FDA label d3e7ad5b-4792-46bb-a229-bb0a0bbe38e8

5 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 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 ) Zoledronic Acid Injection can cause fetal harm. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. ( 5.9 , 8.1 ) 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 ( 5.10 ) 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 )] . Pre-existing 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 bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zoledronic Acid Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic Acid Injection in these patients. 5.9 Use in Pregnancy Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Zoledronic Acid Injection may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations ( 8.1 )] . 5.10 Hypocalcemia Hypocalcemia has been reported in patients treated with Zoledronic Acid Injection. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Caution is advised when Zoledronic Acid Injection is administered with drugs known to cause hypocalcemia, as severe hypocalcemia may develop, [see Drug Interactions ( 7 )]. Serum calcium should be measured and hypocalcemia must be corrected before initiating Zoledronic Acid Injection. Adequately supplement patients with calcium and vitamin D.

<table ID="t7" width="100%"> <caption>Table 7: Percentage of Patients with Adverse Events &#x2265;10% Reported in Three Bone Metastases Clinical Trials by Body System </caption> <col width="36.982%" align="left"/> <col width="10.503%" align="left"/> <col width="10.503%" align="left"/> <col width="10.503%" align="left"/> <col width="10.503%" align="left"/> <col width="10.503%" align="left"/> <col width="10.503%" align="left"/> <tbody> <tr> <td align="left" valign="top"/> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Zoledronic Acid Injection</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Pamidronate</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td align="left" valign="top"/> <td colspan="2" align="center" valign="top"> <content styleCode="bold">4 mg</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">90 mg</content> </td> <td colspan="2" align="center" valign="top"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule"/> <td colspan="2" align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n (%)</content> </td> <td colspan="2" align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n (%)</content> </td> <td colspan="2" align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n (%)</content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Patients Studied</content> </td> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> </tr> <tr> <td align="left" valign="top">Total No. of Patients </td> <td align="center" valign="top">1031 </td> <td align="center" valign="top">(100) </td> <td align="center" valign="top">556 </td> <td align="center" valign="top">(100) </td> <td align="center" valign="top">455 </td> <td align="center" valign="top">(100) </td> </tr> <tr> <td align="left" valign="top">Total No. of Patients with any AE </td> <td align="center" valign="top">1015 </td> <td align="center" valign="top">(98) </td> <td align="center" valign="top">548 </td> <td align="center" valign="top">(99) </td> <td align="center" valign="top">445 </td> <td align="center" valign="top">(98) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Blood and Lymphatic</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Anemia </td> <td align="center" valign="top">344 </td> <td align="center" valign="top">(33) </td> <td align="center" valign="top">175 </td> <td align="center" valign="top">(32) </td> <td align="center" valign="top">128 </td> <td align="center" valign="top">(28) </td> </tr> <tr> <td align="left" valign="top">Neutropenia </td> <td align="center" valign="top">124 </td> <td align="center" valign="top">(12) </td> <td align="center" valign="top">83 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">35 </td> <td align="center" valign="top">(8) </td> </tr> <tr> <td align="left" valign="top">Thrombocytopenia </td> <td align="center" valign="top">102 </td> <td align="center" valign="top">(10) </td> <td align="center" valign="top">53 </td> <td align="center" valign="top">(10) </td> <td align="center" valign="top">20 </td> <td align="center" valign="top">(4) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Gastrointestinal</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Nausea </td> <td align="center" valign="top">476 </td> <td align="center" valign="top">(46) </td> <td align="center" valign="top">266 </td> <td align="center" valign="top">(48) </td> <td align="center" valign="top">171 </td> <td align="center" valign="top">(38) </td> </tr> <tr> <td align="left" valign="top">Vomiting </td> <td align="center" valign="top">333 </td> <td align="center" valign="top">(32) </td> <td align="center" valign="top">183 </td> <td align="center" valign="top">(33) </td> <td align="center" valign="top">122 </td> <td align="center" valign="top">(27) </td> </tr> <tr> <td align="left" valign="top">Constipation </td> <td align="center" valign="top">320 </td> <td align="center" valign="top">(31) </td> <td align="center" valign="top">162 </td> <td align="center" valign="top">(29) </td> <td align="center" valign="top">174 </td> <td align="center" valign="top">(38) </td> </tr> <tr> <td align="left" valign="top">Diarrhea </td> <td align="center" valign="top">249 </td> <td align="center" valign="top">(24) </td> <td align="center" valign="top">162 </td> <td align="center" valign="top">(29) </td> <td align="center" valign="top">83 </td> <td align="center" valign="top">(18) </td> </tr> <tr> <td align="left" valign="top">Abdominal Pain </td> <td align="center" valign="top">143 </td> <td align="center" valign="top">(14) </td> <td align="center" valign="top">81 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">48 </td> <td align="center" valign="top">(11) </td> </tr> <tr> <td align="left" valign="top">Dyspepsia </td> <td align="center" valign="top">105 </td> <td align="center" valign="top">(10) </td> <td align="center" valign="top">74 </td> <td align="center" valign="top">(13) </td> <td align="center" valign="top">31 </td> <td align="center" valign="top">(7) </td> </tr> <tr> <td align="left" valign="top">Stomatitis </td> <td align="center" valign="top">86 </td> <td align="center" valign="top">(8) </td> <td align="center" valign="top">65 </td> <td align="center" valign="top">(12) </td> <td align="center" valign="top">14 </td> <td align="center" valign="top">(3) </td> </tr> <tr> <td align="left" valign="top">Sore Throat </td> <td align="center" valign="top">82 </td> <td align="center" valign="top">(8) </td> <td align="center" valign="top">61 </td> <td align="center" valign="top">(11) </td> <td align="center" valign="top">17 </td> <td align="center" valign="top">(4) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">General Disorders and Administration Site</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Fatigue </td> <td align="center" valign="top">398 </td> <td align="center" valign="top">(39) </td> <td align="center" valign="top">240 </td> <td align="center" valign="top">(43) </td> <td align="center" valign="top">130 </td> <td align="center" valign="top">(29) </td> </tr> <tr> <td align="left" valign="top">Pyrexia </td> <td align="center" valign="top">328 </td> <td align="center" valign="top">(32) </td> <td align="center" valign="top">172 </td> <td align="center" valign="top">(31) </td> <td align="center" valign="top">89 </td> <td align="center" valign="top">(20) </td> </tr> <tr> <td align="left" valign="top">Weakness </td> <td align="center" valign="top">252 </td> <td align="center" valign="top">(24) </td> <td align="center" valign="top">108 </td> <td align="center" valign="top">(19) </td> <td align="center" valign="top">114 </td> <td align="center" valign="top">(25) </td> </tr> <tr> <td align="left" valign="top">Edema Lower Limb </td> <td align="center" valign="top">215 </td> <td align="center" valign="top">(21) </td> <td align="center" valign="top">126 </td> <td align="center" valign="top">(23) </td> <td align="center" valign="top">84 </td> <td align="center" valign="top">(19) </td> </tr> <tr> <td align="left" valign="top">Rigors </td> <td align="center" valign="top">112 </td> <td align="center" valign="top">(11) </td> <td align="center" valign="top">62 </td> <td align="center" valign="top">(11) </td> <td align="center" valign="top">28 </td> <td align="center" valign="top">(6) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Infections</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Urinary Tract Infection </td> <td align="center" valign="top">124 </td> <td align="center" valign="top">(12) </td> <td align="center" valign="top">50 </td> <td align="center" valign="top">(9) </td> <td align="center" valign="top">41 </td> <td align="center" valign="top">(9) </td> </tr> <tr> <td align="left" valign="top">Upper Respiratory Tract Infection </td> <td align="center" valign="top">101 </td> <td align="center" valign="top">(10) </td> <td align="center" valign="top">82 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">30 </td> <td align="center" valign="top">(7) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Metabolism</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Anorexia </td> <td align="center" valign="top">231 </td> <td align="center" valign="top">(22) </td> <td align="center" valign="top">81 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">105 </td> <td align="center" valign="top">(23) </td> </tr> <tr> <td align="left" valign="top">Weight Decreased </td> <td align="center" valign="top">164 </td> <td align="center" valign="top">(16) </td> <td align="center" valign="top">50 </td> <td align="center" valign="top">(9) </td> <td align="center" valign="top">61 </td> <td align="center" valign="top">(13) </td> </tr> <tr> <td align="left" valign="top">Dehydration </td> <td align="center" valign="top">145 </td> <td align="center" valign="top">(14) </td> <td align="center" valign="top">60 </td> <td align="center" valign="top">(11) </td> <td align="center" valign="top">59 </td> <td align="center" valign="top">(13) </td> </tr> <tr> <td align="left" valign="top">Appetite Decreased </td> <td align="center" valign="top">130 </td> <td align="center" valign="top">(13) </td> <td align="center" valign="top">48 </td> <td align="center" valign="top">(9) </td> <td align="center" valign="top">45 </td> <td align="center" valign="top">(10) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Musculoskeletal</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Bone Pain </td> <td align="center" valign="top">569 </td> <td align="center" valign="top">(55) </td> <td align="center" valign="top">316 </td> <td align="center" valign="top">(57) </td> <td align="center" valign="top">284 </td> <td align="center" valign="top">(62) </td> </tr> <tr> <td align="left" valign="top">Myalgia </td> <td align="center" valign="top">239 </td> <td align="center" valign="top">(23) </td> <td align="center" valign="top">143 </td> <td align="center" valign="top">(26) </td> <td align="center" valign="top">74 </td> <td align="center" valign="top">(16) </td> </tr> <tr> <td align="left" valign="top">Arthralgia </td> <td align="center" valign="top">216 </td> <td align="center" valign="top">(21) </td> <td align="center" valign="top">131 </td> <td align="center" valign="top">(24) </td> <td align="center" valign="top">73 </td> <td align="center" valign="top">(16) </td> </tr> <tr> <td align="left" valign="top">Back Pain </td> <td align="center" valign="top">156 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">106 </td> <td align="center" valign="top">(19) </td> <td align="center" valign="top">40 </td> <td align="center" valign="top">(9) </td> </tr> <tr> <td align="left" valign="top">Pain in Limb </td> <td align="center" valign="top">143 </td> <td align="center" valign="top">(14) </td> <td align="center" valign="top">84 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">52 </td> <td align="center" valign="top">(11) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Neoplasms</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Malignant Neoplasm Aggravated </td> <td align="center" valign="top">205 </td> <td align="center" valign="top">(20) </td> <td align="center" valign="top">97 </td> <td align="center" valign="top">(17) </td> <td align="center" valign="top">89 </td> <td align="center" valign="top">(20) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Nervous</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Headache </td> <td align="center" valign="top">191 </td> <td align="center" valign="top">(19) </td> <td align="center" valign="top">149 </td> <td align="center" valign="top">(27) </td> <td align="center" valign="top">50 </td> <td align="center" valign="top">(11) </td> </tr> <tr> <td align="left" valign="top">Dizziness (excluding vertigo) </td> <td align="center" valign="top">180 </td> <td align="center" valign="top">(18) </td> <td align="center" valign="top">91 </td> <td align="center" valign="top">(16) </td> <td align="center" valign="top">58 </td> <td align="center" valign="top">(13) </td> </tr> <tr> <td align="left" valign="top">Insomnia </td> <td align="center" valign="top">166 </td> <td align="center" valign="top">(16) </td> <td align="center" valign="top">111 </td> <td align="center" valign="top">(20) </td> <td align="center" valign="top">73 </td> <td align="center" valign="top">(16) </td> </tr> <tr> <td align="left" valign="top">Paresthesia </td> <td align="center" valign="top">149 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">85 </td> <td align="center" valign="top">(15) </td> <td align="center" valign="top">35 </td> <td align="center" valign="top">(8) </td> </tr> <tr> <td align="left" valign="top">Hypoesthesia </td> <td align="center" valign="top">127 </td> <td align="center" valign="top">(12) </td> <td align="center" valign="top">65 </td> <td align="center" valign="top">(12) </td> <td align="center" valign="top">43 </td> <td align="center" valign="top">(10) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Psychiatric</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Depression </td> <td align="center" valign="top">146 </td> <td align="center" valign="top">(14) </td> <td align="center" valign="top">95 </td> <td align="center" valign="top">(17) </td> <td align="center" valign="top">49 </td> <td align="center" valign="top">(11) </td> </tr> <tr> <td align="left" valign="top">Anxiety </td> <td align="center" valign="top">112 </td> <td align="center" valign="top">(11) </td> <td align="center" valign="top">73 </td> <td align="center" valign="top">(13) </td> <td align="center" valign="top">37 </td> <td align="center" valign="top">(8) </td> </tr> <tr> <td align="left" valign="top">Confusion </td> <td align="center" valign="top">74 </td> <td align="center" valign="top">(7) </td> <td align="center" valign="top">39 </td> <td align="center" valign="top">(7) </td> <td align="center" valign="top">47 </td> <td align="center" valign="top">(10) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Respiratory</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Dyspnea </td> <td align="center" valign="top">282 </td> <td align="center" valign="top">(27) </td> <td align="center" valign="top">155 </td> <td align="center" valign="top">(28) </td> <td align="center" valign="top">107 </td> <td align="center" valign="top">(24) </td> </tr> <tr> <td align="left" valign="top">Cough </td> <td align="center" valign="top">224 </td> <td align="center" valign="top">(22) </td> <td align="center" valign="top">129 </td> <td align="center" valign="top">(23) </td> <td align="center" valign="top">65 </td> <td align="center" valign="top">(14) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Skin</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Alopecia </td> <td align="center" valign="top">125 </td> <td align="center" valign="top">(12) </td> <td align="center" valign="top">80 </td> <td align="center" valign="top">(14) </td> <td align="center" valign="top">36 </td> <td align="center" valign="top">(8) </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule">Dermatitis </td> <td align="center" valign="top" styleCode="Botrule">114 </td> <td align="center" valign="top" styleCode="Botrule">(11) </td> <td align="center" valign="top" styleCode="Botrule">74 </td> <td align="center" valign="top" styleCode="Botrule">(13) </td> <td align="center" valign="top" styleCode="Botrule">38 </td> <td align="center" valign="top" styleCode="Botrule">(8) </td> </tr> </tbody> </table>

<table ID="t8" width="100%"> <caption>Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases </caption> <col width="27.353%" align="left"/> <col width="11.913%" align="left"/> <col width="12.341%" align="left"/> <col width="12.098%" align="left"/> <col width="12.098%" align="left"/> <col width="12.098%" align="left"/> <col width="12.098%" align="left"/> <tfoot> <tr> <td colspan="7" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) </paragraph> </td> </tr> <tr> <td colspan="7" align="left" valign="top"> <paragraph styleCode="footnote"> <content styleCode="bold"> ^* </content> Serum creatinine data for all patients randomized after the 15-minute infusion amendment </paragraph> </td> </tr> <tr> <td colspan="7" align="left" valign="top"> <paragraph styleCode="footnote"> ² Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) </paragraph> </td> </tr> <tr> <td colspan="7" align="left" valign="top"> <paragraph styleCode="footnote"> ³ Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) </paragraph> </td> </tr> <tr> <td colspan="7" align="left" valign="top"> <paragraph styleCode="footnote"> ⁴ Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) </paragraph> </td> </tr> <tr> <td colspan="7" align="left" valign="top" styleCode="Botrule"> <paragraph styleCode="footnote"> ⁵ Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="left" valign="top"/> <td colspan="2" align="center" valign="top"/> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Grade 3</content> </td> <td colspan="2" align="center" valign="middle"/> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Laboratory Parameter</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Zoledronic Acid Injection</content> <content styleCode="bold">4 mg</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Pamidronate</content> <content styleCode="bold">90 mg</content> </td> <td colspan="2" align="center" valign="middle"> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule"/> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">(%)</content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Serum Creatinine</content> <content styleCode="bold"> ^1* </content> </td> <td align="center" valign="top">7/529 </td> <td align="center" valign="top">(1%) </td> <td align="center" valign="top">4/268 </td> <td align="center" valign="top">(2%) </td> <td align="center" valign="top">4/241 </td> <td align="center" valign="top">(2%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypocalcemia</content> <content styleCode="bold"> ² </content> </td> <td align="center" valign="top">6/973 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">4/536 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">0/415 </td> <td align="center" valign="top">--- </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypophosphatemia</content> <content styleCode="bold"> ³ </content> </td> <td align="center" valign="top">115/973 </td> <td align="center" valign="top">(12%) </td> <td align="center" valign="top">38/537 </td> <td align="center" valign="top">(7%) </td> <td align="center" valign="top">14/415 </td> <td align="center" valign="top">(3%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypermagnesemia</content> <content styleCode="bold"> ⁴ </content> </td> <td align="center" valign="top">19/971 </td> <td align="center" valign="top">(2%) </td> <td align="center" valign="top">2/535 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">8/415 </td> <td align="center" valign="top">(2%) </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule"> <content styleCode="bold">Hypomagnesemia</content> <content styleCode="bold"> ⁵ </content> </td> <td align="center" valign="top" styleCode="Botrule">1/971 </td> <td align="center" valign="top" styleCode="Botrule">(&lt;1%) </td> <td align="center" valign="top" styleCode="Botrule">0/535 </td> <td align="center" valign="top" styleCode="Botrule">--- </td> <td align="center" valign="top" styleCode="Botrule">1/415 </td> <td align="center" valign="top" styleCode="Botrule">(&lt;1%) </td> </tr> </tbody> </table>

<table ID="t9" width="100%"> <caption>Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases </caption> <col width="27.347%" align="left"/> <col width="2.087%" align="left"/> <col width="9.836%" align="left"/> <col width="12.336%" align="left"/> <col width="12.098%" align="left"/> <col width="12.098%" align="left"/> <col width="12.098%" align="left"/> <col width="12.098%" align="left"/> <tfoot> <tr> <td colspan="8" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) </paragraph> </td> </tr> <tr> <td colspan="8" align="left" valign="top"> <paragraph styleCode="footnote"> <content styleCode="bold"> ^* </content> Serum creatinine data for all patients randomized after the 15-minute infusion amendment </paragraph> </td> </tr> <tr> <td colspan="8" align="left" valign="top"> <paragraph styleCode="footnote"> ² Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) </paragraph> </td> </tr> <tr> <td colspan="8" align="left" valign="top"> <paragraph styleCode="footnote"> ³ Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) </paragraph> </td> </tr> <tr> <td colspan="8" align="left" valign="top"> <paragraph styleCode="footnote"> ⁴ Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) </paragraph> </td> </tr> <tr> <td colspan="8" align="left" valign="top" styleCode="Botrule"> <paragraph styleCode="footnote"> ⁵ Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td colspan="2" align="center" valign="top"/> <td colspan="6" align="center" valign="top"> <content styleCode="bold">Grade 4</content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Laboratory Parameter</content> </td> <td colspan="3" align="center" valign="top"> <content styleCode="bold">Zoledronic Acid Injection</content> <content styleCode="bold">4 mg</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Pamidronate</content> <content styleCode="bold">90 mg</content> </td> <td colspan="2" align="center" valign="middle"> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule"/> <td colspan="2" align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">(%)</content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Serum Creatinine</content> <content styleCode="bold"> ^1* </content> </td> <td colspan="2" align="center" valign="top">2/529 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">1/268 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">0/241 </td> <td align="center" valign="top">--- </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypocalcemia</content> <content styleCode="bold"> ² </content> </td> <td colspan="2" align="center" valign="top">7/973 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">3/536 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">2/415 </td> <td align="center" valign="top">(&lt;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypophosphatemia</content> <content styleCode="bold"> ³ </content> </td> <td colspan="2" align="center" valign="top">5/973 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">0/537 </td> <td align="center" valign="top">--- </td> <td align="center" valign="top">1/415 </td> <td align="center" valign="top">(&lt;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypermagnesemia</content> <content styleCode="bold"> ⁴ </content> </td> <td colspan="2" align="center" valign="top">0/971 </td> <td align="center" valign="top">--- </td> <td align="center" valign="top">0/535 </td> <td align="center" valign="top">--- </td> <td align="center" valign="top">2/415 </td> <td align="center" valign="top">(&lt;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Hypomagnesemia</content> <content styleCode="bold"> ⁵ </content> </td> <td colspan="2" align="center" valign="top">2/971 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">1/535 </td> <td align="center" valign="top">(&lt;1%) </td> <td align="center" valign="top">0/415 </td> <td align="center" valign="top">--- </td> </tr> </tbody> </table>

<table ID="t10" width="100%"> <caption>Table 10: Percentage of Patients with Treatment-Emergent Renal Function Deterioration by Baseline Serum Creatinine* </caption> <col width="44.671%" align="left"/> <col width="15.257%" align="left"/> <col width="13.357%" align="left"/> <col width="14.057%" align="left"/> <col width="12.657%" align="left"/> <tfoot> <tr> <td colspan="5" align="left" valign="top" styleCode="Botrule"> <paragraph styleCode="footnote"> <content styleCode="bold">*</content>Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zoledronic Acid Injection to 15 minutes. </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td colspan="5" align="left" valign="top" styleCode="Botrule"> <content styleCode="bold">Patient Population/Baseline Creatinine</content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Multiple Myeloma and Breast Cancer</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Zoledronic Acid Injection 4 mg</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Pamidronate 90 mg</content> </td> </tr> <tr> <td align="left" valign="top"/> <td align="center" valign="top"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top"> <content styleCode="bold">(%)</content> </td> </tr> <tr> <td align="left" valign="top">Normal </td> <td align="center" valign="top">27/246 </td> <td align="center" valign="top">(11%) </td> <td align="center" valign="top">23/246 </td> <td align="center" valign="top">(9%) </td> </tr> <tr> <td align="left" valign="top">Abnormal </td> <td align="center" valign="top">2/26 </td> <td align="center" valign="top">(8%) </td> <td align="center" valign="top">2/22 </td> <td align="center" valign="top">(9%) </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule">Total </td> <td align="center" valign="top" styleCode="Botrule">29/272 </td> <td align="center" valign="top" styleCode="Botrule">(11%) </td> <td align="center" valign="top" styleCode="Botrule">25/268 </td> <td align="center" valign="top" styleCode="Botrule">(9%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Solid Tumors</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Zoledronic Acid Injection 4 mg</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td align="left" valign="top"/> <td align="center" valign="top"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top"> <content styleCode="bold">(%)</content> </td> </tr> <tr> <td align="left" valign="top">Normal </td> <td align="center" valign="top">17/154 </td> <td align="center" valign="top">(11%) </td> <td align="center" valign="top">10/143 </td> <td align="center" valign="top">(7%) </td> </tr> <tr> <td align="left" valign="top">Abnormal </td> <td align="center" valign="top">1/11 </td> <td align="center" valign="top">(9%) </td> <td align="center" valign="top">1/20 </td> <td align="center" valign="top">(5%) </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule">Total </td> <td align="center" valign="top" styleCode="Botrule">18/165 </td> <td align="center" valign="top" styleCode="Botrule">(11%) </td> <td align="center" valign="top" styleCode="Botrule">11/163 </td> <td align="center" valign="top" styleCode="Botrule">(7%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Prostate Cancer</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Zoledronic Acid Injection 4 mg</content> </td> <td colspan="2" align="center" valign="bottom"> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td align="left" valign="top"/> <td align="center" valign="top"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top"> <content styleCode="bold">n/N</content> </td> <td align="center" valign="top"> <content styleCode="bold">(%)</content> </td> </tr> <tr> <td align="left" valign="top">Normal </td> <td align="center" valign="top">12/82 </td> <td align="center" valign="top">(15%) </td> <td align="center" valign="top">8/68 </td> <td align="center" valign="top">(12%) </td> </tr> <tr> <td align="left" valign="top">Abnormal </td> <td align="center" valign="top">4/10 </td> <td align="center" valign="top">(40%) </td> <td align="center" valign="top">2/10 </td> <td align="center" valign="top">(20%) </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule">Total </td> <td align="center" valign="top" styleCode="Botrule">16/92 </td> <td align="center" valign="top" styleCode="Botrule">(17%) </td> <td align="center" valign="top" styleCode="Botrule">10/78 </td> <td align="center" valign="top" styleCode="Botrule">(13%) </td> </tr> </tbody> </table>