Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
PROTELOS has been studied in clinical trials involving nearly 8,000 participants.
Long-term safety has been evaluated in postmenopausal women with osteoporosis treated for up to 60 months with strontium ranelate 2 g/day (n=3,352) or placebo (n=3,317) in phase III studies. Mean age was 75 years at inclusion and 23% of the patients enrolled were 80 to 100 years of age.

In a pooled analysis of randomised placebo-controlled studies in post-menopausal osteoporotic patients, the most common adverse reactions consisted of nausea and diarrhoea, which were generally reported at the beginning of treatment with no noticeable difference between groups afterwards. Discontinuation of therapy was mainly due to nausea .
There were no differences in the nature of adverse reactions between treatment groups regardless of whether patients were aged below or above 80 at inclusion.


Tabulated list of adverse reactions
The following adverse reactions have been reported during clinical studies and/or post marketing use with strontium ranelate.
Adverse reactions, listed below using : very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000to <1/100); rare (≥1/10,000to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).


System Organ Class            Frequency           Adverse reaction
Blood and lymphatic           Uncommon            Lymphadenopathy (in association disorders                                         with hypersensitivity skin reactions) Rare                Bone marrow failure#
Eosinophilia (in association with hypersensitivity skin reactions)
Metabolism and nutrition   Common        Hypercholesterolaemia disorders
Psychiatric disorders      Common        Insomnia
Uncommon      Confusion
Nervous system disorders   Common        Headache
Disturbances in consciousness
Memory loss
Dizziness
Paraesthesia
Uncommon     Seizures
Ear and labyrinth disorders Common       Vertigo
Cardiac disorders           Common       Myocardial infarction
Vascular disorders          Common       Venous thromboembolism (VTE) Respiratory, thoracic and   Common       Bronchial hyperreactivity mediastinal disorders
Gastrointestinal disorders  Common       Nausea
Diarrhoea and Loose stools
Vomiting
Abdominal pain
Gastrointestinal pain
Gastrooesophageal reflux
Dyspepsia
Constipation
Flatulence
Uncommon      Oral mucosal irritation (stomatitis and/or mouth ulceration)
Dry mouth
Hepatobiliary disorders    Common        Hepatitis
Uncommon      Serum transaminase increased (in association with hypersensitivity skin reactions)
Skin and subcutaneous      Very common   Hypersensitivity skin reactions (rash, tissue disorders                         pruritus, urticaria, angioedema)§ Common        Eczema
Uncommon      Dermatitis
Alopecia
Rare          Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS) (see
section 4.4)#
Very rare            Severe cutaneous adverse reactions
(SCARs): Stevens-Johnson syndrome and toxic epidermal necrolysis* (see section 4.4)#
Musculoskeletal and         Very common           Musculoskeletal pain (muscle spasm, connective tissue disorders                       myalgia, bone pain, arthralgia and pain in extremity)§
General disorders and        Common               Peripheral oedema administration site          Uncommon             Pyrexia (in association with conditions                                        hypersensitivity skin reactions) Malaise
Investigations               Common               Blood Creatine phosphokinase (CPK) increaseda
§
Frequency in Clinical Trials was similar in the drug and placebo group.
* In Asian countries reported as rare
# For adverse reaction not observed in clinical trials, the upper limit of the 95% confidence interval is not higher than 3/X with X representing the total sample size summed up across all relevant clinical trials and studies.
a
Musculo-skeletal fraction > 3 times the upper limit of the normal range. In most cases, these values spontaneously reverted to normal without change in treatment.

Description of selected adverse reactions
Venous thromboembolism
In phase III studies, the annual incidence of venous thromboembolism (VTE) observed over 5 years was approximately 0.7%, with a relative risk of 1.4 (95% CI = [1.0 ; 2.0]) in strontium ranelate treated patients as compared to placebo (see section 4.4).

Myocardial infarction
In pooled randomised placebo-controlled studies of post-menopausal osteoporotic patients, a significant increase of myocardial infarction has been observed in strontium ranelate treated patients as compared to placebo (1.7% versus 1.1 %), with a relative risk of 1.6 (95% CI = [1.07 ; 2.38]).

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system
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=AdversEffect Medic@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).