Zoledronic Acid

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.

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 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. Creatinine clearance (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* greater than 60 4 mg 50 to 60 3.5 mg 40 to 49 3.3 mg 30 to 39 3 mg *Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 mL/min) During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL For patients with abnormal baseline creatinine, increase of 1 mg/dL In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily. 2.3. Preparation of Solution Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs. 4 mg per 100 mL Single-Use Ready-to-Use Bottle Bottles of zoledronic acid injection ready-to-use solution for infusion contain overfill allowing for the administration of 100 mL of solution (equivalent to 4 mg zoledronic acid). This solution is ready-to-use and may be administered directly to the patient without further preparation. For single-use only. To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection solution from the bottle (see Table 2) and replace with an equal volume of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. Administer the newly-prepared dose-adjusted solution to the patient by infusion. Follow proper aseptic technique. Properly discard previously withdrawn volume of ready-to-use solution - do not store or reuse. Table 2: Preparation of Reduced Doses – Zoledronic Acid Injection ready-to-use-bottle Remove and discard the following Zoledronic acid injection ready-to-use solution (mL) Replace with the following volume of sterile 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP (mL) Dose (mg) 12 12 3.5 18 18 3.3 25 25 3 If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C - 8°C (36°F - 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours. 2.4. Method of Administration Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions ( 5.3 ) ] . In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

WARNINGS AND PRECAUTIONS Patients being treated with zoledronic acid injection should not be treated with Reclast ® . ( 5.1 ) Adequately rehydrate patients with hypercalcemia of malignancy prior to administration of zoledronic acid injection and monitor electrolytes during treatment. ( 5.2 ) Renal toxicity may be greater in patients with renal impairment. Do not use doses greater than 4 mg. Treatment in patients with severe renal impairment is not recommended. Monitor serum creatinine before each dose. ( 5.3 ) Osteonecrosis of the jaw (ONJ) has been reported. Preventive dental exams should be performed before starting zoledronic acid injection. Avoid invasive dental procedures. ( 5.4 ) Severe incapacitating bone, joint, and/or muscle pain may occur. Discontinue zoledronic acid injection if severe symptoms occur. ( 5.5 ) Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy. These fractures may occur after minimal or no trauma. Evaluate patients with thigh or groin pain to rule out a femoral fracture. Consider drug discontinuation in patients suspected to have an atypical femur fracture. ( 5.6 ) Hypocalcemia: Correct before initiating zoledronic acid injection. Adequately supplement patients with calcium and vitamin D. Monitor serum calcium closely with concomitant administration of other drugs known to cause hypocalcemia to avoid severe or life-threatening hypocalcemia ( 5.9 ) Zoledronic acid injection can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Drugs with Same Active Ingredient or in the Same Drug Class Zoledronic acid injection contains the same active ingredient as found in Reclast ® (zoledronic acid). Patients being treated with zoledronic acid injection should not be treated with Reclast or other bisphosphonates. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of zoledronic acid injection. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with zoledronic acid injection in order to avoid hypocalcemia. Zoledronic acid injection should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with zoledronic acid injection. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zoledronic acid injection is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions ( 6.1 ) ]. Preexisting renal insufficiency and multiple cycles of zoledronic acid injection and other bisphosphonates are risk factors for subsequent renal deterioration with zoledronic acid injection. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zoledronic acid injection treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment [ see Dosage and Administration (2.1) ]. In the clinical studies, patients with serum creatinine greater than 400 µmol/L or greater than 4.5 mg/dL were excluded. Zoledronic acid injection treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 µmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with zoledronic acid injection 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology ( 12.3 ) ]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including zoledronic acid injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. The risk of ONJ may increase with duration of exposure to bisphosphonates. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients 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. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions ( 6.2 ) ]. 5.5 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including zoledronic acid injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use 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 [see Adverse Reactions ( 6.2 ) ]. 5.6 Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including zoledronic acid injection. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of zoledronic acid injection therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy. 5.7 Patients with Asthma While not observed in clinical trials with zoledronic acid injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphon

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 )

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 pre-existing 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.

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 Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) 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 to 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 n (%) Pamidronate 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 with zoledronic acid injection. Acute Phase Reaction Within three days after zoledronic acid injection administration, an acute phase reaction has been reported in patients, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness. These symptoms usually resolve within a few days. Pyrexia has been the most commonly associated symptom, occurring in 44% of patients. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia, and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of zoledronic acid injection in patients with HCM are shown in Table 5 and 6. Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Laboratory Parameter Grade 3 Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 2/86 (2%) 3/100 (3%) Hypocalcemia 2 1/86 (1%) 2/100 (2%) Hypophosphatemia 3 36/70 (51%) 27/81 (33%) Hypomagnesemia 4 0/71 0 0/84 0 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal). 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL). 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL). 4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L). 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Laboratory Parameter Grade 4 Zoledronic acid injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 0/86 0 1/100 (1%) Hypocalcemia 2 0/86 0 0/100 0 Hypophosphatemia 3 1/70 (1%) 4/81 (5%) Hypomagnesemia 4 0/71 0 1/84 (1%) Injection-Site Reactions Local reactions at the infusion-site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24 to 48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including zoledronic acid injection. No cases of iritis, scleritis, or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions ( 6.2 )] . Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with zoledronic acid injection 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for zoledronic acid injection 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug. Table 7: Percentage of Patients with Adverse Events Greater Than or Equal to 10% Reported in Three Bone Metastases Clinical Trials by Body System Zoledronic Acid Injection 4 mg n (%) Pamidronate 90 mg n (%) Placebo n(%) Patients Studied Total No. of Patients Total No. of Patients with any AE 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.