Dafiro

Posology The recommended dose of Dafiro is one tablet per day. Dafiro 5 mg/80 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 80 mg alone. Dafiro 5 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 160 mg alone.

Dafiro 10 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with Dafiro 5 mg/160 mg. Dafiro can be used with or without food. e. amlodipine and valsartan) is recommended before changing to the fixed dose combination.

When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered. For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be switched to Dafiro containing the same component doses.

Renal impairment There are no available clinical data in severely renally impaired patients. No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

3). 4). In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment.

1) with hepatic impairment to amlodipine or Dafiro, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used. Elderly (age 65 years or over) In elderly patients, caution is required when increasing the dosage.

1) to amlodipine or Dafiro, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used. Paediatric population The safety and efficacy of Dafiro in children aged below 18 years have not been established.

No data are available. Method of administration Oral use. It is recommended to take Dafiro with some water. 4

Summary of the safety profile The safety of Dafiro 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 System organ class Adverse reactions Frequency Dafiro Amlodipine Valsartan Infections and infestations Nasopharyngitis Common -- -- Influenza Common -- -- Blood and lymphatic system disorders Haemoglobin and haematocrit decreased -- -- Not known Leukopenia -- Very rare -- Neutropenia -- -- Not known Thrombocytopenia, sometimes with purpura -- Very rare Not known Immune system disorders Hypersensitivity Rare Very rare Not known Metabolism and nutrition disorders Hyperglycaemia -- Very rare -- Hyponatraemia Uncommon -- -- Psychiatric disorders Depression -- Uncommon -- Anxiety Rare -- -- Insomnia/sleep disorders -- Uncommon -- Mood swings -- Uncommon -- Confusion -- Rare -- 10 Nervous system disorders Coordination abnormal Uncommon -- -- Dizziness Uncommon Common -- Dizziness postural Uncommon -- -- Dysgeusia -- Uncommon -- Extrapyramidal syndrome -- Not known -- Headache Common Common -- Hypertonia -- Very rare -- Paraesthesia Uncommon Uncommon -- Peripheral neuropathy, neuropathy -- Very rare -- Somnolence Uncommon Common -- Syncope -- Uncommon -- Tremor -- Uncommon -- Hypoesthesia -- Uncommon -- Eye disorders Visual disturbance Rare Uncommon -- Visual impairment Uncommon Uncommon -- Ear and labyrinth disorders Tinnitus Rare Uncommon -- Vertigo Uncommon -- Uncommon Cardiac disorders Palpitations Uncommon Common -- Syncope Rare -- -- Tachycardia Uncommon -- -- Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) -- Very rare -- Myocardial infarction -- Very rare -- Vascular disorders Flushing -- Common -- Hypotension Rare Uncommon -- Orthostatic hypotension Uncommon -- -- Vasculitis -- Very rare Not known Respiratory, thoracic and mediastinal disorders Cough Uncommon Very rare Uncommon Dyspnoea -- Uncommon -- Pharyngolaryngeal pain Uncommon -- -- Rhinitis -- Uncommon -- Gastrointestinal disorders Abdominal discomfort, abdominal pain upper Uncommon Common Uncommon 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 -- Intestinal angioedema -- -- Very rare Hepatobiliary disorders Liver function test abnormal, including blood bilirubin increase -- Very rare* Not known Hepatitis -- Very rare -- Intrahepatic cholestasis, jaundice -- Very rare -- Alopecia -- Uncommon -- Angioedema -- Very rare Not known 11 Skin and subcutaneous 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 rash -- Very rare -- Exfoliative dermatitis -- Very rare -- Stevens-Johnson syndrome -- Very rare -- Quincke oedema -- Very rare -- Toxic Epidermal Necrolysis -- Not known -- Musculoskeletal and connective tissue disorders Arthralgia Uncommon Uncommon -- Back pain Uncommon Uncommon -- Joint swelling Uncommon -- -- Muscle spasm Rare Uncommon -- Myalgia -- Uncommon Not known Ankle swelling -- Common -- Sensation of heaviness Rare -- -- Renal and urinary disorders Blood creatinine increased -- -- Not known Micturition disorder -- Uncommon -- Nocturia -- Uncommon -- Pollakiuria Rare Uncommon -- Polyuria Rare -- -- Renal failure and impairment -- -- Not known Reproductive system and breast disorders Impotence -- Uncommon -- Erectile dysfunction Rare -- -- Gynaecomastia -- Uncommon -- General disorders and administration site conditions Asthenia Common Uncommon -- Discomfort, malaise -- Uncommon -- Fatigue Common Common Uncommon 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 12 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.

The safety and efficacy of amlodipine in hypertensive crisis have not been established. Pregnancy Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

6). 4% of patients with uncomplicated hypertension treated with Dafiro in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur.

Correction of this condition prior to administration of Dafiro or close medical supervision at the start of treatment is recommended. If hypotension occurs with Dafiro, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

Treatment can be continued once blood pressure has been stabilised. ) should be undertaken with caution and with frequent monitoring of potassium levels. Renal artery stenosis Dafiro should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

Kidney transplantation To date there is no experience of the safe use of Dafiro in patients who have had a recent kidney transplantation. 5 Hepatic impairment Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established.

Particular caution should be exercised when administering Dafiro to patients with mild to moderate hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.

1. • Severe hepatic impairment, biliary cirrhosis or cholestasis. 1). 6). • Severe hypotension. • Shock (including cardiogenic shock). g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis). • Haemodynamically unstable heart failure after acute myocardial infarction.