Zoledronic Acid

1 INDICATIONS AND USAGE Zoledronic Acid Injection is a bisphosphonate indicated for the treatment of: • Hypercalcemia of malignancy. ( 1.1 ) • Patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. ( 1.2 ) Limitations of Use : The safety and efficacy of Zoledronic Acid Injection has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia. 1.1 Hypercalcemia of Malignancy Zoledronic Acid Injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL – patient albumin [g/dL]). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zoledronic Acid Injection is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Limitations of Use The safety and efficacy of Zoledronic Acid Injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established.

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) (…

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 (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 …

4 CONTRAINDICATIONS Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic Acid Injection Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2) ] . Hypersensitivity to any component of Zoledronic Acid Injection ( 4 )

7 DRUG INTERACTIONS In vitro studies indicate that the plasma protein binding of zoledronic acid is low, with the unbound fraction ranging from 60% to 77%. In vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. • Aminoglycosides : May have an additive effect to lower serum calcium for prolonged periods ( 7.1 ) • Loop Diuretics : Concomitant use with Zoledronic Acid Injection may increase risk of hypocalcemia ( 7.2 ) • Nephrotoxic Drugs : Use with caution ( 7.3 ) 7.1 Aminoglycosides and Calcitonin Caution is advised when bisphosphonates are administered with aminoglycosides or calcitonin, 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 Injection 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. 7.4 Thalidomide No dose adjustment for Zoledronic Acid Injection 4 mg is needed when coadministered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zoledronic Acid Injection 4 mg given as a 15-minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1 to 14 and 200 mg once daily on days 15 to 28). Coadministration of thalidomide with Zoledronic Acid Injection did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were ≥ 2.4 times the human clinical exposure based on AUC (see Data) . 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. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (greater than or equal to 0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of greater than or equal to 0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved, or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group at 0.1 mg/kg/day (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (less than or equal to 0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses greater than or equal to 0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been c…

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 BPI Labs, LLC at 727-471-0850 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 Pamidronate 90 mg n (%) 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 multi-center 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 Zoledro…