Adverse reactions : תופעות לוואי

4.8 UNDESIRABLE EFFECTS
Adverse Reaction Overview
Cilazapril and hydrochlorothiazide) has been evaluated for safety in 4,102 individuals (3,992 patients treated for essential hypertension and 110 normal volunteers enrolled in pharmacokinetic studies). In controlled clinical trials, 1,097 patients received the combination, cilazapril and hydrochlorothiazide, 225 received placebo, 437 received cilazapril alone and 340 received hydrochlorothiazide alone.

The most common adverse effects with cilazapril include dry cough, rash, hypotension, dizziness, fatigue, headache, and nausea, dyspepsia and other gastrointestinal disturbances. The most common adverse effects with hydrochlorothiazide are nausea, fatigue and dizziness.

The most serious adverse reactions reported included hypotension (0.3%) and angioedema (0.1%) (see 4.4 special warnings and precautions). The most frequent adverse reactions reported for the cilazapril/hydrochlorothiazide combination were headache (5.5%), dizziness (3.9%), fatigue (2.8%), coughing (2.6%), and somnolence (1.2%). Discontinuation of treatment due to adverse events occurred in 2.7% of patients.

Adverse events that have occurred have been those that were previously reported with cilazapril or hydrochlorothiazide when used separately for the treatment of hypertension.
Description of selected adverse events
Hypotension may occur when starting treatment or increasing dose, especially in at-risk patients (see 4.4 SPECIAL WARNINGS AND PRECAUTIONS). Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.

Renal impairment and acute renal failure are more likely in patients with severe heart failure, renal artery stenosis, pre-existing renal disorders or volume depletion (see 4.4 special warnings and precautions).

Hyperkalemia is most likely to occur in patients with renal impairment and those taking potassium sparing diuretics or potassium supplements.

The events of transient ischemic attack and ischemic stroke reported rarely in association with ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular disease.
Similarly, myocardial ischemia may be related to hypotension in patients with underlying ischemic heart disease.

Hypokalemia may occur in patients receiving CILARIL PLUS, although less commonly than in patients receiving thiazide monotherapy.

The risk of hyponatremia is greater in women, patients with hypokalemia or low sodium/solute intake, and the elderly.

Non-melanoma skin cancer
Some pharmaco-epidemiological studies have suggested a higher risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin with increasing use of hydrochlorothiazide. A systematic review and meta-analysis suggested that, with important uncertainty, the use of hydrochlorothiazide for several years (>3 years) could lead to:
• 122 additional cases (95% CI, from 112 to 133 additional cases) of SCC per 1,000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 3 observational studies);
• 31 additional cases (95% CI, from 24 to 37 additional cases) of BCC per 1,000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 2 observational studies).


Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
See Table 3 for common adverse reactions (≥1%) reported by hypertensive patients treated with cilazapril and hydrochlorothiazide. The frequencies of ADRs from clinical trials for patients treated with cilazapril hydrochlorothiazide alone, and placebo alone in controlled clinical trials are also tabulated below. For comparison, adverse reactions tabulated for patients treated with cilazapril alone are as reported in the Product Monograph for cilazapril (cilazapril) tablets.
Table 3 Common Adverse Reactions (≥1%) reported by hypertensive patients treated with cilazapril and hydrochlorothiazide


Table Includes Frequencies for Hydrochlorothiazide Alone, and Placebo in Controlled Clinical Trials Cilazapril plus
Hydro-
Body System/               Cilazapril         Hydro-                                  Placebo chlorothiazide
Adverse Reaction            (N=2586)       chlorothiazide                              (N=225) (N=340)
(N=1097)
Gastrointestinal disorders
Nausea                               1.3%             1.0%                 1.8%                  0.4% General disorders and administration site conditions
Fatigue                              2.1%             2.8%                 2.1%                  2.2% Nervous system disorders
Headache                             5.1%             5.5%                 6.5%                  6.7% Dizziness                            3.0%             3.9%                 3.5%                  1.3% Somnolence                           0.5%             1.2%                   -                   0.9% Renal and urinary disorders
Micturition Frequency                0.2%             1.0%                 0.6%                  0.4% Respiratory, thoracic and mediastinal disorders
Coughing                             1.8%             2.6%                 0.3%                  0.4% 
Less Common Clinical Trial Adverse Reactions
Adverse reactions reported by patients treated with cilazapril and hydrochlorothiazide at a frequency <1% are as follows:

Cardiac disorders and Vascular disorders:
Palpitation (0.9%), Chest Pain (0.4%), Tachycardia (0.3%), Angina Pectoris (0.3%), Hypotension (0.3%), Postural Hypotension (0.1%), Edema Peripheral (0.3%), Edema Dependent (0.2%), Extrasystoles (0.2%), Myocardial Infarction (0.2%). Reported ≤0.1% were: Atrial Fibrillation, Bradycardia.

Gastrointestinal disorders:
Abdominal Pain (0.7%), Dyspepsia (0.7%), Diarrhea (0.5%), Flatulence (0.2%), Constipation (0.3%).
Reported ≤0.1% were: Anorexia, Melena, Vomiting.

General disorders and administration site conditions:
Asthenia (0.6%), Malaise (0.3%), Hot Flushes (0.2%). Reported ≤0.1% were: Pain, Allergy, Face Edema, Fever, Weight Increase, Rigors, Hypothermia, Polyuria, Nocturia, Flushing, Peripheral Ischemia, Cerebrovascular Disorder, Vasodilation, Vision Abnormal, Diplopia, Tinnitus, Ear Blockage, Purpura, Bleeding Time Increased, Gout, Thirst, Leukorrhea.

Musculoskeletal and connective tissue disorders
Back Pain (0.6%), Leg Cramps (0.6%), Arthralgia (0.3%), Myalgia (0.4%).

Nervous system disorders:
Hypoesthesia (0.3%), Paresthesia (0.3%), Vertigo (0.2%), Impotence (0.4%), Mouth Dry (0.3%), Sweating Increased (0.4%), Anxiety (0.2%), Depression (0.3%), Insomnia (0.1%), Nervousness (0.2%), Confusion (0.3%), Libido Decreased (0.2%). Reported ≤0.1% were: Libido Increased, Crying Abnormal, Paroniria, Dreaming Abnormal, Depersonalization, Neurosis.

Respiratory, thoracic and mediastinal disorders:
Rhinitis (0.7%), Upper Respiratory Tract Infection (0.1%), Pharyngitis (0.2%), Sinusitis (0.2%), Bronchitis (0.1%), Dyspnea (0.4%).

Skin and subcutaneous tissue disorders:
Rash (0.8%), Pruritus (0.4%). Reported ≤0.1% were: Dermatitis, Angioedema, Dry Skin.

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings
One thousand and ninety-seven patients received the combination test treatment. Clinically relevant laboratory abnormalities were reported most frequently for placebo. Laboratory abnormalities occurring in ≥1% of these patients were assessed as comparable with placebo except for the following parameters: low absolute neutrophil count, low potassium, low cholesterol-HDL, high glucose, high uric acid, high phosphorus and WBC in urine quantitative. Except for low cholesterol-HDL, all the above laboratory parameters were reported at equivalent or higher incidence for cilazapril alone or hydrochlorothiazide alone. Definitive evaluation of the effect of cilazapril and hydrochlorothiazide on cholesterol-HDL was not possible because controlled diet was not included in the design of this placebo-controlled trial.

Table 4 Overview Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings Abnormalities                       Quantity

Hematology                           Clinical relevant changes in        In 1.5% of patients neutrophil count                    (placebo: 1.3%)

Clinical relevant changes in        In 0.3% of patients white blood cell count              (placebo: 0.4%)

Clinical relevant changes in low    In 0.3% of patients hemoglobin count                    (placebo: 0.9%)
Leukopenia and Neutropenia   Neutropenia                  In 1% (11/1,097) of patients 
(These eleven patients had neutropenia with a neutrophil count <1,000. Ten of these patients had no clinical symptoms associated with these reported findings. In many of these cases, the findings were transient and believed to be due to laboratory handling problems.
Some patients had a neutrophil count between 1,000 and 2,000 but none were associated with clinically serious adverse experiences.)

Leukopenia                   None of the patients evaluated during the study developed leukopenia (defined as a leukocyte count of <2,000).
Electrolytes                 Decreased serum sodium       In 0.3% of patients (<130 mEq/L)                 (was not observed to be clinically relevant as two patients experienced no clinical symptoms and the third incidence of decreased serum sodium was caused by laboratory sample mishandling)
Liver Function Tests         High SGPT                    In 0.6% of patients (clinical relevant change)
Abnormalities                Quantity

High SGOT                    In 0.4% of patients
(clinical relevant change)

Renal                        High BUN                     In 0.4% of patients (clinical relevant change)
Post-Market Adverse Reactions
The following adverse reactions have been seen in association with cilazapril and/or other ACE inhibitors alone, hydrochlorothiazide and/or other thiazide-type diuretics alone, and in those receiving combined therapy.

Frequency categories are as follows1:

Very common ≥ 1/10
Common      ≥ 1/100 and <
1/10 Uncommon
< 1/100
1Estimates of   frequency are based on the proportion of patients reporting each adverse reaction during cilazapril and hydrochlorothiazide clinical trials that included a total combined population of 1,097 patients. Adverse reactions that were not observed during cilazapril and hydrochlorothiazide clinical trials but have been reported in association with monotherapy with either component or with other ACE inhibitors or thiazide diuretics, or derived from post-marketing case reports, are classified as `uncommon’ (<1/100). The category
`uncommon’ incorporates `rare’ (≥1/10,000 and <1/1,000) and `very rare’ (<1/10,000).
The frequency of adverse reactions attributable to cilazapril, occurring in patients receiving combination therapy (cilazapril+ hydrochlorothiazide), may differ from that seen in patients receiving cilazapril monotherapy. Reasons may include (i) differences between the target populations treated with cilazapril and hydrochlorothiazide and cilazapril, (ii) differences in cilazapril dose, and (iii) specific effects of combination therapy.

Adverse reactions to cilazapril
The most common adverse effects with cilazapril include dry cough, rash, hypotension, dizziness, fatigue, headache, and nausea, dyspepsia and other gastrointestinal disturbances.

Blood and lymphatic systems disorders
Uncommon: Neutropenia, agranulocytosis (especially in patients with renal failure and those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, anemia

Cardiac disorders
Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in patients with heart failure and in sodium- or volume depleted patients. Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischemic heart disease or cerebrovascular disease. Other cardiovascular effects that have occurred include tachycardia, palpitations, and chest pain.

Gastrointestinal disorders
Common: Nausea
Uncommon: Pancreatitis (in some cases fatal)

General disorders and administration site conditions
Common: Fatigue
Hepatobiliary disorders
Uncommon: Abnormal liver function test (including transaminases, bilirubin, alkaline phosphatase, gamma GT), cholestatic hepatitis with or without necrosis.

Immune system disorders
Uncommon: Angioedema (may involve the face, lips, tongue, glottis, larynx or gastrointestinal tract, see 4.4 special warnings and precautions), anaphylaxis (see 4.4 special warnings and precautions), lupus-like syndrome (symptoms may include vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies, increased erythrocyte sedimentation rate, eosinophilia and leukocytosis).

Nervous system disorders
Common: Headache
Uncommon: Dysgeusia, transient ischemic attack, ischemic stroke (may be related in some cases to hypotension in patients with underlying cerebrovascular disease)

Renal and urinary disorders
Cases of acute renal failure have been reported in patients with severe heart failure, renal artery stenosis or renal disorders (see 4.4 special warnings and precautions).

Uncommon: Renal impairment, acute renal failure, blood creatinine increased, blood urea increased, hyperkalemia, hyponatremia (see 4.4 special warnings and precautions).

Respiratory, thoracic and mediastinal disorders
Common: Cough (sometimes severe)

Skin and subcutaneous tissue disorders
Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, bullous pemphigoid, exfoliative dermatitis, dermatitis psoriasiform, psoriasis (exacerbation), lichen planus, urticaria, vasculitis, photosensitivity reactions, rash, alopecia, onycholysis,

Not known: pseudoporphyria

Vascular disorders
Common: Dizziness
Uncommon: Hypotension (sometimes severe, see 7 WARNINGS AND PRECAUTIONS) Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.


Adverse reactions to hydrochlorothiazide
Blood and lymphatic disorders
Uncommon: Thrombocytopenia, hemolytic anemia, granulocytopenia

Cardiac disorders
Uncommon: Arrhythmia

Eye disorders
Uncommon: Lacrimation decreased, visual impairment
Unknown: Choroidal effusion, acute myopia, acute angle-closure glaucoma Gastrointestinal disorders
Common: Nausea
Uncommon: Dry mouth, sialoadenitis, loss of appetite

General disorders and administration site conditions
Common: Fatigue

Hepatobiliary disorders
Uncommon: Cholestatic jaundice
Immune system disorders
Uncommon: Hypersensitivity (angioedema, anaphylaxis)

Metabolism and nutrition disorders
Uncommon: Hypokalemia, hyponatremia, hypochloremia, hypomagnesemia, hypercalcemia, hypocalciuria, hypovolemia/dehydration, metabolic alkalosis, hyperglycemia, hyperuricemia, gout, hypercholesterolemia (increased total, LDL and VLDL cholesterol) hypertriglyceridemia 
Musculoskeletal and connective tissue disorders
Uncommon: Muscle cramp

Nervous system disorders
Common: Dizziness
Psychiatric disorders
Uncommon: Sleep disorder, depression

Renal and urinary disorders
Uncommon: Interstitial nephritis, renal impairment

Reproductive system and breast disorders
Uncommon: Sexual dysfunction
Respiratory, thoracic and mediastinal disorders
Uncommon: Acute interstitial pneumonitis, acute pulmonary edema, acute respiratory distress syndrome (ARDS) (see section 4.4 special warnings and precautions).

Skin and subcutaneous tissue disorders
Uncommon: Rash, photosensitivity, pseudoporphyria, cutaneous vasculitis 
Vascular disorders
Uncommon: Hypotension

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/
In addition, you can address “Unipharm Ltd.”.