Zoledronic acid

Warnings and Precautions, Atypical Fractures Including Femoral Fractures ( 5.5 )..........................02/2026

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 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hypercalcemia of malignancy (2.1) • 4 mg as a single-use intravenous infusion over no less than 15 minutes. • 4 mg as retreatment after a minimum of 7 days. Multiple myeloma and bone metastasis from solid tumors. (2.2) • 4 mg as a single-use intravenous infusion over no less than 15 minutes every 3 to 4 weeks for patients with creatinine clearance of greater than 60 mL/min. • Reduce the dose for patients with renal impairment. • Coadminister oral calcium supplements of 500 mg and a multiple vitamin containing 400 International units of vitamin D daily. Administer through a separate vented infusion line and do not allow to come in contact with any calcium or divalent cation-containing solutions. (2.3) 2.1 Hypercalcemia of Malignancy The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes . Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment. Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL). Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [ see Warnings and Precautions (5.2)] . Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic Acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [ see Warnings and Precautions (5.2) ]. 2.2 Multiple Myeloma and Bone Metastases of Solid Tumors The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known. Upon treatment initiation, the recommended Zoledronic Acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)] . Table 1: Reduced Doses for Patients with Baseline CrCl Less than or Equal to 60 mL/min Baseline Creatinine Clearance (mL/min) Zoledronic Acid Injection Recommended Dose (mg)* greater than 60 4 50 to 60 3.5 40 to 49 3.3 30 to 39 3 *Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 …

3 DOSAGE FORMS AND STRENGTHS Injection: 4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior to intravenous infusion. Injection: 4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior to intravenous infusion ( 3 )

4 CONTRAINDICATIONS Zoledronic acid injection 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 )

6 ADVERSE REACTIONS The most common adverse events (greater than 25%) were nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, and dyspnea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 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. Hypercalcemia of Malignancy The safety of zoledronic acid injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either zoledronic acid injection 4 mg given as a 5-minute intravenous infusion (n = 86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n = 103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of zoledronic acid injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when zoledronic acid injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic Acid Injection should be administered by intravenous infusion over no less than 15 minutes [ see Warnings and Precautions (5.3), Dosage and Administration (2.4) ]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4). Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with zoledronic acid injection 4 mg or pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 4: Percentage of Patients With Adverse Events Greater Than or Equal to 10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zoledronic Acid Injection 4 mg Pamidronate n (%) 90 mg n (%) Patients Studied Total No. of Patients Studied 86 (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea 25 (29) 28 (27) Constipation 23 (27) 13 (13) Diarrhea 15 (17) 17 (17) Abdominal Pain 14 (16) 13 (13) Vomiting 12 (14) 17 (17) Anorexia 8 (9) 14 (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2) Hypokalemia 10 (12) 16 (16) Hypomagnesemia 9 (11) 5 (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia 13 (15) 10 (10) Anxiety 12 (14) 8 (8) Confusion 11 (13) 13 (13) Agitation 11 (13) 8 (8) Respiratory Dyspnea 19 (22) 20 (19) Coughing 10 (12) 12 (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with zoledronic acid injection 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment wit …

7 DRUG INTERACTIONS No in vivo drug interaction studies have been performed for zoledronic acid injection. 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 injection is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when zoledronic acid injection 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 USE IN SPECIFIC POPULATIONS . • Pregnancy: Discontinue when pregnancy is recognized ( 8.1 ) • Pediatric Use: Not indicated for use in pediatric patients ( 8.4 ) • Geriatric Use: Special care to monitor renal function ( 8.5 ) 8.1 Pregnancy Risk Summary Available data on the use of zoledronic acid injection in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue zoledronic acid injection 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% to 4% and 15% to 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 morta …

12.1 Mechanism of Action Zoledronic acid injection is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

11 DESCRIPTION Zoledronic Acid Injection 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 is a white crystalline powder. Its molecular formula is C 5 H 10 N 2 O 7 P 2 • H 2 O and its molar mass is 290.1g/mol. Zoledronic acid 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 a 0.7% solution of zoledronic acid in water is approximately 2.0. Zoledronic Acid Injection is available in 5 mL vials as a sterile liquid solution for dilution prior to intravenous infusion. Each 5 mL solution for dilution prior to intravenous infusion vial contains 4.264 mg zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis, 220 mg of mannitol, USP, water for injection, and 24 mg of sodium citrate, USP. Inactive Ingredients: mannitol, USP, as bulking agent, water for injection and sodium citrate, USP, as buffering agent. Zoledronic acid structural formula

10 OVERDOSAGE Clinical experience with acute overdosage of zoledronic acid injection is limited. Two patients received zoledronic acid injection 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin's lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100 unit/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of zoledronic acid injection 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, zoledronic acid injection 8 mg has been shown to be associated with an increased risk of renal toxicity compared to zoledronic acid injection 4 mg, even when given as a 15- minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage and Administration ( 2.4 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Zoledronic acid injection is supplied as follows: NDC Zoledronic Acid Injection (0.05 mg per mL) Package Factor 72266-152-01 5 mg per 100 mL ready-to-infuse solution in a single-dose bag 1 bag per carton Handling After entering the IV administration port, the solution is stable for 24 hours at 2° to 8°C (36° to 46°F). If refrigerated, allow the refrigerated solution to reach room temperature before administration. Storage Conditions Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Single-dose only. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free. The container closure is not made with natural rubber latex.