ZOLEDRONIC ACID (Page 3 of 8)
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypercalcemia of Malignancy
The safety of Zoledronic acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 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.
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.
Grade 3 | ||||
---|---|---|---|---|
Laboratory Parameter | Zoledronic acid Injection | Pamidronate | ||
4 mg | 90 mg | |||
n/N | (%) | n/N | (%) | |
Serum Creatinine 1 | 2/86 | (2%) | 3/100 | (3%) |
Hypocalcemia 2 | 1/86 | (1%) | 2/100 | (2%) |
Hypophosphatemia 3 | 36/70 | (51%) | 27/81 | (33%) |
Hypomagnesemia 4 | 0/71 | — | 0/84 | — |
Grade 4 | ||||
---|---|---|---|---|
Laboratory Parameter | Zoledronic acid Injection | Pamidronate | ||
4 mg | 90 mg | |||
n/N | (%) | n/N | (%) | |
Serum Creatinine 1 | 0/86 | — | 1/100 | (1%) |
Hypocalcemia 2 | 0/86 | — | 0/100 | — |
Hypophosphatemia 3 | 1/70 | (1%) | 4/81 | (5%) |
Hypomagnesemia 4 | 0/71 | — | 1/84 | (1%) |
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 Reaction (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 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.
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 | ||||||
Laboratory Parameter | Grade 3 | |||||
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 | ||||||
Laboratory Parameter | Grade 4 | |||||
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 Toxicity
In 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).
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%) |
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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