Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of Exforge has been evaluated in five controlled clinical studies with 5,175 patients, 2,613 of whom received valsartan in combination with amlodipine. The following adverse reactions were found to be the most frequently occurring or the most significant or severe: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia and hot flush.

Tabulated list of adverse reactions
Adverse reactions have been ranked under headings of frequency 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).

MedDRA              Adverse reactions                               Frequency System organ                                          Exforge       Amlodipine      Valsartan class
Infections and      Nasopharyngitis                   Common             --             -- infestations        Influenza                         Common             --             -- Blood and           Haemoglobin and                     --               --         Not known lymphatic system    haematocrit decreased disorders           Leukopenia                            --         Very rare          -- Neutropenia                           --            --          Not known Thrombocytopenia,                     --         Very rare      Not known sometimes with purpura
Immune system       Hypersensitivity                    Rare         Very rare      Not known disorders
Metabolism and      Hyperglycaemia                      --           Very rare           -- nutrition           Hyponatraemia                   Uncommon            --               -- disorders
Psychiatric         Depression                          --          Uncommon             -- disorders           Anxiety                            Rare             --               -- Insomnia/sleep disorders            --          Uncommon             -- Mood swings                         --          Uncommon             -- Confusion                           --             Rare              -- Nervous system      Coordination abnormal           Uncommon            --               -- disorders           Dizziness                       Uncommon         Common              -- Dizziness postural              Uncommon            --               -- Dysgeusia                           --          Uncommon             -- Extrapyramidal syndrome             --          Not known            -- Headache                         Common          Common              -- Hypertonia                          --           Very rare           -- Paraesthesia                    Uncommon        Uncommon             -- Peripheral neuropathy,              --           Very rare           -- neuropathy
Somnolence                      Uncommon         Common             -- Syncope                             --          Uncommon            -- Tremor                              --          Uncommon            -- Hypoesthesia                        --          Uncommon            -- Eye disorders       Visual disturbance                Rare          Uncommon            -- Visual impairment               Uncommon        Uncommon            -- Ear and labyrinth   Tinnitus                          Rare          Uncommon            -- disorders           Vertigo                         Uncommon            --          Uncommon 

Cardiac disorders   Palpitations                    Uncommon   Common             -- Syncope                           Rare        --              --
Tachycardia                     Uncommon      --              --
Arrhythmias (including              --     Very rare          -- bradycardia, ventricular tachycardia, and atrial fibrillation)
Myocardial infarction               --      Very rare       --
Vascular            Flushing                            --      Common          -- disorders           Hypotension                       Rare     Uncommon         -- Orthostatic hypotension         Uncommon       --           --
Vasculitis                          --      Very rare   Not known
Respiratory,        Cough                           Uncommon    Very rare   Uncommon thoracic and        Dyspnoea                            --     Uncommon         -- mediastinal         Pharyngolaryngeal pain          Uncommon       --           -- disorders           Rhinitis                            --     Uncommon         -- Gastrointestinal    Abdominal discomfort,           Uncommon    Common      Uncommon disorders           abdominal pain upper
Change of bowel habit               --     Uncommon         --
Constipation                    Uncommon       --           --
Diarrhoea                       Uncommon   Uncommon         --
Dry mouth                       Uncommon   Uncommon         --
Dyspepsia                           --     Uncommon         --
Gastritis                           --      Very rare       --
Gingival hyperplasia                --      Very rare       --
Nausea                          Uncommon    Common          --
Pancreatitis                        --      Very rare       --
Vomiting                            --     Uncommon         --
Hepatobiliary       Liver function test abnormal,       --     Very rare*   Not known disorders           including blood bilirubin increase
Hepatitis                          --      Very rare          --
Intrahepatic cholestasis,          --      Very rare          -- jaundice
Skin and            Alopecia                            --     Uncommon         -- subcutaneous        Angioedema                          --      Very rare   Not known tissue disorders    Dermatitis bullous                  --         --       Not known Erythema                        Uncommon       --           --
Erythema multiforme                 --      Very rare       --
Exanthema                         Rare     Uncommon         --
Hyperhidrosis                     Rare     Uncommon         --
Photosensitivity reaction           --     Uncommon         --
Pruritus                          Rare     Uncommon     Not known
Purpura                             --     Uncommon         --
Rash                            Uncommon   Uncommon     Not known
Skin discolouration                 --     Uncommon         --
Urticaria and other forms of        --      Very rare       -- rash
Exfoliative dermatitis             --      Very rare          --
Stevens-Johnson syndrome           --      Very rare          --
Quincke oedema                     --      Very rare          --
Toxic Epidermal Necrolysis         --      Not known          --


Musculoskeletal     Arthralgia                       Uncommon       Uncommon           -- and connective      Back pain                        Uncommon       Uncommon           -- tissue disorders    Joint swelling                   Uncommon           --             -- Muscle spasm                       Rare         Uncommon           -- Myalgia                              --         Uncommon       Not known Ankle swelling                       --          Common            -- Sensation of heaviness             Rare             --             -- Renal and           Blood creatinine increased           --             --         Not known urinary disorders   Micturition disorder                 --         Uncommon           -- Nocturia                             --         Uncommon           -- Pollakiuria                        Rare         Uncommon           -- Polyuria                           Rare             --             -- Renal failure and                    --             --         Not known impairment
Reproductive        Impotence                            --         Uncommon          -- system and          Erectile dysfunction                Rare            --            -- breast disorders    Gynaecomastia                        --         Uncommon          -- General disorders   Asthenia                          Common        Uncommon          -- and                 Discomfort, malaise                  --         Uncommon          -- administration      Fatigue                           Common         Common       Uncommon site conditions     Facial oedema                     Common            --            -- Flushing, hot flush               Common            --            --
Non cardiac chest pain               --         Uncommon          --
Oedema                            Common         Common           --
Oedema peripheral                 Common            --            --
Pain                                 --         Uncommon          --
Pitting oedema                    Common            --            --
Investigations      Blood potassium increased            --             --        Not known Weight increase                      --         Uncommon          --
Weight decrease                      --         Uncommon          --

*     Mostly consistent with cholestasis

Additional information on the combination
Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower incidence in patients who received the amlodipine/valsartan combination than in those who received amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by dose was as follows:


% of patients who experienced                          Valsartan (mg) peripheral oedema
0        40         80      160        320
0             3.0       5.5        2.4     1.6        0.9
Amlodipine (mg)          2.5           8.0       2.3        5.4     2.4        3.9 5             3.1       4.8        2.3     2.1        2.4
10           10.3       NA         NA      9.0        9.5

The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the amlodipine/valsartan combination.

Additional information on the individual components

Adverse reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential adverse reactions with Exforge as well, even if not observed in clinical trials or during the post-marketing period.

Amlodipine
Common          Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.
Uncommon        Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnoea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, increased urinary frequency, impotence, gynaecomastia, chest pain, malaise, weight increase, weight decrease.
Rare            Confusion.
Very rare       Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycaemia, hypertonia, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, hepatic enzymes increased*, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity.
Not known       Toxic Epidermal Necrolysis
* mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

Valsartan
Not known       Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia, increase of serum potassium, elevation of liver function values including increase of serum bilirubin, renal failure and impairment, elevation of serum creatinine, angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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/