ZOLEDRONIC (Page 2 of 6)

4 CONTRAINDICATIONS

4.1 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) ].

5 WARNINGS AND PRECAUTIONS

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. In the clinical studies, patients with serum creatinine greater than 400 mcmol/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 mcmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zoledronic acid Injection 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min [see Clinical Pharmacology (12.3) ].

5.4 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zoledronic acid Injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.

Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2) ].

5.5 Musculoskeletal Pain

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including Zoledronic acid Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2) ].

5.6 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zoledronic acid Injection. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.
Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zoledronic acid Injection therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.

5.7 Patients with Asthma

While not observed in clinical trials with Zoledronic acid Injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.

5.8 Hepatic Impairment

Only limited clinical data are available for use of Zoledronic acid Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic acid Injection in these patients.

5.9 Use in Pregnancy


Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.
Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].

5.10 Hypocalcemia

Hypocalcemia has been reported in patients treated with Zoledronic acid Injection. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Hypocalcemia must be corrected before initiating Zoledronic acid Injection. Adequately supplement patients with calcium and vitamin D.

6 ADVERSE REACTIONS

6.1 Clinical Studies 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 33-84 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 3).Table 3 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 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System
Zoledronic acid Injection Pamidronate
4 mg 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 multicenter 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 Zoledronic acid Injection.

Acute Phase Reaction
Within three days after Zoledronic acid Injection 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 Injection in patients with HCM are shown in Table 4 and 5.

Table 4: 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 Pamidronate
4 mg 90 mg
n/N (%) n/N (%)
Serum Creatinine1 2/86 (2%) 3/100 (3%)
Hypocalcemia2 1/86 (1%) 2/100 (2%)
Hypophosphatemia3 36/70 (51%) 27/81 (33%)
Hypomagnesemia4 0/71 0/84
Table 5: 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 Pamidronate
4 mg 90 mg
n/N (%) n/N (%)
Serum Creatinine1 0/86 1/100 (1%)
Hypocalcemia2 0/86 0/100
Hypophosphatemia3 1/70 (1%) 4/81 (5%)
Hypomagnesemia4 0/71 1/84 (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 24-48 hours.
Ocular Adverse Events
Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zoledronic acid Injection. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing 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 2,042 patients treated with Zoledronic acid Injection 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 Injection 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.Table 6 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug.

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

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zoledronic acid Injection in patients with bone metastases are shown in Tables 7 and 8.

Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases
Grade 3
Laboratory Parameter Zoledronic acid Injection Pamidronate Placebo
4 mg 90 mg
n/N (%) n/N (%) n/N (%)
Serum Creatinine 1* 7/529 (1%) 4/268 (2%) 4/241 (2%)
Hypocalcemia 2 6/973 (<1%) 4/536 (<1%) 0/415
Hypophosphatemia 3 115/973 (12%) 38/537 (7%) 14/415 (3%)
Hypermagnesemia 4 19/971 (2%) 2/535 (<1%) 8/415 (2%)
Hypomagnesemia 5 1/971 (<1%) 0/535 1/415 (<1%)
1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) * Serum creatinine data for all patients randomized after the 15-minute infusion amendment 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 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)
Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases
Grade 4
Laboratory Parameter Zoledronic acid Injection Pamidronate Placebo
4 mg 90 mg
n/N (%) n/N (%) n/N (%)
Serum Creatinine 1* 2/529 (<1%) 1/268 (<1%) 0/241
Hypocalcemia 2 7/973 (<1%) 3/536 (<1%) 2/415 (<1%)
Hypophosphatemia 3 5/973 (<1%) 0/537 1/415 (<1%)
Hypermagnesemia 4 0/971 0/535 2/415 (<1%)
Hypomagnesemia 5 2/971 (<1%) 1/535 (<1%) 0/415
1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) * Serum creatinine data for all patients randomized after the 15-minute infusion amendment 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 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)

Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zoledronic acid Injection 4 mg and pamidronate groups) compared to the placebo group.
Less common adverse events reported more often with Zoledronic acid Injection 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zoledronic acid Injection 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zoledronic acid Injection 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.
Renal ToxicityIn the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zoledronic acid Injection 4 mg over 15 minutes in these trials (see Table 9).

Table 9: Percentage of Patients with Treatment-Emergent Renal Function Deterioration by Baseline Serum Creatinine*
Patient Population/Baseline Creatinine
Multiple Myeloma and Breast Cancer Zoledronic acid Injection 4 mg Pamidronate 90 mg
n/N (%) n/N (%)
Normal 27/246 (11%) 23/246 (9%)
Abnormal 2/26 (8%) 2/22 (9%)
Total 29/272 (11%) 25/268 (9%)
Solid Tumors Zoledronic acid Injection 4 mg Placebo
n/N (%) n/N (%)
Normal 17/154 (11%) 10/143 (7%)
Abnormal 1/11 (9%) 1/20 (5%)
Total 18/165 (11%) 11/163 (7%)
Prostate Cancer Zoledronic acid Injection 4 mg Placebo
n/N (%) n/N (%)
Normal 12/82 (15%) 8/68 (12%)
Abnormal 4/10 (40%) 2/10 (20%)
Total 16/92 (17%) 10/78 (13%)
*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zoledronic acid Injection to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zoledronic acid Injection (4 mg over 15 minutes), placebo, or pamidronate.In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zoledronic acid Injection dose.

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