Viacoram 3,5/2,5 mg & 7/5 mg & 14/10 mg Tablet.

Viacoram is indicated for the treatment of essential hypertension in adults.

Posology
For oral administration. Viacoram should be taken as a single dose, preferably in the morning and before a meal. Viacoram 3,5/2,5 mg is intended for first line therapy in patients with arterial hypertension. The recommended starting dose of Viacoram is 3,5/2,5 mg once daily. After at least four weeks of treatment, the dose may be increased to 7/5 mg once daily in patients whose blood pressure is not adequately controlled with Viacoram 3,5/2,5 mg. If necessary, titration to 14/10 mg once daily may be considered in adult patients insufficiently controlled after four weeks of treatment with 7/5 mg.
Special populations
Patients with renal impairment (see sections 4.3, 4.4 and 5.2) Viacoram is contraindicated in patients with severe renal impairment (Creatinine clearance below 30 ml/min) (see section 4.3). In patients with moderate renal impairment (Creatinine clearance between 30 ml/min to 60 ml/min), the initial recommended dose of Viacoram is 3,5/2,5 mg every other day. In patients whose blood pressure is not adequately controlled, the dose of Viacoram 3,5/2,5 mg may be taken once daily. If necessary, the dose may be increased in patients insufficiently controlled. Medical follow-up includes monitoring of creatinine and potassium (see sections 4.4 and 5.2). Patients with hepatic impairment (see sections 4.4 and 5.2) Caution should be exercised when prescribing Viacoram to patients with severe hepatic impairment. Elderly patients ( u2265 65 years of age) (see sections 4.4 and 5.2) Caution is advised with the treatment of elderly patients. Renal function should be checked before initiating treatment. After initiation of the treatment, renal function should be monitored before increase of the dosage, particularly in patients aged 75 years and above. The usual medical follow-up should include monitoring of creatinine and potassium. Paediatric population The safety and efficacy of Viacoram in children aged below 18 years have not been established. No data are available.

• Hypersensitivity to the active substances, to ACE-inhibitors, to dihydropyridines derivatives, or to any of the excipients listed in section 6.1.
• Severe renal function impairment (creatinine clearance less than 30 ml/min) (see sections 4.2 and 4.4).
• History of angioedema associated with previous ACE-inhibitor therapy or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe hypotension.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria.
• Haemodynamically unstable heart failure after acute myocardial infarction.
• Concomitant use of Viacoram with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1,73 mu00b2) (see sections 4.5 and 5.1).
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5).
• Significant bilateral renal artery stenosis.
• Renal artery stenosis in a single functioning kidney (see section 4.4).
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria.
• Concomitant use with sacubitril/valsartan therapy, Perindopril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).
• Pregnancy and lactation (see section 4.6).
• Lithium therapy: Concomitant administration with Viacoram may lead to toxic lithium blood concentrations (see section 4.5).
• Concomitant use of Viacoram with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1,73mu00b2) (see sections 4.4, 4.5 and 5.1).
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5).
• Concomitant use of fluoroquinolones with ACE-inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (Creatinine Clearance u2264 30 mL/min) and in elderly patients.
• Linked to amlodipine - Severe hypotension.
• Hypersensitivity to amlodipine, or dihydropyridine derivatives.
• Shock (including cardiogenic shock).
• Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis).
• Haemodynamically unstable heart failure after acute myocardial infarction.
• Severe impairment of hepatic function (Child Pugh C).

Special warnings
Hypersensitivity/Angioedema Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx with difficult breathing has been reported in patients treated with ACE-inhibitors, including perindopril (see section 4.8). This may occur at any time during therapy. In such cases, Viacoram should promptly be discontinued and appropriate management and monitoring should be initiated and continued until complete resolution of symptoms has occurred. In those instances where swelling was confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of epinephrine (adrenaline) and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred. Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving Viacoram (see section 4.3). Intestinal angioedema has been reported in patients treated with ACE-inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE-inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE-inhibitors presenting with abdominal pain (see section 4.8). Should a woman become pregnant while receiving Viacoram, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine. (see sections 4.3 and 4.6).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting medicine (see sections 4.3, 4.4 and 5.1). Medicines increasing the risk of angioedema Concomitant use of ACE-inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Concomitant use of ACE-inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk for angioedema (see section 4.4). Medicines inducing hyperkalaemia Some medicines or therapeutic classes may increase the occurrence of hyperkalaemia such as aliskiren, potassium salts, potassium-sparing diuretics, ACE-inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant medicines such as ciclosporin or tacrolimus, trimethoprim and fixed dose combination with sulfamethoxazole (Co-trimoxazole). The combination of Viacoram with these medicines increases the risk of hyperkalaemia (see section 4.4). The combination of Viacoram with the above-mentioned medicines is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium. Concomitant use contraindicated (see section 4.3) Fluoroquinolones Concomitant use of fluoroquinolones and ACE-inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3). Aliskiren In patients with diabetes mellitus or with impaired renal function, the risk of hyperkalaemia, deterioration of renal function, and cardiovascular morbidity and mortality are increased. Extracorporeal treatments Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate should be avoided due to an increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. NEP inhibitors The concomitant use of perindopril with sacubitril/valsartan is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema.

Viacoram is contraindicated in pregnancy and lactation.
Pregnancy
Linked to perindopril The use of Viacoram is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take Viacoram during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with Viacoram should be stopped immediately and alternative therapy should be started. Foetal exposure to ACE-inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spina bifida) and of kidney malformations. Viacoram passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of Viacoram during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see section 4.3).
Linked to amlodipine
Amlodipine should not be used in pregnancy as the safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses.
Breastfeeding
Linked to perindopril Women on treatment with perindopril should not breastfeed their babies. No information is available regarding the use of perindopril during breastfeeding.
Linked to amlodipine Women on treatment with amlodipine should not breastfeed their babies. Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 u2013 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown.
Fertility
Linked to perindopril There was no effect on reproductive performance or fertility in animal studies.
Linked to amlodipine Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Perindopril and amlodipine influence the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with Viacoram affects them. If patients suffer from dizziness, headache, fatigue, weariness or nausea, the ability to react may be impaired. Caution is recommended with Viacoram especially at the start of treatment.

Summary of the safety profile The safety profile of Viacoram has been evaluated on a 6-month controlled study involving 1 771 patients, 887 of whom received Viacoram, a 6-week controlled study involving 837 patients, 279 of whom received Viacoram, and an 8-week placebo-controlled study involving 1 581 patients, 249 of whom received Viacoram. In these clinical studies, no significant new adverse reactions were observed with the combination compared to the known effects of the individual monocomponents. The following adverse reactions were found to be the most frequently reported during clinical trials dizziness, cough and oedema. The adverse drug reactions previously reported during clinical trials and/or post-marketing experience with one of the individual components of Viacoram (perindopril and amlodipine) have been listed in the following table since they may occur with the fixed-dose combination. List of adverse reactions reported during clinical trials The following undesirable effects have been observed during clinical trials treatment with Viacoram, perindopril or amlodipine given separately and ranked under the MedDRA classification by body system and under the following frequency Very common ( u2265 1/10) ; common ( u2265 1/100 to < 1/10) ; uncommon ( u2265 1/1 000 to < 1/100) ; rare ( u2265 1/10 000 to < 1/1 000) ; very rare (< 1/10 000) ; not known (cannot be estimated from the available data.

There is no experience of overdose with Viacoram. For amlodipine, experience with intentional overdose in humans is limited. Symptoms available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 - 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors. Treatment clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. For perindopril, limited data are available for overdosage in humans. Symptoms associated with the overdosage of ACE-inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. The recommended treatment of overdosage is intravenous infusion of 0,9 % sodium chloride solution. If hypotension occurs, the patient should be placed in the shock position (patient to lie on their back with legs elevated above heart level). If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Perindopril can be removed from the systemic circulation by haemodialysis (see section 4.4). Pacemaker therapy is indicated for treatment-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.