Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Within three days after Zomera administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see description of selected adverse reactions).

The following are the important identified risks with Zomera in the approved indications: Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks are shown in Table 1.


ZOM CON API NOV16 CL V10                                                               EU SmPC 06.2016 Tabulated list of adverse reactions
The following adverse reactions, listed in Table 1, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: 
Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders
Common:                            Anaemia
Uncommon:                          Thrombocytopenia, leukopenia
Rare:                              Pancytopenia
Immune system disorders
Uncommon:                          Hypersensitivity reaction
Rare:                              Angioneurotic oedema
Psychiatric disorders
Uncommon:                          Anxiety, sleep disturbance
Rare:                              Confusion
Nervous system disorders
Common:                            Headache
Uncommon:                          Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor,
somnolence
Very rare:                       Convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia)
Eye disorders
Common:                          Conjunctivitis
Uncommon:                        Blurred vision, scleritis and orbital inflammation
Rare:                            Uveitis
Very rare:                       Episcleritis
Cardiac disorders
Uncommon:                        Hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse
Rare:                            Bradycardia, cardiac arrhythmia (secondary to hypocalcaemia)
Respiratory, thoracic and mediastinal disorders
Uncommon:                         Dyspnoea, cough, bronchoconstriction Rare:                             Interstitial lung disease
Gastrointestinal disorders
Common:                           Nausea, vomiting, decreased appetite Uncommon:                         Diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth
Skin and subcutaneous tissue disorders
Uncommon:                           Pruritus, rash (including erythematous and macular rash), increased sweating
Musculoskeletal and connective tissue disorders
Common:                             Bone pain, myalgia, arthralgia, generalised pain
Uncommon:                        Muscle spasms, osteonecrosis of the jaw 
ZOM CON API NOV16 CL V10                                                          EU SmPC 06.2016 Very rare:                           Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)
Renal and urinary disorders
Common:                                Renal impairment
Uncommon:                              Acute renal failure, haematuria, proteinuria Rare:                                  Acquired Fanconi syndrome
General disorders and administration site conditions
Common:                            Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing)
Uncommon:                          Asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling,
induration), chest pain, weight increase,
anaphylactic reaction/shock, urticaria
Rare:                              Arthritis and joint swelling as a symptom of acute phase reaction
Investigations
Very common:                       Hypophosphataemia
Common:                            Blood creatinine and blood urea increased, hypocalcaemia
Uncommon:                          Hypomagnesaemia, hypokalaemia
Rare:                              Hyperkalaemia, hypernatraemia

Description of selected adverse reactions
Renal function impairment
Zomera has been associated with reports of renal dysfunction. In a pooled analysis of safety data from Zomera registration trials for the prevention of skeletal-related events in patients with advanced malignancies involving bone, the frequency of renal impairment adverse events suspected to be related to Zomera (adverse reactions) was as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung and other solid tumours (3.2%). Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zomera 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 4 mg zoledronic acid (see section 4.4).

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, such as Zomera (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.

Atrial fibrillation
In one 3-year, randomised, 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 Zomera (zoledronic acid) 4 mg every 3-4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown.


ZOM CON API NOV16 CL V10                                                             EU SmPC 06.2016 Acute phase reaction
This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhoea arthralgia and arthritis with subsequent joint swelling. The onset time is ≤ 3 days post-Zomera infusion, and the reaction is also referred to using the terms “flu-like” or “post-dose” symptoms.

Atypical fractures of the femur
During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphopsphonate class adverse reaction).

Hypocalcaemia-related ADRs
Hypocalcaemia is an important identified risk with Zomera in the approved indications. Based on the review of both clinical trial and post-marketing cases, there is sufficient evidence to support an association between Zomera therapy, the reported event of hypocalcaemia, and the secondary development of cardiac arrhythmia. Furthermore, there is evidence of an association between hypocalcaemia and secondary neurological events reported in these cases including; convulsions, hypoaesthesia and tetany (see section 4.4).

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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go v.il