Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety of Vasodip Combo has been evaluated in five double-blind controlled clinical studies and in two long term open-label extension phases. In total, 1,141 patients have received Vasodip Combo at a dose of 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg. The undesirable effects observed with combination therapy have been similar to those already observed with one or the other of the constituents given alone. The most commonly reported adverse reactions during treatment with Vasodip Combo were cough (4.03%), dizziness (1.67%) and headache (1.67%).

Tabulated summary of adverse reactions
In the table below, adverse reactions reported in clinical studies with Vasodip Combo 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg and for which a reasonable causal relationship exists are listed by MedDRA system organ class and frequency: 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
Uncommon:            Thrombocytopenia
Rare:                Haemoglobin decreased
Immune System Disorders
Rare:                Hypersensitivity
Metabolism and nutrition disorders
Uncommon:            Hyperkalaemia
Psychiatric disorders
Uncommon:            Anxiety
Nervous system disorders
Common:              Dizziness, headache
Uncommon:            Dizziness postural
Ear and labyrinth disorders
Uncommon:            Vertigo
Rare:                Tinnitus
Cardiac Disorders
Uncommon:            Tachycardia, palpitations
Vascular disorders
Uncommon:            Flushing, hypotension
Rare:                Circulatory collapse
Respiratory, thoracic and mediastinal disorders
Common:              Cough
Rare:                Dry throat, oropharingeal pain
Gastrointestinal disorders
Uncommon:            Abdominal pain, constipation, nausea
Rare:                Dyspepsia, lip oedema, tongue disorder, diarrhoea, dry mouth, gingivitis
Hepatobiliary Disorders
Uncommon:            ALT increased, AST increased
Skin and sub-cutaneous tissue disorders
Uncommon:            Erythema
Rare:                Angioedema, swelling face, dermatitis, rash, urticaria Musculoskeletal, connective tissue disorders
Uncommon:            Arthralgia
Renal and urinary disorders
Uncommon:            Pollakiuria
Rare:                Nocturia, polyuria

Reproductive System and Breast Disorders
Rare:                 Erectile dysfunction
General disorders and administration site conditions
Uncommon:             Asthenia, fatigue, feeling hot, oedema peripheral Undesirable effects occurring in one patient only are reported under the frequency rare.

Additional information on the individual components

Adverse reactions reported with one of the individual components (enalapril or lercanidipine) may be potential undesirable effect with Vasodip Combo as well, even if not observed in clinical trials or during the post-marketing period.

Enalapril alone
Among the adverse drug reactions reported for enalapril are:

Blood and lymphatic system disorders:
Uncommon: anaemia (including aplastic and haemolytic)
Rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases

Endocrine disorders:
Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH) 
Metabolism and nutrition disorders:
Uncommon: hypoglycaemia (see section 4.4)

Psychiatric disorders:
Common: depression
Uncommon: confusion, nervousness, insomnia
Rare: dream abnormality, sleep disorders
Nervous system disorders:
Very common: dizziness
Common: headache, syncope, taste alteration
Uncommon: somnolence, paraesthesia, vertigo

Eye disorders:
Very common: blurred vision

Ear and labyrinth disorders:
Uncommon: tinnitus
Cardiac disorders:
Common: chest pain, rhythm disturbances, angina pectoris, tachycardia Uncommon: palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high-risk patients (see section 4.4) * Incidence rates were comparable to those in the placebo and active control groups in the clinical trials.

Vascular disorders:
Common: hypotension (including orthostatic hypotension)
Uncommon: flushing, orthostatic hypotension
Rare: Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders:
Very common: cough
Common: dyspnoea
Uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma Rare: pulmonary infiltrates, rhinitis, allergic alveolitis /eosinophilic pneumonia 
Gastrointestinal disorders:
Very common: nausea
Common: diarrhoea, abdominal pain
Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer
Rare: stomatitis/aphthous ulcerations, glossitis
Very rare: intestinal angioedema

Hepatobiliary disorders:
Rare: hepatic failure, hepatitis - either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)
Skin and subcutaneous tissue disorders:
Common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4) Uncommon: diaphoresis, pruritus, urticaria, alopecia
Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

Musculoskeletal, connective tissue, bone disorders:
Uncommon: muscle cramps

Renal and urinary disorders:
Uncommon: renal dysfunction, renal failure, proteinuria
Rare: oliguria
Reproductive system and breast disorders:
Uncommon: impotence
Rare: gynaecomastia

General disorders and administration site conditions:
Very common: asthenia
Common: fatigue
Uncommon: malaise, fever

Investigations:
Common: hyperkalaemia, increases in serum creatinine
Uncommon: increases in blood urea, hyponatremia
Rare: elevation of liver enzymes, elevation of serum bilirubin
Lercanidipine alone
The adverse drug reactions most commonly reported in clinical trials and in the post- marketing experience are peripheral oedema, headache, flushing, tachycardia and palpitations.


Immune system disorders
Rare: hypersensitivity

Nervous system disorders
Common: headache
Uncommon: dizziness
Rare: somnolence, syncope

Cardiac disorders
Common: tachycardia, palpitations
Rare: angina pectoris
Vascular disorders
Common: flushing
Uncommon: hypotension

Gastrointestinal disorders
Uncommon: nausea, dyspepsia, abdominal pain upper,
Rare: vomiting, diarrhoea
Not known: gingival hypertrophy1, peritoneal cloudy effluent1

Hepatobiliary disorders:
Not known: serum transaminase increased1
Skin and subcutaneous tissue disorders
Uncommon: rash, pruritus
Rare: urticaria
Not known: angioedema1

Musculoskeletal and connective tissue disorders
Uncommon: myalgia

Renal and urinary disorders
Uncommon: polyuria
Rare: pollakiuria
General disorders and administration site conditions
Common: oedema peripheral
Uncommon: asthenia, fatigue
Rare: chest pain
1 adverse reactions from spontaneous reporting in the worldwide post-marketing experience.

Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely, patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed.
Lercanidipine does not appear to have any adverse effect on blood sugar or serum lipid levels.

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