Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the Safety Profile
The presented adverse reactions in this section have been derived from different studies in the clinical program.
Aclasta was studied in postmenopausal osteoporosis in the pivotal fracture trial, a randomised, double-blind, placebo-controlled, multinational study including 7,736 women and in Paget’s disease in two double blind, randomised 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 randomised, double-blind, placebo- controlled, multinational endpoint study of 2,127 men and women.
Aclasta was studied in the treatment and prevention of glucocorticoid-induced osteoporosis in a randomised, multicentre, double-blind, stratified, active-controlled study of 833 men and women.
Finally, Aclasta was studied in the prevention of bone loss in postmenopausal women with osteopenia in a 2-year randomised, multi-centre, double-blind, placebo-controlled study of 581 postmenopausal women.

Treatment of postmenopausal osteoporosis, osteoporosis in men, prevention of clinical fractures after low ACL API MAY21 V13                              Page 5 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 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.

Tabulated summary of adverse drug reactions from clinical trials:
Adverse drug reactions from clinical trials (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.

Table 1
Infections and infestations
Uncommon:             Influenza, nasopharyngitis
Blood and lymphatic system disorders
Uncommon:             Anaemia
Immune system disorders
Not known***          Hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock
Metabolism and nutrition disorders
Common:               Hypocalcaemia**
Uncommon:             Decreased appetite

Rare:                    Hypophosphataemia
Psychatric disorders
Uncommon:                Insomnia

Nervous system disorders
Common:             Headache, dizziness
Uncommon:           Lethargy*, paraesthesia, somnolence, tremor, syncope, dysgeusia Eye disorders
Common:             Ocular hyperaemia
Uncommon:           Conjunctivitis, eye pain
Rare:               Uveitis*, episcleritis, iritis
Not known***:       Scleritis and parophthalmia
Ear and labyrinth disorders
Uncommon:           Vertigo
Cardiac disorders
Common:                  Atrial fibrillation
Uncommon:                Palpitations
Vascular disorders
Uncommon:                Hypertension, flushing
ACL API MAY21 V13                              Page 6 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 Not known***:        Hypotension (some of the patients had underlying risk factors) Respiratory, thoracic and mediastinal disorders
Uncommon:            Cough, dyspnoea*
Gastrointestinal disorders
Common:              Nausea, vomiting, diarrhoea
Uncommon:            Dyspepsia*, abdominal pain upper, abdominal pain*, gastro- oesophageal reflux disease, constipation, dry mouth, oesophagitis* toothache, gastritis #
Skin and subcutaneous tissue disorders
Uncommon:            Rash, hyperhidrosis*, pruritus, erythema
Musculoskeletal and connective tissue disorders
Common:              Myalgia*, arthralgia*, bone pain, back pain, pain in extremity.
Uncommon:            Neck pain, musculoskeletal stiffness*, joint swelling*, muscle spasms, musculoskeletal chest pain*, musculoskeletal pain, joint stiffness*,
arthritis, muscular weakness
Rare:                Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)
Very rare:            Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)

Not known***:         Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects) Renal and urinary disorders
Uncommon:            Blood creatinine increased, pollakiuria, proteinuria 
Not known***:      Renal impairment. Rare cases of renal failure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre- existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period (see sections 4.4 and 4.8 Class effects).
General disorders and administration site conditions
Very common:        Pyrexia
Common:             Influenza-like illness, chills, fatigue*, asthenia, pain*, malaise, infusion site reaction
Uncommon:           Peripheral oedema, thirst*, acute phase reaction*, non-cardiac chest pain
Not known***:       Dehydration secondary to acute phase reactions (post-dose symptoms such as pyrexia, vomiting and diarrhoea)
Investigations
Common:               C-reactive protein increased
Uncommon:             Blood calcium decreased


*       Adverse reactions reported most frequently in the individual studies are: Very common: myalgia, arthralgia, fatigue, pain Common: lethargy, dyspnoea, dyspepsia, oesophagitis, abdominal pain, hyperhidrosis, musculoskeletal (muscle) stiffness, joint swelling, musculoskeletal chest pain, joint stiffness, decreased appetite, thirst, acute phase reaction Uncommon: uveitis.
**      Common in Paget’s disease only.
*** Based on post-marketing reports. Frequency cannot be estimated from available data.
#
Observed in patients taking concomitant glucocorticosteroids.
†      Identified in post-marketing experience.
ACL API MAY21 V13                              Page 7 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 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).

Table 2             Suspected adverse reactions to Aclasta (investigator assessment) in prevention of postmenopausal osteoporosis. The adverse reactions listed are either in addition to or reported with a higher frequency than those in Table 1 Metabolism and nutrition disorders
Common:              Anorexia
Psychiatric disorders
Uncommon:            Anxiety
Nervous system disorders
Very Common:         Headache
Common:              Tremor, lethargy
Uncommon:            Hypoaesthesia,
Eye disorders
Common:              Conjunctivitis, eye pain, iritis
Uncommon:            Vision blurred
Gastrointestinal disorders
Very Common:         Nausea
Common:              Abdominal pain, abdominal pain upper, constipation Skin and subcutaneous tissue disorders
Common:              Night sweats
Musculoskeletal and connective tissue disorders
Very common:         Myalgia
Common:              Musculoskeletal pain, muscle spasms, musculoskeletal chest pain, pain in jaw, neck pain
Uncommon:            Flank pain
General disorders and administration site conditions
Very common:         Pain, chills
Common:              Oedema peripheral, infusion related reaction, non cardiac chest pain 
Description of selected adverse reactions

Atrial fibrillation
In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), 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 Aclasta and placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving Aclasta (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo.


ACL API MAY21 V13                               Page 8 of 17                    EU SmPC Mar2021, NZ DS AUG 2020 Class effects
Renal impairment
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 dysfunction 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 3–4 weeks, but it has been observed in patients after a single administration.

In clinical trials in 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 treatment groups over three 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.

Hypocalcaemia
In clinical trials in osteoporosis, 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 hypocalcaemia were observed.
In the Paget’s disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.
Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range (less than 2.10 mmol/l) occurred in 2.3% of Aclasta-treated patients in a large clinical trial compared to 21% of Aclasta- treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was much lower following subsequent infusions.
All patients received adequate supplementation with vitamin D and calcium in the post-menopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials (see also section 4.2).
In the trial for the prevention of clinical fractures following a recent hip fracture, vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin D prior to Aclasta administration (see section 4.2).

Local reactions
In a large clinical 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 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 of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, including zoledronic acid (see section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with Aclasta and one patient treated with placebo. Cases of ONJ have been reported in the post-marketing setting for Aclasta.

Acute phase reactions
The overall percentage of patients who reported acute phase reactions or post-dose symptoms (including serious cases) after Aclasta administration is as follows (frequencies derived from the study in treatment of post-menopausal osteoporosis): fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occurred 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 with subsequent annual doses of Aclasta. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used (see section 4.4).


ACL API MAY21 V13                                 Page 9 of 17                     EU SmPC Mar2021, NZ DS AUG 2020 Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/