1). 1 ). 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.
Treatment of Osteoporosis in Postmenopausal Women The safety of zoledronic acid injection in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65 to 89 years with osteoporosis, diagnosed by BMD or the presence of a prevalent vertebral fracture.
The duration of the trial was three years with 3862 patients exposed to zoledronic acid injection and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses.
All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day. 9% in the placebo group. 1% in the placebo group. 8% for the zoledronic acid injection and placebo groups, respectively.
The safety of zoledronic acid injection in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50 to 95 years; 1065 patients were randomized to zoledronic acid injection and 1062 patients were randomized to placebo.
Zoledronic acid injection was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug.
Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions.
3% in the placebo group. 3% in the placebo group. 7% for the zoledronic acid injection and placebo groups, respectively. Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the zoledronic acid injection-treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.
Table 1. 0% of Patients with Osteoporosis and More Frequently Than in Placebo-Treated Patients Abbreviation: IV, intravenous or intravenously. , increased serum creatinine) and in rare cases, acute renal failure. 5 mg/dL during the screening visits were excluded.
The change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the zoledronic acid injection and placebo treatment groups over 3 years, including patients with creatinine clearance between 30-60 mL/min at baseline.
3) ] . Acute Phase Reaction The signs and symptoms of acute phase reaction occurred in Study 1 following zoledronic acid injection infusion, including fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%).
The majority of these symptoms occurred within the first 3 days following the dose of zoledronic acid injection and usually resolved within 3 days of onset but resolution could take up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed.
Zoledronic acid injection was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of zoledronic acid injection.
5 mg/dL) following zoledronic acid injection administration. No symptomatic cases of hypocalcemia were observed. 5 mg/dL. 5% of patients following administration of placebo. Osteonecrosis of the Jaw In the postmenopausal osteoporosis trial, Study 1, in 7736 patients, after initiation of therapy, symptoms consistent with ONJ occurred in one patient treated with placebo and one patient treated with zoledronic acid injection.
4) ] . No reports of ONJ were reported in either treatment group in Study 2. 4% (17 out of 3852) in the placebo group. 5% of patients (96 out of 3862) in the zoledronic acid injection group vs. 9% of patients (75 out of 3852) in the placebo group.
Over 90% of these events in both treatment groups occurred more than a month after the infusion. In an ECG sub-study, ECG measurements were performed on a subset of 559 patients before and 9 to 11 days after treatment. There was no difference in the incidence of atrial fibrillation between treatment groups suggesting these events were not related to the acute infusions.
2% (13 out of 1057) in the placebo group demonstrating no difference between treatment groups. Ocular Adverse Events Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid.
1%) patient treated with placebo developed iritis/uveitis/episcleritis. Prevention of Osteoporosis in Postmenopausal Women The safety of zoledronic acid injection in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged greater than or equal to 45 years.
Patients were randomized to one of three treatment groups: (1) zoledronic acid injection given at randomization and Month 12 (n = 198); (2) zoledronic acid injection given at randomization and placebo at Month 12 (n = 181); and (3) placebo given at randomization and Month 12 (n = 202).
Zoledronic acid injection was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 international units vitamin D supplementation per day.
4%). 0% in the two zoledronic acid injection groups and placebo group, respectively. Adverse reactions reported in at least 2% of patients with osteopenia and more frequently in the zoledronic acid injection-treated patients than placebo-treated patients are shown in Table 2.
Table 2. Adverse Reactions Occurring in Greater Than or Equal to 2% of Patients with Osteopenia and More Frequently Than in Placebo-Treated Patients Abbreviation: IV, intravenous or intravenously. 0 Abdominal pain Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one Adverse Drug Reaction (ADR).
0 Musculoskeletal pain Combined musculoskeletal pain and musculoskeletal chest pain as one ADR. 5 Ocular Adverse Events Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid.
1%) patients treated with zoledronic acid injection and 0 (0%) patients treated with placebo developed iritis/uveitis. 7%), which occurred within the first 3 days following the dose of zoledronic acid injection. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days.
Osteoporosis in Men The safety of zoledronic acid injection in men with osteoporosis or osteoporosis secondary to hypogonadism was assessed in a two year randomized, multicenter, double-blind, active controlled group study of 302 men aged 25 to 86 years.
One hundred fifty three (153) patients were exposed to zoledronic acid injection administered once annually with a 5 mg dose in 100 mL infused over 15 minutes for up to a total of two doses, and 148 patients were exposed to a commercially-available oral weekly bisphosphonate (active control) for up to two years.
All participants received 1000 mg of elemental calcium plus 800 to 1000 international units of vitamin D supplementation per day. The incidence of all-cause mortality (one in each group) and serious adverse events were similar between the zoledronic acid injection and active control treatment groups.
The percentage of patients experiencing at least one adverse event was comparable between the zoledronic acid injection and active control groups, with the exception of a higher incidence of post-dose symptoms in the zoledronic acid injection group that occurred within 3 days after infusion.
The overall safety and tolerability of zoledronic acid injection was similar to the active control. Adverse reactions reported in at least 2% of men with osteoporosis and more frequently in the zoledronic acid injection-treated patients than the active control-treated patients and either (1) not reported in the postmenopausal osteoporosis treatment trial or (2) reported more frequently in the trial of osteoporosis in men are presented in Table 3.
Therefore, Table 3 should be viewed in conjunction with Table 1.
Table 3:
Adverse Reactions Occurring in Greater Than or Equal to 2% of Men with Osteoporosis and More Frequently in the Zoledronic Acid Injection-Treated Patients Than the Active Control-Treated Patients and Either (1) Not Reported in the Postmenopausal Osteoporosis Treatment Trial or (2) Reported More Frequently in This Trial Abbreviation: IV, intravenous or intravenously.
7 Abdominal pain Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one Adverse Drug Reaction (ADR). 8 Musculoskeletal pain Combined musculoskeletal pain and musculoskeletal chest pain as one ADR. 3) ] . 3%), which occurred within the first 3 days following the dose of zoledronic acid injection.
The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of zoledronic acid injection.
0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the zoledronic acid injection treatment group. 5 mg/dL. 6%) on zoledronic acid injection vs.
4%) on active control with local-site reactions. 4) ] . 5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: less than or equal to 3 months prior to randomization (prevention subpopulation), and greater than 3 months prior to randomization (treatment subpopulation).
The duration of the trial was one year with 416 patients exposed to zoledronic acid injection administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control) for one year.
All participants received 1000 mg of elemental calcium plus 400 to 1000 international units of vitamin D supplementation per day. 7% in the active control group. 0%, respectively. 2% in the zoledronic acid injection group vs. 4% in the active control group.
The overall safety and tolerability were similar between zoledronic acid injection and active control groups with the exception of a higher incidence of post-dose symptoms in the zoledronic acid injection group that occurred within 3 days after infusion.
The overall safety and tolerability profile of zoledronic acid injection in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the zoledronic acid injection postmenopausal osteoporosis clinical trial.
7%). 2%). 3%). 3) ] . Acute Phase Reaction Zoledronic acid injection was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the zoledronic acid injection postmenopausal osteoporosis clinical trial.
7% (3 of 416) in the zoledronic acid injection group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events. One patient had atrial flutter in the active control group.
5 mg/dL. Injection-Site Reactions There were no local reactions at the infusion site. 4) ] . Paget’s Disease of Bone In the Paget’s disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men, and women aged greater than 30 years with moderate to severe disease and with confirmed Paget’s disease of bone, 177 patients were exposed to zoledronic acid injection and 172 patients exposed to risedronate.
Zoledronic acid injection was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months. 4% in the risedronate group. 2% for the zoledronic acid injection and risedronate groups, respectively.
Adverse reactions occurring in at least 2% of the Paget’s patients receiving zoledronic acid injection (single 5 mg intravenous infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4.
Table 4. Adverse Reactions Reported in at Least 2% of Paget’s Patients Receiving Zoledronic Acid Injection (Single 5 mg Intravenous Infusion) or Risedronate (Oral 30 mg Daily for 2 Months) Over a 6-Month Follow-up Period Abbreviation: IV, intravenous or intravenously.
System Organ Class 5 mg IV Zoledronic Acid Injection % (N = 177) 30 mg/day x 2 Months Risedronate % (N = 172) Infections and Infestations Influenza 7 5 Metabolism and Nutrition Disorders Hypocalcemia 3 1 Anorexia 2 2 Nervous System Disorders Headache 11 10 Dizziness 9 4 Lethargy 5 1 Paresthesia 2 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 5 1 Gastrointestinal Disorders Nausea 9 6 Diarrhea 6 6 Constipation 6 5 Dyspepsia 5 4 Abdominal distension 2 1 Abdominal pain 2 2 Vomiting 2 2 Abdominal pain upper 1 2 Skin and Subcutaneous Tissue Disorders Rash 3 2 Musculoskeletal, Connective Tissue and Bone Disorders Arthralgia 9 11 Bone pain 9 5 Myalgia 7 4 Back pain 4 7 Musculoskeletal stiffness 2 1 General Disorders and Administrative-Site Conditions Influenza-like illness 11 6 Pyrexia 9 2 Fatigue 8 4 Rigors 8 1 Pain 5 4 Peripheral edema 3 1 Asthenia 2 1 Laboratory Findings In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels were observed.
4 mg/dL 9-11 days following zoledronic acid injection administration. 3) ] . Acute Phase Reaction The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the zoledronic acid injection-treated group compared to 8% in the risedronate-treated group.
Symptoms usually occur within the first 3 days following zoledronic acid injection administration. The majority of these symptoms resolved within 4 days of onset. 4) ] . 2 Post-Marketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during post approval use of zoledronic acid injection or bisphosphonate products: Acute Phase Reactions Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia.
Symptoms may be significant and lead to dehydration. Acute Renal Failure Acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors, such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period.
Transient rise in serum creatinine can be correctable with intravenous fluids. Allergic Reactions Allergic reactions with intravenous zoledronic acid, including anaphylactic reaction/shock, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported.
Asthma Exacerbations Asthma exacerbations have been reported. Hypocalcemia Hypocalcemia has been reported. Hypophosphatemia Hypophosphatemia has been reported. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported. Osteonecrosis of Other Bones Cases of osteonecrosis of other bones (including femur, hip, knee, ankle, wrist and humerus) have been reported; causality has not been determined in the population treated with zoledronic acid injection.
5) ] . Ocular Adverse Events Cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis, and orbital inflammation/edema. Other Hypotension in patients with underlying risk factors has been reported.