Zoledronic Acid 4 mg/5mL Injection, Solution, Concentrate
Other active recalls for Zoledronic Acid (different manufacturers) — 1 · tap to view
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Bisphosphonate class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Zoledronic acid is used to prevent or treat osteoporosis (condition in which the bones become thin and weak and break easily) and treat Paget's disease of bone (a condition in which the bones are soft and weak and may be deformed, painful, or easily broken). Zoledronic acid is also used to treat high levels of calcium in the blood that may be caused by certain types of cancer and to treat bone damage caused by multiple myeloma [cancer that begins in the plasma cells (white blood cells that produce substances needed to fight infection)] or by cancer that began in another part of the body but h...
Read the full MedlinePlus article ↗- Great question — it surprised a lot of patients at first. Zoledronic acid binds extremely tightly to bone mineral, so after your infusion, it stays embedded in your bone tissue and...
- Why do I only need this infusion once a year? How can that be enough?
- The most common ones — especially after your first infusion — feel a lot like the flu: fever, muscle aches, joint pain, headache, and chills. These usually show up within the first...
- What side effects should I expect after my infusion?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Zoledronic Acid — tap one for details:
Where does this data come from?
Ask a licensed pharmacist directly — free, answered by our team.
🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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220 mg / 5 mL
UNII 3OWL53L36A
A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
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24 mg / 5 mL
UNII 1Q73Q2JULR
Sodium citrate is a salt derived from citric acid. It works as a buffer to maintain the medicine's pH level and may also help improve taste or act as a preservative in the formulation.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
3 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
| Medicare Part B allowsASP · J3489 | $3.361 / J3489 unit | — |
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🧾 Billing & reimbursement
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Zoledronic Acid 4 mg/5mL 00143-9642-01 | Hikma | 5 ml | — | AP | FDA listed | — |
| Zoledronic acid 4 mg/5mL 16729-0242-31 | Accord | 1 vial | — | AP | FDA listed | — |
| Zoledronic acid 4 mg/5mL 23155-0170-31 | Heritage | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 43598-0233-11 | Dr. | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 43598-0330-11 | Dr. | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 54288-0100-01 | BPI | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mLthis 54288-0183-01 | BPI | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 55111-0685-07 | Dr. | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 55150-0266-05 | AuroMedics | 1 vial | — | — | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 63323-0961-98 | Fresenius | 1 vial | — | AP | FDA listed | — |
| Zoledronic acid 4 mg/5mL 67457-0390-54 | Mylan | 1 vial | — | AP | FDA listed | — |
| Zoledronic acid 4 mg/5mL 68001-0437-25 | BluePoint | 1 vial | — | AP | FDA listed | — |
| Zoledronic acid 4 mg/5mL 68001-0610-25 | BluePoint | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 68083-0116-01 | Gland | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 68083-0615-01 | Gland | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 69367-0190-50 | Westminster | 1 vial | — | AP | FDA listed | — |
| Zoledronic acid 4 mg/5mL 72603-0198-01 | NORTHSTAR | 1 vial | — | AP | FDA listed | — |
| Zoledronic Acid 4 mg/5mL 83634-0801-05 | Avenacy | 1 vial | — | AP | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 54288-0183-01 You're viewing this | 1 VIAL, GLASS in 1 CARTON (54288-183-01) / 5 mL in 1 VIAL, GLASS | 2025-06-05 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | ✓ Available |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
Questions about this listing
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
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.
1.1Hypercalcemia 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]).
1.2Multiple 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.
⏱️ Dosage and Administration ▾
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 )
2.1Hypercalcemia 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) ].
2.2Multiple 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) (…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS 4 mg/5 mL (0.8 mg/mL) single-dose ready-to-use vial for dilution prior to intravenous infusion. 4 mg/5 mL (0.8 mg/mL) single-dose vial for dilution prior to intravenous infusion ( 3 )
⛔ Contraindications ▾
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 )
⚠️ Warnings and Cautions ▾
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 )
5.1Drugs 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.
5.2Hydration 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.
5.3Renal 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…
🤒 Adverse Reactions ▾
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 .
6.1Clinical 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…
🔄 Drug Interactions ▾
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 )
7.1Aminoglycosides 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.
7.2Loop Diuretics Caution should also be exercised when Zoledronic Acid Injection is used in combination with loop diuretics due to an increased risk of hypocalcemia.
7.3Nephrotoxic Drugs Caution is indicated when Zoledronic Acid Injection is used with other potentially nephrotoxic drugs.
7.4Thalidomide 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.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed ( 8.2 ) • Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of Zoledronic Acid Injection. May impair fertility. Counsel patients on pregnancy planning and prevention ( 8.3 ) • Pediatric Use: Not indicated for use in pediatric patients ( 8.4 ) • Geriatric Use: Special care to monitor renal function ( 8.5 )
8.1Pregnancy 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 equa…
🤰 Pregnancy ▾
8.1Pregnancy 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…
🧒 Pediatric Use ▾
8.4Pediatric Use Zoledronic Acid Injection is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year, active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1 to 17 years, 55% male, 84% Caucasian, with a mean lumbar spine bone mineral density (BMD) of 0.431 gm/cm 2 , which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7).
At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zoledronic Acid Injection use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases.
However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zoledronic Acid Injection should only be used in children if the potential benefit outweighs the potential risk.
Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3 to 8 years and 6 in the age group of 9 to 17 years) infused with 0.05 mg/kg dose over 30 min. Mean C max and AUC (0-last) was 167 ng/mL and 220 ng•h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of Zoledronic Acid Injection in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zoledronic Acid Injection as compared to younger patients. Controlled clinical studies of Zoledronic Acid Injection in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients.
Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.
🆘 Overdosage ▾
10 OVERDOSAGE Clinical experience with acute overdosage of Zoledronic Acid Injection is limited. Two patients received Zoledronic Acid Injection 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity.
Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error.
Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg.
The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100 unit/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zoledronic Acid Injection 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion.
In controlled clinical trials, Zoledronic Acid Injection 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zoledronic Acid Injection 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage and Administration (2.4) ].
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro , zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis.
Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
12.2Pharmacodynamics Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zoledronic Acid Injection are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion. Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate.
This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy. Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma. Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present.
Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation [ see Dosage and Administration (2.1) ] .
12.3Pharmacokinetics Pharmacokinetic data in patients with hypercalcemia are not available. Distribution Single or multiple (every 28 days) 5-minute or 15-minute infusions of 2, 4, 8, or 16 mg Zoledronic Acid Injection were given to 64 patients with cancer and bone metastases. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end of infusion to less than 1% of C max 24 hours post-infusion with population half-lives of t 1/2α 0.24 hours and t 1/2β 1.87 hours for the early disposition phases of the drug.
The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between Days 2 and 28 post-infusion, and a terminal elimination half-life t 1/2γ of 146 hours. The area under the plasma concentration versus time curve (AUC…
🧬 Mechanism of Action ▾
12.1Mechanism of Action The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro , zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis.
Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Zoledronic Acid Injection is supplied as follows: NDC Zoledronic Acid Injection (0.8 mg per mL) Package Factor 54288-183-01 4 mg/5 mL single-dose Glass vial for dilution prior to intravenous infusion 1 vial per carton Storage Conditions Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature]. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.
📋 Description ▾
11 DESCRIPTION Zoledronic Acid Injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is: Zoledronic acid is a white crystalline powder. Its molecular formula is C 5 H 10 N 2 O 7 P 2 •H 2 O and its molar mass is 290.1 g/mol.
Zoledronic acid is sparingly soluble in 0.1N sodium hydroxide solution and slightly soluble in water. The pH of a 0.25% solution of zoledronic acid in water is 1.5 to 2.5. 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. struture
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION 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. Brands listed are the trademarks of their respective owners. Manufactured for: BPI Labs, LLC 12393 Belcher Road S, Suite 450 Largo, FL 33773, USA.
Made in India. LI73I R-2401 Revised: January 2024.