COVERSYL 10MG TAB (TABLET)

Dosage / Direction for Use: HTN Starting dose: 5 mg once daily. Patients w/ a strongly activated renin-angiotensin-aldosterone system (renovascular HTN, salt &/or vol depletion, cardiac decompensation or severe HTN) Starting dose: 2.5 mg. May be increased to 10 mg once daily after 1 mth. Concomitant treatment w/ diuretics: Discontinue diuretic 2-3 days before start of Coversyl. If not possible, initiate Coversyl w/ 2.5 mg & monitor renal function & serum K, adjust subsequent dosage according to response. Elderly Initially 2.5 mg, may increase to 5 mg after 1 mth, then 10 mg if necessary depending on renal function. Stable CAD Starting dose: 5 mg once daily for 2 wk, then increase to 10 mg once daily, depending on renal function & if well tolerated. Elderly 2.5 mg once daily for 1 wk, then 5 mg once daily the next wk, before increasing up to 10 mg once daily, depending on renal function & if tolerated. Patients w/ renal impairment CrCl ≥60 5 mg/day. 30-60 CrCl 2.5 mg/day. 15-30 CrCl 2.5 mg every other day. <15 mg CrCl 2.5 mg on the day of dialysis. The dose should be taken after dialysis in hemodialysis patients. 5 mg: Symptomatic heart failure Starting dose: 2.5 mg/day. May be increased to 5 mg once daily after 2 wk if tolerated. Overdosage: Limited data are available for overdosage in humans. Symptoms associated with 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 sodium chloride 9 mg/ml (0.9%) 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 may be removed from the general circulation by hemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously. Administration: Should be taken on an empty stomach: Preferably taken in the morning. Contraindications: Hypersensitivity to any ACE inhibitor. History of angioedema associated w/ previous ACE inhibitor therapy. Hereditary or idiopathic angioedema. Concomitant use w/ aliskiren-containing products in patients w/ DM or renal impairment (GFR <60 mL/min/1.73 m2). Concomitant use w/ sacubitril/valsartan. Extracorporeal treatments leading to contact of blood w/ negatively charged surfaces. Significant bilateral renal artery stenosis of the artery to a single functioning kidney. Pregnancy (2nd & 3rd trimesters). Special Precautions: Perform careful appraisal of the benefit/risk if an episode of unstable angina pectoris (major or not) may occur during the 1st mth of therapy. May cause hypotension in patients who have been vol-depleted (eg, by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting) or who have severe renin-dependent HTN, symptomatic heart failure w/ or w/o associated renal insufficiency, severe degrees of heart failure, ischemic heart or cerebrovascular disease. Mitral valve stenosis & obstruction in the outflow of the left ventricle eg, aortic stenosis or hypertrophic cardiomyopathy. Renal impairment (CrCl <60 mL/min), bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, preexisting renal impairment. Routine monitoring of K & creatinine. Hemodialysis. Recent kidney transplantation. Angioedema. Anaphylactoid reactions during desensitization & LDL apheresis. Discontinue in patients who develop jaundice or marked elevations of hepatic enzymes. Neutropenia/agranulocytosis/thrombocytopenia/anemia. Patients w/ collagen vascular disease, immunosuppressant therapy, treatment w/ allopurinol or procainamide, or a combination of these complicating factors especially if there is preexisting impaired renal function. Renal impairment. Periodic monitoring of WBC. Higher prevalence of low-renin states in Black patients. Cough. Discontinue 1 day prior to surgery. Risk factors for hyperkalemia include renal insufficiency, worsening renal function, patients >70 yr, DM, intercurrent events particularly dehydration, acute cardiac decompensation, metabolic acidosis, concomitant use of K-sparing diuretics, K supplements or K-containing salt substitutes, taking other drugs associated w/ increases in serum K (eg, heparin). Diabetic patients. Concomitant use w/ lithium; K-sparing drugs, K supplements or K-containing salts. Dual blockade of renin-angiotensin-aldosterone system. Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. May impair ability to drive or operate machinery. Use In Pregnancy & Lactation: Pregnancy: The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimester 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. Lactation: Because no information is available regarding the use of Perindopril (Coversyl) during breastfeeding, Perindopril (Coversyl) is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant. Fertility: There was no effect on reproductive performance or fertility. Side Effects / Adverse Reactions: Dizziness, headache, paresthesia, vertigo; visual disturbances; tinnitus; hypotension; cough, dyspnea; abdominal pain, constipation, diarrhea, dysgeusia, dyspepsia, nausea, vomiting; pruritus, rash; muscle cramps; asthenia. Interactions: Hypotension, hyperkalemia & decreased renal function (including acute renal failure) w/ other ACE inhibitors, angiotensin II receptor blockers or aliskiren. Increased risk of hyperkalemia w/ aliskiren, K salts, K-sparing diuretics (eg, triamterene, amiloride), ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents eg, ciclosporin or tacrolimus, trimethoprim. Increased risk of angioedema w/ estramustine, racecadotril, mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus) & gliptines (linagliptine, saxagliptine, sitagliptine, vildagliptine). Increased serum lithium conc & toxicity. May increase blood-glucose lowering effect of antidiabetics (insulins, oral hypoglycemic agents). Increased antihypertensive effect w/ baclofen. Reduction in BP w/ diuretics; TCAs & antipsychotics. Risk of hyperkalemia w/ K-sparing diuretics (eplerenone or spironolactone) at doses between 12.5-50 mg by day. Attenuated antihypertensive effect w/ NSAIDs. May increase hypotensive effects w/ nitroglycerin & other nitrates, or other vasodilators. May reduce antihypertensive effects of ACE inhibitors w/ sympathomimetics. Nitritoid reactions (symptoms include facial flushing, nausea, vomiting & hypotension) w/ inj gold (Na aurothiomalate). Mechanism of Action: Pharmacology: Pharmacodynamics: Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough). Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro. Pharmacokinetics: Absorption: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour. Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours. As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal. It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure. Distribution: The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent. Elimination: Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days. Special population: Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure. Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance). Dialysis clearance of perindoprilat is equal to 70 ml/min. Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required.