Zoledronic acid

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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

11 DESCRIPTION

DESCRIPTION SECTION

Zoledronic acid injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is: Zoledronic acid is a white crystalline powder. Its molecular formula is C 5 H 10 N 2 O 7 P 2 •H 2 O and its molar mass is 290.1g/mol. Zoledronic acid is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.0. Zoledronic acid injection is available in 5 mL vials as a sterile liquid solution for dilution prior to intravenous infusion. Each 5 mL solution for dilution prior to intravenous infusion vial contains 4.264 mg zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis, 220 mg of mannitol, USP, water for injection, and 24 mg of sodium citrate, USP. Inactive Ingredients: mannitol, USP, as bulking agent, water for injection, and sodium citrate, USP, as buffering agent.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior to intravenous infusion Carton of 1 vial ..................................................................................................................... NDC 23155-170-31 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Discard unused portion.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Drugs With Same Active Ingredient or in the Same Drug Class Inform patients not to take Reclast or other bisphosphonates during the course of their zoledronic acid injection therapy [see Warnings and Precautions ( 5.1 )]. Renal Impairment • Instruct patients to tell their doctor if they have kidney problems before being given zoledronic acid injection. • Inform patients of the importance of getting their blood tests (serum creatinine) during the course of their zoledronic acid injection therapy [see Warnings and Precautions ( 5.3 )]. Osteonecrosis of the Jaw (ONJ) • Advise patients to have a dental examination prior to treatment with zoledronic acid injection and to avoid invasive dental procedures during treatment. • Inform patients of the importance of good dental hygiene, routine dental care, and regular dental check-ups. • Advise patients to immediately tell their doctor about any oral symptoms such as loosening of a tooth, pain, swelling, or non-healing of sores or discharge during treatment with zoledronic acid injection [see Warnings and Precautions ( 5.4 )] . Musculoskeletal Pain Advise patients to immediately tell their doctor about any severe bone, joint, and/or muscle pain [see Warnings and Precautions ( 5.5 )]. Atypical Subtrochanteric and Diaphyseal Femoral Fracture Advise patients to report any thigh, hip, or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy [see Warnings and Precautions ( 5.6 )]. Patients With Asthma There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including zoledronic acid. Before being given zoledronic acid, instruct patients to tell their doctor if they are aspirin-sensitive [see Warnings and Precautions ( 5.7 )] . Hypocalcemia Advise patients with multiple myeloma and bone metastasis of solid tumors to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily [see Warnings and Precautions ( 5.9 )]. Embryo-Fetal Toxicity • Zoledronic acid injection should not be given if the patient is pregnant or plans to become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Warnings and Precautions ( 5.10 )] . • Advise females of reproductive potential to use effective contraception during and after treatment with zoledronic acid injection [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.1 , 8.3 )]. Lactation Advise lactating women not to breastfeed during and after treatment with zoledronic acid injection [see Use in Specific Populations ( 8.2 )] . Common Adverse Reactions Advise patients that the most common side effects of zoledronic acid injection are nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, and dyspnea. RECLAST ® is a registered trademark of Novartis. Manufactured by: Emcure Pharmaceuticals Ltd., Sanand, Ahmedabad - 382110, India. Manufactured for: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Revised: 08/2023

PACKAGE LABEL PRINCIPAL DISPLAY PANEL - LABEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 23155- 170 -31 Zoledronic Acid Injection 4 mg/5 mL (0.8 mg/mL) Rx only For Intravenous Infusion after Dilution Not for direct injection. Dose must be diluted. S terile Single-dose 5 mL vial

PACKAGE LABEL PRINCIPAL DISPLAY PANEL - CARTON

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 23155- 170 -31 Zoledronic Acid Injection 4 mg/5 mL (0.8 mg/mL) Rx only For Intravenous Infusion after Dilution Not for direct injection. Dose must be diluted. One single-dose 5 mL vial Sterile