration • Prior to administration of each dose of Reclast, obtain a serum creatinine and creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Reclast dose. Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment. A 5 mg dose of Reclast administered intravenously is recommended for patients with creatinine clearance greater than or equal to 35 mL/min. There are no safety or efficacy data to support the adjustment of the Reclast dose based on baseline renal function. Therefore, no dose adjustment is required in patients with creatinine clearance greater than or equal to 35 mL/min . • A routine oral examination should be performed by the prescriber prior to initiation of Reclast treatment

Calcium and Vitamin D Supplementation • Instruct patients being treated for Paget’s disease of bone on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia. All patients should take 1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 international units vitamin D daily, particularly in the 2 weeks following Reclast administration . • Instruct patients being treated for osteoporosis to take supplemental calcium and vitamin D if their dietary intake is inadequate. An average of at least 1200 mg calcium and 800-1000 international units vitamin D daily is recommended

Method of Administration The Reclast infusion time must not be less than 15 minutes given over a constant infusion rate. The intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line. Reclast solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line. If refrigerated, allow the refrigerated solution to reach room temperature before administration. After opening, the solution is stable for 24 hours at 2°C to 8°C (36°F to 46°F) .

• Products Containing Same Active Ingredient: Patients receiving Zometa should not receive Reclast • Hypocalcemia may worsen during treatment . Patients must be adequately supplemented with calcium and vitamin D • Renal Impairment: A single dose should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Renal toxicity may be greater in patients with underlying renal impairment or with other risk factors, including advanced age or dehydration. Monitor creatinine clearance before each dose • Osteonecrosis of the Jaw (ONJ) has been reported. All patients should have a routine oral exam by the prescriber prior to treatment • Atypical Fractures Including Femoral Fractures have been reported. Patients with thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered • Severe Bone, Joint, and Muscle Pain may occur. Withhold future doses of Reclast if severe symptoms occur 5.1 Drug Products With Same Active Ingredient Reclast contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated with Zometa should not be treated with Reclast

Hypocalcemia and Mineral Metabolism Preexisting hypocalcemia and disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery; malabsorption syndromes, excision of small intestine) must be effectively treated before initiating therapy with Reclast. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients . Hypocalcemia following Reclast administration is a significant risk in Paget’s disease. All patients should be instructed about the symptoms of hypocalcemia and the importance of calcium and vitamin D supplementation in maintaining serum calcium levels . All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels

Renal Impairment A single dose of Reclast should not exceed 5 mg and the duration of infusion should be no less than 15 minutes . Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment . If history or physical signs suggest dehydration, Reclast therapy should be withheld until normovolemic status has been achieved . Reclast should be used with caution in patients with chronic renal impairment. Acute renal impairment, including renal failure, has been observed following the administration of zoledronic acid, especially in patients with preexisting renal compromise, advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration occurring before or after Reclast administration. Acute renal failure (ARF) has been observed in patients after a single administration. Rare reports of hospitalization and/or dialysis or fatal outcome occurred in patients with underlying moderate to severe renal impairment or with any of the risk factors described in this section . Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites that are primarily renally excreted . Creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Reclast dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; interim monitoring of creatinine clearance should be performed in at-risk patients. Elderly patients and those receiving diuretic therapy are at increased risk of acute renal failure. These patients should have their fluid status assessed and be appropriately hydrated prior to administration of Reclast. Reclast should be used with caution with other nephrotoxic drugs . Consider monitoring creatinine clearance in patients at-risk for ARF who are taking concomitant medications that are primarily excreted by the kidney

Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, preexisting dental disease or infection, anemia, coagulopathy). The risk of ONJ may increase with duration of exposure to bisphosphonates. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment

Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including zolendronic acid, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered

Musculoskeletal Pain In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Reclast. The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future Reclast treatment if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate

Patients With Asthma While not observed in clinical trials with Reclast, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Use Reclast with caution in aspirin-sensitive patients.

No in vivo drug interaction studies have been performed for Reclast. In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood. In vitro mean zoledronic acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. • Aminoglycosides: May lower serum calcium for prolonged periods • Loop Diuretics: May increase risk of hypocalcemia • Nephrotoxic Drugs: Use with caution • Drugs Primarily Excreted by the Kidney: Exposure may be increased with renal impairment. Monitor serum creatinine in patients at risk 7.1 Aminoglycosides Caution is advised when bisphosphonates, including zoledronic acid, are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in zoledronic acid clinical trials

Loop Diuretics Caution should also be exercised when Reclast is used in combination with loop diuretics due to an increased risk of hypocalcemia

Nephrotoxic Drugs Caution is indicated when Reclast is used with other potentially nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs)

Drugs Primarily Excreted by the Kidney Renal impairment has been observed following the administration of zoledronic acid in patients with preexisting renal compromise or other risk factors . In patients with renal impairment, the exposure to concomitant medications that are primarily renally excreted (e.g., digoxin) may increase. Consider monitoring serum creatinine in patients at risk for renal impairment who are taking concomitant medications that are primarily excreted by the kidney.