Zoledronic Acid

1 INDICATIONS AND USAGE Zoledronic acid injection is a bisphosphonate indicated for: Treatment and prevention of postmenopausal osteoporosis ( 1.1 , 1.2 ) Treatment to increase bone mass in men with osteoporosis ( 1.3 ) Treatment and prevention of glucocorticoid-induced osteoporosis ( 1.4 ) Treatment of Paget’s disease of bone in men and women (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 Zoledronic acid injection is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, zoledronic acid injection 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, zoledronic acid injection reduces the incidence of new clinical fractures [see Clinical Studies (14.1) ] . 1.2 Prevention of Osteoporosis in Postmenopausal Women Zoledronic acid injection is indicated for prevention of osteoporosis in postmenopausal women [see Clinical Studies (14.2) ] . 1.3 Osteoporosis in Men Zoledronic acid injection is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3) ] . 1.4 Glucocorticoid-Induced Osteoporosis Zoledronic acid injection 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 [see Clinical Studies (14.4) ] . 1.5 Paget's Disease of Bone Zoledronic acid injection 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 [see Clinical Studies (14.5) ] . 1.6 Important Limitations of Use The safety and effectiveness of zoledronic acid injection 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.

2 DOSAGE AND ADMINISTRATION Infusion given intravenously over no less than 15 minutes: Treatment of postmenopausal osteoporosis ( 2.2 ); treatment to increase bone mass in men with osteoporosis ( 2.4 ): treatment and prevention of glucocorticoid-induced osteoporosis ( 2.5 ): 5 mg once a year Prevention of postmenopausal osteoporosis: 5 mg once every 2 years ( 2.3 ) Treatment of Paget’s disease of bone: a single 5 mg infusion. Patients should receive 1,500 mg elemental calcium and 800 international units vitamin D daily (2.6) 2.1 Important Administration Instructions Zoledronic acid injection must be administered as an intravenous infusion over no less than 15 minutes. Patients must be appropriately hydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.3) ]. 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 zoledronic acid injection administration may reduce the incidence of acute-phase reaction symptoms. 2.2 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. 2.3 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. 2.4 Osteoporosis in Men The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes. 2.5 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. 2.6 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 zoledronic acid injection in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with zoledronic acid injection 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. 2.7 Laboratory Testing and Oral Examination Prior to Administration Prior to administration of each dose of zoledronic acid injection, obtain a serum creatinine and creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each zoledronic acid injection dose. Zoledronic acid injection 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 zoledronic acid injection 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 zoledronic acid injection 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 [see Contraindications (4) , Warnings and Precautions (5.3) ] . A routine oral examination should be performed by the prescriber prior to initiation of zoledronic acid injection treatment [see Warnings and Precautions (5.4) ] . 2.8 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 1,500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 internation…

5 WARNINGS AND PRECAUTIONS Products Containing Same Active Ingredient : Patients receiving Zometa should not receive zoledronic acid injection (5.1) Hypocalcemia may worsen during treatment. Patients must be adequately supplemented with calcium and vitamin D (5.2) 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 (2.7 , 5.3) Osteonecrosis of the Jaw (ONJ) has been reported. All patients should have a routine oral exam by the prescriber prior to treatment (5.4) 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 reevaluated in these patients and interruption of bisphosphonate therapy should be considered (5.5) Severe Bone, Joint, and Muscle Pain may occur. Withhold future doses of zoledronic acid if severe symptoms occur (5.6) 5.1 Drug Products With Same Active Ingredient Zoledronic acid injection contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated with Zometa should not be treated with zoledronic acid injection. 5.2 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 zoledronic acid. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients [see Contraindications (4) ] . Hypocalcemia following zoledronic acid 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 [see Dosage and Administration (2.8) , Adverse Reactions (6.1) , Patient Counseling Information (17) ] . All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels [see Dosage and Administration (2.8) , Adverse Reactions (6.1) , Patient Counseling Information (17) ] . 5.3 Renal Impairment A single dose of zoledronic acid should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [see Dosage and Administration (2) ] . Zoledronic acid is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment [see Contraindications (4) ] . If history or physical signs suggest dehydration, zoledronic acid therapy should be withheld until normovolemic status has been achieved [see Adverse Reactions (6.2) ] . Zoledronic acid 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 zoledronic acid 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 [see Adverse Reactions (6.2) ] . Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites that are primarily renally excreted [see Drug Interactions (7.4) ] . Creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula b…

4 CONTRAINDICATIONS Zoledronic acid is contraindicated in patients with the following conditions: Hypocalcemia [see Warnings and Precautions (5.2) ] Creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure [see Warnings and Precautions (5.3) ] . Known hypersensitivity to zoledronic acid or any components of zoledronic acid injection. Hypersensitivity reactions, including urticaria, angioedema, and anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2) ] . Hypocalcemia (4) Patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment (4 , 5.3) Hypersensitivity to any component of zoledronic acid injection (4 , 6.2)

7 DRUG INTERACTIONS No in vivo drug interaction studies have been performed for zoledronic acid. 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 (7.1) Loop Diuretics: May increase risk of hypocalcemia (7.2) Nephrotoxic Drugs: Use with caution (7.3) Drugs Primarily Excreted by the Kidney: Exposure may be increased with renal impairment. Monitor serum creatinine in patients at risk (7.4) 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. 7.2 Loop Diuretics Caution should also be exercised when zoledronic acid is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when zoledronic acid is used with other potentially nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs). 7.4 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 [see Warnings and Precautions (5.3) ] . 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.

8.1 Pregnancy Risk Summary Available data on the use of zoledronic acid in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue zoledronic acid when pregnancy is recognized. In animal reproduction studies, daily subcutaneous administration of zoledronic acid to pregnant rats during organogenesis resulted in increases in fetal skeletal, visceral, and external malformations, decreases in postimplantation survival, and decreases in viable fetuses and fetal weight starting at doses equivalent to 2 times the recommended human 5 mg intravenous dose (based on AUC). Subcutaneous administration of zoledronic acid to rabbits during organogenesis did not cause adverse fetal effects at up to 0.4 times the human 5 mg intravenous dose (based on body surface area, mg/m 2 ), but resulted in maternal mortality and abortion associated with hypocalcemia starting at doses equivalent to 0.04 times the human 5 mg intravenous dose. Subcutaneous dosing of female rats from before mating through gestation and lactation and allowed to deliver caused maternal dystocia and periparturient mortality, increases in stillbirths and neonatal deaths, and reduced pup body weight starting at doses equivalent to 0.1 times the human 5 mg intravenous dose (based on AUC) ( 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 populations 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 In pregnant rats given daily subcutaneous doses of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg during organogenesis, fetal skeletal, visceral, and external malformations, increases in pre-and post-implantation loss, and decreases in viable fetuses and fetal weight were observed at 0.2 and 0.4 mg/kg/day (equivalent to 2 and 4 times the human 5 mg intravenous dose, based on AUC). Adverse fetal skeletal effects at 0.4 mg/kg/day (4 times the human 5 mg dose) included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects at this dose included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were observed in all groups starting at 0.1 mg/kg/day (1.2 times the human 5 mg dose). Signs of maternal toxicity, including reduced body weight and food consumption were observed at 0.4 mg/kg/day (4 times the human 5 mg dose). In pregnant rabbits given daily subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg during gestation, no adverse fetal effects were observed up to 0.1 mg/kg/day (0.4 times the human 5 mg intravenous dose, based on body surface area, mg/m 2 ). Maternal mortality and abortion were observed in all dose groups (starting at 0.04 times the human 5 mg dose). Adverse maternal effects were associated with drug-induced hypocalcemia. In female rats given daily subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg, beginnin…

8.3 Females and Males of Reproductive Potential Infertility There are no data available in humans. Female fertility may be impaired based on animal studies demonstrating adverse effects of zoledronic acid on fertility parameters [see Nonclinical Toxicology (13.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: • Drugs with Same Active Ingredient [see Warnings and Precautions (5.1) ] • Hypocalcemia and Mineral Metabolism [see Warnings and Precautions (5.2) ] • Renal Impairment [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) ] • Musculoskeletal Pain [see Warnings and Precautions (5.6) ] • Patients with Asthma [see Warnings and Precautions (5.7) ] The most common adverse reactions (greater than 10%) were pyrexia, myalgia, headache, arthralgia, pain in extremity (6.1) . Other important adverse reactions were flu-like illness, nausea, vomiting, diarrhea (6.2) , and eye inflammation (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 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 practice. Treatment of Osteoporosis in Postmenopausal Women The safety of zoledronic acid in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65 to 89 years with osteoporosis, diagnosed by BMD or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to zoledronic acid and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1,000 to 1,500 mg of elemental calcium plus 400 to 1,200 international units of vitamin D supplementation per day. The incidence of all-cause mortality was similar between groups: 3.4% in the zoledronic acid group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the zoledronic acid group and 30.1% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the zoledronic acid and placebo groups, respectively. The safety of zoledronic acid in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50 to 95 years; 1065 patients were randomized to zoledronic acid and 1062 patients were randomized to placebo. Zoledronic acid was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions. The incidence of all-cause mortality was 9.6% in the zoledronic acid group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the zoledronic acid group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the zoledronic acid and placebo groups, respectively. Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the zoledronic acid-treated patients than placebo-treated patients in either osteoporosis trial…