COVERAM 5MG/10MG TAB (TABLET)

Dosage / Direction for Use: 1 tab/day as single dose preferably in the morning. Overdosage: There is no information on overdosage with Perindopril arginine + Amlodipine besilate (COVERAM) in humans. For amlodipine, experience with intentional overdose in humans is limited. Symptoms: available data suggest that gross overdosage could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. 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 normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Perindopril can be removed from the systemic circulation by hemodialysis. Pacemaker therapy is indicated for treatment resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously. Administration: Should be taken on an empty stomach: Avoid grapefruit & grapefruit juice. Contraindications: Hypersensitivity to perindopril, amlodipine or dihydropyridines & any other ACE inhibitors. DM or renal impairment (GFR <60 mL/min/1.73 m2). Perindopril: History of angioedema associated w/ previous ACE inhibitor therapy; hereditary or idiopathic angioedema; concomitant use w/ sacubitril/valsartan; extracorporeal treatments leading to contact of blood w/ negatively charged surfaces; significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. Pregnancy (2nd & 3rd trimester). Amlodipine: Severe hypotension; cardiogenic shock; high-grade aortic stenosis; hemodynamically unstable heart failure after acute MI. Warnings: All warnings related to each monocomponent, as listed as follows, should apply also to the fixed combination of Perindopril arginine + Amlodipine besilate (COVERAM). Linked to perindopril: Hypersensitivity/Angioedema: Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including perindopril. This may occur at any time during therapy. In such cases, Perindopril arginine + Amlodipine besilate (COVERAM) should promptly be discontinued and appropriate 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 edema 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 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 an ACE inhibitor. Intestinal angioedema has been reported rarely 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. Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment). Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis. Anaphylactoid reactions during desensitization: Patients receiving ACE inhibitors during desensitization treatment (e.g. hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia: Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Use in Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitors is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Special Precautions: Concomitant use w/ lithium, K-sparing drugs, K-supplements or dantrolene is not recommended. Renal impairment (CrCl <60 mL/min). Severe hepatic impairment. Galactose intolerance, glucose-galactose malabsorption or Lapp lactase deficiency. May affect ability to drive or operate machinery. Not recommended during pregnancy (1st trimester) & lactation. Do not use in childn & adolescents. Perindopril: Hypersensitivity/angioedema. Anaphylactoid reactions during LDL apheresis & desensitisation. Monitor WBC if used in patients w/ collagen vascular disease, immunosuppressant therapy, treatment w/ allopurinol or procainamide. Dual blockade of renin-angiotensin-aldosterone system through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended. Monitor BP, renal function & serum K in patients at high risk of hypotension. Mitral valve stenosis & left ventricle outflow obstruction eg, aortic stenosis or hypertrophic cardiomyopathy; bilateral renal artery stenosis. Higher rate of angioedema in Black patients. Non-productive & persistent cough. Discontinue treatment 1 day prior to surgery. Patients at risk of hyperkalemia. Closely monitor glycemic control in diabetic patients treated w/ oral antidiabetic agents or insulin during the 1st mth of treatment. Increased risk for angioedema in patients taking concomitant mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus). Amlodipine: Hypertensive crisis. Patients w/ severe heart failure (NYHA class II & IV), CHF. Slow dose titration & careful monitoring in patients w/ severe hepatic impairment. Use In Pregnancy & Lactation: Given the effects of the individual components in this combination product on pregnancy and lactation: Perindopril arginine + Amlodipine besilate (COVERAM) is not recommended during the first trimester of pregnancy. It is contraindicated during the second and third trimesters of pregnancy. Perindopril arginine + Amlodipine besilate (COVERAM) is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue Perindopril arginine + Amlodipine besilate (COVERAM) taking account the importance of this therapy for the mother. Pregnancy: Linked to perindopril: The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension. Linked to amlodipine: The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and fetus. Breastfeeding: Linked to perindopril: Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Linked to amlodipine: It is not known whether amlodipine is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother. Fertility: Linked to perindopril: There was no effect on reproductive performance or fertility. 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. Side Effects / Adverse Reactions: Dizziness, headache; visual impairment; dyspnea; abdominal pain, nausea, dyspepsia, diarrhea, constipation, nausea; muscle spasms; asthenia. Amlodipine: Edema. Somnolence; diplopia; palpitations; flushing; change of bowel habit; joint swelling; fatigue. Perindopril: Dysgeusia; paresthesia, tinnitus, vertigo; hypotension; cough; vomiting; pruritus, rash, exanthema. Interactions: Increased antihypertensive effect w/ baclofen. Increased hypotensive effects w/ β-blockers & vasodilators; may further reduce BP w/ nitroglycerine, other nitrates or other vasodilators; reduction in antihypertensive effect & increased risk of orthostatic hypotension w/ prazosin, alfuzosin, doxazosin, tamsulosin, terazosin, TCA/antipsychotic/anesth; may potentiate antihypertensive effect of amifostine.