Summary of the safety profile:
The presented adverse reactions have been derived from different studies in the clinical program (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). Aclasta was studied in postmenopausal osteoporosis in the pivotal fracture trial, a randomized, double-blind, placebo-controlled, multinational (HORIZON-PFT) study including 7,736 women and it's extension study including 2,456 women. Paget's disease in two double-blind, randomized safety and efficacy trials involving 357 patients; the prevention of clinical fractures in patients who suffered from a recent low-trauma hip fracture was demonstrated in a randomized, double-blind, placebo-controlled, multinational endpoint (HORIZON-RFT) study of 2,127 men and women. Aclasta was studied in the treatment and prevention of glucocorticoid-induced osteoporosis in a randomized, multicentre, double-blind, stratified, active-controlled study of 833 men and women. Aclasta was studied in men with osteoporosis or significant osteoporosis secondary to hypogonadism in a randomized, multicentre, double-blind, active-controlled study of 302 men. Finally, Aclasta was studied in the prevention of bone loss in postmenopausal women with osteopenia in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women.
Treatment of postmenopausal osteoporosis, osteoporosis in men, prevention of clinical fractures after low trauma hip fracture, treatment and prevention of glucocorticoid-induced osteoporosis and paget's disease of the bone:
In the studies to support the indications treatment of osteoporosis in men and postmenopausal women, prevention of clinical fractures after low trauma hip fracture, treatment and prevention of glucocorticoid-induced osteoporosis and Paget's disease of the bone, there were no significant differences in the overall incidence of serious adverse events compared to placebo or comparator and most adverse events were mild to moderate. Aclasta was administered once a year in all aforementioned studies.
Consistent with the intravenous administration of bisphosphonates, Aclasta has been most commonly associated with the following post-dose symptoms (frequencies derived from the study in treatment of postmenopausal osteoporosis: Fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occur within the first 3 days following Aclasta administration. The majority of these symptoms were mild to moderate in nature and resolved within 3 days of the event onset. The incidence of these symptoms decreased markedly with subsequent annual doses of Aclasta.
The incidence of post-dose symptoms occurring within the first 3 days after administration of Aclasta, can be reduced by approximately 50% with the administration of paracetamol or ibuprofen shortly following Aclasta administration as needed.
Tabulated summary of adverse drug reactions from clinical trials:
Adverse drug reactions from clinical trials (see Table 1) are listed according to system organ classes in MedDRA. These are suspected adverse reactions to Aclasta (investigator assessment) in the pooled studies supporting the indications: treatment of osteoporosis in men and postmenopausal women, prevention of clinical fractures after low trauma hip fracture, treatment and prevention of glucocorticoid-induced osteoporosis and Paget's disease of the bone. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency using the following convention (CIOMS III) is also provided for each adverse drug reaction: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports. (See Table 1.)
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Additional adverse reactions which were reported in the individual studies but are not included in the Table 1 (due to a lower frequency in the Aclasta group compared with that of the placebo group when the data was pooled) include: Cardiac disorders:
Atrial fibrillation*, palpitations.
General disorders and administration site conditions:
Infusion site reaction.
Increased C-reactive protein.
Metabolism and nutrition disorders:
Nervous system disorders:
*see Atrial Fibrillation under Description of Selected Adverse Reactions.
Prevention of Postmenopausal Osteoporosis:
The overall safety and tolerability profile of Aclasta in the prevention of osteoporosis was comparable to the adverse reaction profile reported in the Aclasta postmenopausal osteoporosis treatment trial, however, there was a higher incidence of post-dose symptoms in the Aclasta-treated osteopenic patients that occurred within 3 days after infusion: Pain, fever, chills, myalgia, nausea, headache, fatigue, dizziness and arthralgia. The majority of these symptoms were mild to moderate and resolved within 3 days of the reaction onset. The incidence of these symptoms decreased with a subsequent dose of Aclasta. Suspected adverse reactions to Aclasta (investigator assessment) in prevention of postmenopausal osteoporosis which occurred more than once and which are either not included in Table 1 or reported with a higher frequency in the prevention of postmenopausal osteoporosis trial are summarised in Table 2 using the following convention: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100).
The adverse reactions listed are either in addition to or reported with a higher frequency than those in Table 1. (See Table 2.)
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Description of selected adverse reactions: Renal impairment:
Treatment with intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise or additional risk factors (e.g. advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 4 mg dose every 3 to 4 weeks, but it has also been observed in patients after a single administration.
In the HORIZON-PFT core trial, the change in creatinine clearance (measured annually prior to dosing), and the incidence of renal failure and impairment was comparable for both the Aclasta and placebo treatment groups over 3 years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of Aclasta-treated patients versus 0.8% of placebo-treated patients.
In the 3-year HORIZON-PFT extension trial, 2.9% of the patients who continued to receive Aclasta (i.e. 6-years total exposure to Aclasta) vs. 0.65% of the patients who discontinued (i.e. 3-years Aclasta in the core then 3-years placebo in the extension trial) had transient increases in serum creatinine. However, the mean change from baseline in serum creatinine over time was <0.5 micromol/L for both treatment groups at the end of the trial (i.e. +0.4 and -0.26 micromol/L for both treatments, respectively).
In the studies to support the indications prevention of clinical fractures after hip fracture in men and women, treatment of osteoporosis in men, treatment and prevention of glucocorticoid-induced osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Aclasta and placebo or comparator treatment groups.
In the prevention of postmenopausal osteoporosis trial, the change in creatinine clearance (measured annually prior to dosing and at one month after the first dose) and the incidence of renal failure and impairment were comparable in the Aclasta and placebo groups.
In the HORIZON-PFT core trial, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/L) following Aclasta administration.
No symptomatic cases of hypocalcemia were observed.
In the HORIZON-PFT extension trial, 0.4% of patients who received placebo during the core trial and Aclasta during the extension trial had confirmed events of hypocalcaemia (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). There were no confirmed hypocalcaemia events in the other treatment groups. All of the cases were asymptomatic, no treatment or intervention was required.
In the HORIZON-RFT, treatment of male osteoporosis and treatment and prevention of glucocorticoid-induced osteoporosis trials, there were no patients who had treatment emergent serum calcium levels below 1.87 mmol/L.
In the prevention of postmenopausal osteoporosis trial, there was one patient who had treatment emergent serum calcium levels below 1.87 mmol/L.
In the Paget's disease trials, symptomatic hypocalcemia was observed in approximately 1% of patients, all of which resolved.
In the HORIZON-PFT trial, local reactions at the infusion site such as redness, swelling and/or pain were reported (0.7%) following the administration of zoledronic acid.
In the HORIZON-RFT trial, the event rate was comparable for both the Aclasta and placebo treatment groups.
In the treatment of male osteoporosis trial, the event rate was 2.6% in the zoledronic acid treatment group and 1.4% in the alendronate treatment group.
In the treatment and prevention of glucocorticoid-induced osteoporosis trial, no local reactions were reported.
In the prevention of postmenopausal osteoporosis trial, the event rate was 1.1% in Aclasta-treated patients compared to 2.0% in placebo-treated patients.
Osteonecrosis of the Jaw:
Cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates, including zoledronic acid (uncommon). Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw (ONJ) has multiple well-documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, antiangiogenic drugs, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anemia, coagulopathies, infection, pre-existing dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see Precautions).
In the HORIZON-PFT core trial in 7,736 intention-to-treated (ITT) patients, ONJ has been reported in one patient treated with Aclasta and one patient treated with placebo. Both cases resolved.
In the HORIZON-PFT extension trial in 2,456 ITT patients, there were two confirmed cases of ONJ, one in the group of patients receiving Aclasta during the core and the extension trial (i.e. 6-years total exposure to Aclasta) and one in the group of patients receiving placebo in the core and Aclasta in the extension trial (i.e. 3-years exposure to Aclasta). Both patients had a history of poor dental hygiene and both made a complete recovery.
In the HORIZON-RFT, treatment of male osteoporosis, treatment and prevention of glucocorticoid-induced osteoporosis and prevention of postmenopausal osteoporosis trials there were no cases of Osteonecrosis of the jaw.
In one 3 year trial in postmenopausal women with osteoporosis (HORIZON-PFT), the overall incidence of all atrial fibrillation adverse events was 2.5% (96 out of 3,862) in the Aclasta group vs. 1.9% (75 out of 3,852) in the placebo group. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3,862) in patients receiving Aclasta compared with 0.6% (22 out of 3,852) in patients receiving placebo. The mechanism behind the increased incidence of atrial fibrillation is unknown. The imbalance observed in this trial has not been observed in other clinical trials with zoledronic acid.
In the HORIZON-PFT extension trial, the incidence of atrial fibrillation adverse events was 3.4% (21 out of 613) in the group of patients who received Aclasta in the core and extension trial (i.e. 6-years of total exposure to Aclasta) vs. 2.1% (13 out of 616) in patients who received Aclasta in the core (i.e. 3-years exposure) and placebo in the extension trial. The rate of atrial fibrillation serious adverse events was 2% (12 out of 613) in patients who received 6-years Aclasta compared with 1.1% (7 out of 616) in patients who received 3-years Aclasta then 3-years placebo. These imbalances were not statistically significant.
Adverse drug reactions from post-marketing spontaneous reports:
The following adverse drug reactions have been derived from post-marketing experience with Aclasta via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, adverse drug reactions are presented in order of decreasing seriousness.
Immune system disorders:
Hypersensitivity reactions including anaphylactic reaction, anaphylactic shock, angioedema, bronchospasm, urticaria.
Metabolism and nutrition disorders:
dehydration secondary to post-dose symptoms such as pyrexia, vomiting and diarrhea; hypotension in patients with underlying risk factors.
Musculoskeletal and connective tissue disorders:
osteonecrosis of jaw (see Precautions).
Renal and urinary disorders:
renal failure requiring dialysis or with fatal outcome*, renal impairment (see Precautions).
*Especially in patients with pre-existing renal compromise or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy or dehydration in the post-infusion period.