Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of safety profile
The safety profile of ramipril + hydrochlorothiazide includes adverse reactions occurring in the context of hypotension and/or fluid depletion due to increased diuresis. The ramipril active substance may induce persistent dry cough, while the hydrochlorothiazide active substance may lead to worsening of glucose, lipid and uric acid metabolism. The two active substances have inverse effects on plasma potassium. Serious adverse reactions include angioedema or anaphylactic reaction, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Tabulated list of adverse reactions

Adverse reactions frequency is defined 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).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Common          Uncommon          Very rare        Not known
Neoplasms                                                                Non-melanoma benign,                                                                  skin cancer* malignant and                                                            (Basal cell unspecified                                                              carcinoma and (incl cysts and                                                          Squamous cell polyps)                                                                  carcinoma) 
*Non-melanoma skin cancer: Based on available data from
epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed
(see also sections
4.4 and 5.1).
Blood and                          White blood cell                   Bone marrow lymphatic                          count                              failure, system                             decreased, red                     neutropenia disorders                          blood cell count                   including decreased,                         agranulocytosis,
haemoglobin                        pancytopenia,
decreased,                         eosinophilia,
haemolytic                         haemoconcentratio anaemia,                           n in the context of platelet count                     fluid depletion decreased
Immune system                                                         Anaphylactic or disorders                                                             anaphylactoid reactions to either ramipril or anaphylactic reaction to hydrochlorothiazid e, antinuclear antibody increased
Endocrine                                                             Syndrome of disorders                                                             inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and   Diabetes          Anorexia,          Blood           Blood sodium nutrition        mellitus          decreased          potassium       decreased disorders        inadequate        appetite           increased due control,                             to ramipril     Glycosuria, glucose           Blood                              metabolic tolerance         potassium                          alkalosis, decreased,        decreased,                         hypochloraemia, blood glucose     thirst due to                      hypomagnesaemia increased,        hydrochlorothia                    , hypercalcaemia, blood uric acid   zide                               dehydration due to increased,                                           hydrochlorothiazid gout                                                 e aggravated,
blood cholesterol and/or

triglycerides increased due to hydrochlorothi azide
Psychiatric                       Depressed          Confusional state, disorders                         mood, apathy,      restlessness, anxiety,           disturbance in nervousness,       attention sleep disorders including somnolence
Nervous system   Headache,        Vertigo,           Cerebral disorders        dizziness        paraesthesia,      ischaemia tremor, balance    including disorder,          ischaemic stroke burning            and transient sensation,         ischaemic attack,
dysgeusia,         psychomotor skills ageusia            impaired, parosmia
Eye disorders                     Visual             Xanthopsia, disturbance        lacrimation including          decreased due to blurred vision,    hydrochlorothiazid conjunctivitis     e; choroidal effusion,
secondary acute angle- closure glaucoma and/or acute myopia due to hydrochlorothiazid e
Ear and                           Tinnitus           Hearing impaired labyrinth disorders
Cardiac                           Myocardial         Myocardial disorders                         ischaemia          infarction including angina pectoris,
tachycardia,
arrhythmia,
palpitations,
oedema peripheral
Vascular                          Hypotension,       Thrombosis in the disorders                         orthostatic        context of severe blood pressure     fluid depletion,
decreased,         vascular stenosis,
hypoperfusion,

syncope,                           Raynaud’s flushing                           phenomenon,
vasculitis
Respiratory,       Non-productive Sinusitis,           Acute          Bronchospasm thoracic and       tickling cough, dyspnoea,           respiratory    including asthma mediastinal        bronchitis      nasal               distress       aggravated disorders                          congestion          syndrome (ARDS) (see    Alveolitis allergic,
section 4.4)   non cardiogenic pulmonary oedema due to hydrochlorothiazid e
Gastrointestinal                   Gastrointestinal    Vomiting,      Pancreatitis (cases disorders                          inflammation,       aphtous        of fatal outcome digestive           stomatitis,    have been very disturbances,       glossitis,     exceptionally abdominal           diarrhoea,     reported with ACE discomfort,         abdominal      inhibitors),
dyspepsia,          pain upper,    pancreatic gastritis,          dry mouth      enzymes nausea,                            increased, small constipation                       bowel angioedema

Gingivitis due to                  Sialoadenitis due hydrochlorothia                    to zide                               hydrochlorothiazid e
Hepatobiliary                      Cholestatic or                     Acute hepatic disorders                          cytolytic                          failure, jaundice hepatitis (fatal                   cholestatic,
outcome has                        hepatocellular been very                          damage exceptional),
hepatic enzyme and/or bilirubin conjugated increased

Calculous cholecystitis due to hydrochlorothia zide
Skin and                           Angioedema:                        Toxic epidermal subcutaneous                       very                               necrolysis, tissue disorders                   exceptionally,                     Stevens-Johnson the airway                         syndrome,
obstruction                        erythema resulting from                     multiforme,

angioedema        pemphigus,
may have a        psoriasis fatal outcome;    aggravated,
dermatitis        exfoliative psoriasiform,     dermatitis,
hyperhidrosis,    photosensitivity rash, in          reaction,
particular        onycholysis,
maculo-papular,   pemphigoid or pruritus,         lichenoid alopecia          exanthema or enanthema,
urticaria

Systemic lupus erythematosus due to hydrochlorothiazid e
Musculoskeletal               Myalgia           Arthralgia, muscle and connective                                  spasms tissue disorders
Muscular weakness,
musculoskeletal stiffness, tetany due to hydrochlorothiazid e
Renal and                     Renal             Worsening of a urinary                       impairment        pre-existing disorders                     including renal   proteinuria failure acute,
urine output      Interstitial nephritis increased,        due to blood urea        hydrochlorothiazid increased,        e blood creatinine increased
Reproductive                  Transient         Libido decreased, system and                    erectile          gynaecomastia breast disorders              impotence
General            Fatigue,   Chest pain,
disorders and      asthenia   pyrexia administration site conditions


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/