Zoltero 4 Adverse Reactions

Summary of the safety profile: The most serious adverse drug reactions reported in patients receiving Zoledronic acid in the approved indications are: anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal function impairment, acute phase reaction, and hypocalcaemia. The frequencies of these adverse reactions are shown in Table 7 or shown as adverse reactions from 'Spontaneous reports and literature cases' with 'not known' frequency.
Frequencies of adverse reactions for Zoledronic acid 4 mg are mainly based on data collected from chronic treatment. Adverse reactions to Zoledronic acid are usually mild and transient and similar to those reported for other bisphosphonates. Those reactions can be expected to occur in approximately one third of patients treated with Zoledronic acid.
Within three days after Zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including pyrexia, fatigue, bone pain, chills, influenza-like illness, arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see Description of selected adverse reaction as follows). Cases of arthralgia and myalgia have been reported.
Very commonly, the reduction in renal calcium excretion is accompanied by a fall in serum phosphate levels, which is asymptomatic not requiring treatment. Commonly, the serum calcium may fall to asymptomatic hypocalcaemic levels.
Gastrointestinal reactions, such as nausea and vomiting have been commonly reported following intravenous infusion of Zoledronic acid. Uncommonly, local reactions at the infusion site such as redness or swelling and/or pain were also observed.
Anorexia was commonly reported in patients treated with Zoledronic acid 4 mg. Rash or pruritus has been uncommonly observed.
As with other bisphosphonates, cases of conjunctivitis have been commonly reported.
Based on pooled analysis of placebo controlled studies, severe anaemia (Hb < 8.0 g/dL) was commonly reported in patients receiving Zoledronic acid 4 mg.
Adverse reactions (Table 7) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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). (See Table 7.)

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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse reactions have been reported during post-marketing experience with Zoledronic acid via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency (which is therefore categorized as not known) or establish a causal relationship to drug exposure.
Immune system disorders: anaphylactic reaction/shock.
Nervous system disorders: somnolence.
Eye disorders: episcleritis, scleritis and orbital inflammation.
Cardiac disorders: atrial fibrillation.
Vascular disorders: hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors.
Respiratory, thoracic and mediastinal disorders: bronchospasm.
Skin and subcutaneous tissue disorders: urticaria.
Musculoskeletal and connective tissue disorders: severe and occasionally incapacitating bone, joint, and/or muscle pain, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction, including Zoledronic acid).
Description of selected adverse reactions: Renal function impairment: Zoledronic acid has been associated with reports of renal function impairment. In a pooled analysis of safety data from Zoledronic acid registration trials for the prevention of skeletalrelated events in patients with advanced malignancy involving bone, the frequency of renal function impairment adverse events suspected to be related to Zoledronic acid (adverse reactions) was as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung and other solid tumors (3.2%). Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoledronic acid or other bisphosphonates, as well as concomitant use of nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of Zoledronic acid (see Precautions and Interactions).
Osteonecrosis of the jaw: Cases of osteonecrosis (primarily of the jaws) 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 jaws has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see Precautions). Data suggests a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).
Acute phase reaction: This adverse drug reaction consists of a constellation of symptoms that includes pyrexia, fatigue, bone pain, chills, influenza-like illness, arthritis with subsequent joint swelling. The onset time is ≤ 3 days post-Zoledronic acid infusion, and the reaction is also referred to using the terms "flu-like" or "post-dose" symptoms; these symptoms usually resolve within a few days.
Atrial fibrillation: In one 3 year, randomized, double-blind controlled trial that evaluated the efficacy and safety of zoledronic acid 5 mg once yearly vs placebo in the treatment of postmenopausal osteoporosis (PMO), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed in other trials with zoledronic acid, including those with Zoledronic acid (zoledronic acid) 4 mg every 3 to 4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown.