1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. gov/medwatch . 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 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. 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 n (%) Pamidronate 90 mg 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 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 Laboratory Parameter Grade 3 Zoledronic Acid Injection 4 mg Pamidronate 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 0/84 0 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). 5 mEq/L). 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 Laboratory Parameter Grade 4 Zoledronic acid injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 0/86 0 1/100 (1%) Hypocalcemia 2 0/86 0 0/100 0 Hypophosphatemia 3 1/70 (1%) 4/81 (5%) Hypomagnesemia 4 0/71 0 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 to 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. 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). 0 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 Greater Than or Equal to 10% Reported in Three Bone Metastases Clinical Trials by Body System Zoledronic Acid Injection 4 mg n (%) Pamidronate 90 mg n (%) Placebo n(%) Patients Studied Total No.
of Patients Total No. of Patients with any AE 1,031 1,015 (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 (28) (8) (4) Gastrointestinal Nausea Vomiting Constipation Diarrhea Abdominal Pain Dyspepsia Stomatitis Sore Throat 476 333 320 249 143 105 86 82 (46) (32) (31) (24) (14) (10) (8) (8) 266 183 162 162 81 74 65 61 (48) (33) (29) (29) (15) (13) (12) (11) 171 122 174 83 48 31 14 17 (38) (27) (38) (18) (11) (7) (3) (4) General Disorders and Administration Site Fatigue Pyrexia Weakness Edema Lower Limb Rigors 398 328 252 215 112 (39) (32) (24) (21) (11) 240 172 108 126 62 (43) (31) (19) (23) (11) 130 89 114 84 28 (29) (20) (25) (19) (6) Infections Urinary Tract Infection Upper Respiratory Tract Infection 124 101 (12) (10) 50 82 (9) (15) 41 30 (9) (7) Metabolism Anorexia Weight Decreased Dehydration Appetite Decreased 231 164 145 130 (22) (16) (14) (13) 81 50 60 48 (15) (9) (11) (9) 105 61 59 45 (23) (13) (13) (10) Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb 569 239 216 156 143 (55) (23) (21) (15) (14) 316 143 131 106 84 (57) (26) (24) (19) (15) 284 74 73 40 52 (62) (16) (16) (9) (11) Neoplasms Malignant Neoplasm Aggravated 205 (20) 97 (17) 89 (20) Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia 191 180 166 149 127 (19) (18) (16) (15) (12) 149 91 111 85 65 (27) (16) (20) (15) (12) 50 58 73 35 43 (11) (13) (16) (8) (10) Psychiatric Depression Anxiety Confusion 146 112 74 (14) (11) (7) 95 73 39 (17) (13) (7) 49 37 47 (11) (8) (10) Respiratory Dyspnea Cough 282 224 (27) (22) 155 129 (28) (23) 107 65 (24) (14) Skin Alopecia Dermatitis 125 114 (12) (11) 80 74 (14) (13) 36 38 (8) (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 8 and 9.
Table 8:
Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases *Serum creatinine data for all patients randomized after the 15-minute infusion amendment.
7 mEq/L) Laboratory Parameter Grade 3 Zoledronic Acid Injection 4 mg Pamidronate 90 mg Placebo 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 0 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%) * Serum creatinine data for all patients randomized after the 15-minute infusion amendment.
1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal). 7 mEq/L) Table 9: 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 4 mg Pamidronate 90 mg Placebo n/N (%) n/N (%) n/N (%) Serum Creatinine 1* 2/529 (<1%) 1/268 (<1%) 0/241 0 Hypocalcemia 2 7/973 (<1%) 3/536 (<1%) 2/415 (<1%) Hypophosphatemia 3 5/973 (<1%) 0/537 0 1/415 (<1%) Hypermagnesemia 4 0/971 0 0/535 0 2/415 (<1%) Hypomagnesemia 5 2/971 (<1%) 1/535 (<1%) 0/415 0 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.
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 10).
Table 10:
Percentage of Patients with Treatment-Emergent Renal Function Deterioration by Baseline Serum Creatinine* *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.
Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Normal Abnormal Total 27/246 2/26 29/272 (11%) (8%) (11%) 23/246 2/22 25/268 (9%) (9%) (9%) Solid Tumors Zoledronic Acid Injection 4 mg Placebo n/N (%) n/N (%) Normal Abnormal Total 17/154 1/11 18/165 (11%) (9%) (11%) 10/143 1/20 11/163 (7%) (5%) (7%) Prostate Cancer Zoledronic Acid Injection 4 mg Placebo n/N (%) n/N (%) Normal Abnormal Total 12/82 4/10 16/92 (15%) (40%) (17%) 8/68 2/10 10/78 (12%) (20%) (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. 2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of zoledronic acid injection. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaw but also of other anatomical sites including hip, femur and external auditory canal) have 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 a risk factor for ONJ. Caution is advised when zoledronic acid injection is administered with anti-angiogenic drugs as an increased incidence of ONJ has been observed with concomitant use of these drugs.
Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction.
4 ) ]. Acute Phase Reaction Within three days after zoledronic acid injection administration, an acute phase reaction has been reported, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, influenza-like illness and arthritis with subsequent joint swelling; these symptoms usually resolve within three days of onset, but resolution could take up to 7 to 14 days.
However, some of these symptoms have been reported to persist for a longer duration. 5) ]. 6 ) ]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use.
In some cases, symptoms resolved with topical steroids. Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have been reported.
Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.
Additional adverse reactions reported in postmarketing use include:
CNS : taste disturbance, hyperesthesia, tremor; Special Senses : blurred vision; uveitis; Gastrointestinal : dry mouth; Skin : Increased sweating; Musculoskeletal : muscle cramps; Cardiovascular : hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchospasms, interstitial lung disease (ILD) with positive rechallenge; Renal: hematuria, proteinuria, acquired Fanconi syndrome; General Disorders and Administration Site : weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities : hyperkalemia, hypernatremia, hypocalcemia (cardiac arrhythmias and neurologic adverse events including seizures, tetany, and numbness have been reported due to severe hypocalcemia).