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 nontumor-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 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4 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 nontumor-related conditions have not been established.
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 ( 4 )
Warnings and precautions
Patients being treated with zoledronic acid should not be treated with Reclast ® . ( 5.1 ) Adequately rehydrate patients with hypercalcemia of malignancy prior to administration of zoledronic acid 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. Avoid invasive dental procedures. ( 5.4 ) Severe incapacitating bone, joint and/or muscle pain may occur. Discontinue zoledronic acid 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. 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 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 contains the same active ingredient as found in Reclast ® (zoledronic acid). Patients being treated with zoledronic acid 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. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. Zoledronic acid 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.
If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short‑term supplemental therapy may be necessary.
5.3Renal Impairment
Zoledronic acid 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 and other bisphosphonates are risk factors for subsequent renal deterioration with zoledronic acid.
Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zoledronic acid 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 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 mg/dL were excluded and there were only 8 of 564 patients treated with zoledronic acid 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. 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. Post marketing 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 ) ] .
5.5Musculoskeletal Pain
In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including zoledronic acid. 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 ) ].
5.6Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including zoledronic acid. 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 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.
5.7Patients with Asthma While
not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.
5.8Hepatic Impairment
Only limited clinical data are available for use of zoledronic acid to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidanc
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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 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 clinical trials.
7.2Loop Diuretics
Caution should also be exercised when zoledronic acid is used in combination with loop diuretics due to an increased risk of hypocalcemia.
7.3Nephrotoxic Drugs
Caution is indicated when zoledronic acid is used with other potentially nephrotoxic drugs.
7.4Thalidomide
No dose adjustment for zoledronic acid 4 mg is needed when coadministered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, zoledronic acid 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 did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies and its mechanism of action, zoledronic acid 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, 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%-4% and of miscarriage is 15%-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 post-implantation 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 caused by, drug-induced hypocalcemia.
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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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 was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either zoledronic acid 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 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 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid 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 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 ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zoledronic Acid Injection 4 mg n (%) Pamidronate 90 mg n (%) Patients Studied Total No. of Patients Studied Total No. of Patients with any AE 86 81 (100) (94) 103 95 (100) (92) Body as a Whole Fever Progression of Cancer 38 14 (44) (16) 34 21 (33) (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea Constipation Diarrhea Abdominal Pain Vomitting Anorexia 25 23 15 14 12 8 (29) (27) (17) (16) (14) (9) 28 13 17 13 17 14 (27) (13) (17) (13) (17) (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia 11 10 9 (13) (12) (11) 2 16 5 (2) (16) (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia Anxiety Confusion Agitation 13 12 11 11 (15) (14) (13) (13) 10 8 13 8 (10) (8) (13) (8) Respiratory Dyspnea Coughing 19 10 (22) (12) 20 12 (19) (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with zoledronic acid 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%.
Adverse events are listed regardless of presumed causality to study drug: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with zoledronic acid. Acute Phase Reaction Within three days after zoledronic acid administration, an acute phase reaction has been reported in patients, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness.
These symptoms usually resolve within a few days. Pyrexia has been the most commonly associated symptom, occurring in 44% of patients. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of zoledronic acid in patients with HCM are shown in Table 5 and 6 .
Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 Hypocalcemia 2 Hypophosphatemia 3 Hypomagnesemia 4 2/86 1/86 36/70 0/71 (2%) (1%) (51%) — 3/100 2/100 27/81 0/84 (3%) (2%) (33%) — 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 4 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 Hypocalcemia 2 Hypophosphatemia 3 Hypomagnesemia 4 0/86 0/86 1/70 0/71 — — (1%) — 1/100 0/100 4/81 1/84 (1%) — (5%) (1%) 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently.
In most cases, no specific treatment is required and the symptoms subside after 24 to 48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including zoledronic acid. No cases of iritis, scleritis, or uveitis were reported during these clinical trials. However, cases have been seen in post-marketing use [see Adverse Reactions ( 6.2 ) ] . Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials.
The analysis includes the 2042 patients treated with zoledronic acid 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients).
The median duration of exposure for safety analysis for zoledronic acid 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4 months for other solid tumors. Table 7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug. Table 7: Percentage of Patients with Adverse Events ≥ 10% Reported in Three Bone Metastases Clinical Trials by Body System Zoledronic Acid Injection 4 mg Pamidronate 90 mg Placebo n (%) n (%) n (%) Patients Studied Total No. of Patients Total No. of Patients with any AE 1031 1015 (100) (98) 556 548 (100) (99) 455 445 (100) (98) Blood and Lymphatic Anemia Neutropenia Thrombocytopenia 344 124 102 (33) (12) (10) 175 83 53 (32) (15) (10) 128 35 20 (2
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Composition
Active ingredients
ZOLEDRONIC ACID EQ 4MG BASE/5ML
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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