Coversyl Arginine

Perindopril arginine.

COVERSYL ARGININE 5 mg: One film-coated tablet contains 3.395 mg perindopril corresponding to 5 mg perindopril arginine.
The tablet can be divided into equal doses.
COVERSYL ARGININE 10 mg: One film-coated tablet contains 6.790 mg perindopril corresponding to 10 mg perindopril arginine.

Pharmacotherapeutic group: ACE inhibitors, plain. ATC code: C09A A04.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Clinical efficacy and safety: Hypertension: Perindopril is active in all grades of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.
Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate.
Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged.
The antihypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained for at least 24 hours: trough effects are about 87-100% of peak effects.
The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.
Discontinuation of treatment does not lead to a rebound effect.
Perindopril reduces left ventricular hypertrophy.
In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media:lumen ratio of small arteries.
An adjunctive therapy with a thiazide diuretic produces an additive-type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.
Heart failure: Perindopril reduces cardiac work by a decrease in pre-load and after-load.
Studies in patients with heart failure have demonstrated: decreased left and right ventricular filling pressures; reduced total peripheral vascular resistance; increased cardiac output and improved cardiac index.
In comparative studies, the first administration of 2.5 mg of perindopril arginine to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure as compared to placebo.
Patients with stable coronary artery disease: The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (n=6110) or placebo (n=6108).
The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.
The main efficacy criterion was the composite of cardiovascular mortality, non fatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, 95%CI [9.4; 28.6] - p<0.001).
In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] - p<0.001) in the primary endpoint was observed by comparison to placebo.
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 (see "Recommended dose" and "Mode of Administration" under Dosage & Administration and "Precautions").

This drug is recommended in: The treatment of arterial hypertension; The treatment of congestive heart failure; Combination with indapamide to reduce the risk of stroke recurrence in patients with history of stroke or TIA (Transient ischemic attack); Reduction of risk of cardiovascular events in patients with stable coronary artery disease, on top of other preventive medications.

Recommended dose: For arterial hypertension: The recommended dosage is 5 mg daily in the morning. This may be increased to 10 mg daily in a single dose, if necessary, after 1 month of treatment.
In the elderly patient, treatment should be started with 2.5 mg daily in the morning and this may be increased to 5 mg daily, if necessary, after 1 month of treatment.
In case of renal failure, the dosage of perindopril must be adjusted according to the degree of renal failure.
In these patients, normal medical practice involves periodic determination of serum potassium and creatinine levels.
For congestive heart failure: The treatment should be started under close medical supervision. The recommended initial dose is 2.5 mg daily in the morning. This may be increased to 5 mg daily once blood pressure acceptability has been demonstrated.
For prevention of stroke recurrence: In patients with a history of cerebrovascular disease, COVERSYL ARGININE should be introduced at a dose of 2.5 mg daily for two weeks, then increased to 5 mg daily for a further 2 weeks before introducing indapamide.
Treatment can be initiated at any time from 2 weeks up to several years after the initial stroke episode.
For reduction of risk of cardiovascular event: In patients with stable coronary artery disease, COVERSYL ARGININE should be introduced at a dose of 5 mg once daily for two weeks, then increased to 10 mg once daily, depending on renal function.
Elderly patients should receive a dose of 2.5 mg once daily for one week, then 5 mg once daily the next week, before increasing the dose up to 10 mg once daily depending on renal function.
Mode of Administration: For adults only: Oral route, before meal.
In all cases strictly comply with the physician's prescription.

Overdosage and treatment: Hypotension is the most likely result of overdosage. If significant hypotension occurs, it may be countered by making the patient lie down with the legs elevated.
If the malaise persists, inform the doctor immediately.
Course of action to take when one or more doses have been missed: Resume treatment normally.
Do not take a double dose to compensate for the dose that the patient missed.

This medicine SHOULD NOT BE USED in the following cases: allergy to this medicine, including angioneurotic oedema-type reactions; during the second and third trimesters of pregnancy; in general, this medicine should not be used during the first trimester of pregnancy or during lactation, unless the doctor advises otherwise; Diabetes or impaired kidney function and is treated with a blood pressure lowering medicine containing aliskiren; Concomitant use with sacubitril/valsartan (see "Precautions" and "Interactions"); Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see "Interactions"); Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see "Precautions").
The drug is generally not recommended in combination with potassium-sparing diuretics, potassium salts, lithium and estramustine (see "Interactions").

Stop taking COVERSYL ARGININE and contact the doctor immediately if the patient experiences any of the following: swelling of the face, lips, tongue and/or larynx, which result in difficulty in breathing or swallowing.
If any of the following applies to the patient, please talk to the doctor or pharmacist or nurse before taking Coversyl, if the patient: has aortic stenosis (narrowing of the main blood vessel leading from the heart) or hypertrophic cardiomyopathy (cardiac muscle disease) or renal artery stenosis (narrowing of the artery supplying the kidney with blood); has any other heart problems; has liver problems; has kidney problems or if the patient is receiving dialysis; suffers from a collagen vascular disease (disease of the connective tissue) such as systemic lupus erythematosus or scleroderma; has diabetes; is on a salt restricted diet or use salt substitutes which contain potassium; is to undergo anaesthesia and/or major surgery; is to undergo LDL apheresis (which is removal of cholesterol from the blood by a machine); is going to have treatment to make the patient less sensitive to the effects of an allergy to bee or wasp stings; has recently suffered from diarrhoea or vomiting, or is dehydrated; has been told by the doctor that the patient has an intolerance to some sugars; has been told by the doctor that the patient has phenylketonuria; is taking any of the following medicines used to treat high blood pressure: an "angiotensin II receptor blocker" (ARBs) (also known as sartans - for example valsartan, telmisartan, irbesartan), in particular if the patient has diabetes-related kidney problems; Aliskiren.
The doctor may check the kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in the blood at regular intervals. See also information under "Contraindications".
Hyperkalaemia; patients taking other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole); is of black origin since the patient may have a higher risk of angioedema and this medicine may be less effective in lowering the blood pressure than in non-black patients; is taking any of the following medicines, the risk of angioedema is increased: racecadotril (used to treat diarrhea); sirolimus, everolimus, temsirolimus and other drugs belonging to the class of so-called mTor inhibitors (used to avoid rejection of transplanted organs).
Angioedema: Angioedema (a severe allergic reaction with swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing) has been reported in patients treated with ACE inhibitors, including Coversyl. This may occur at any time during treatment. If the patient develops such symptoms, the patient should stop taking Coversyl and see a doctor immediately (see "Adverse Reactions").
The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see "Contraindications"). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see "Contraindications" and "Interactions"). Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema (see "Interactions"). Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on perindopril.
Renovascular hypertension: There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors (see "Contraindications"). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.
Primary aldosteronism: Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.
Drivers and machinery operators: Special care should be taken by drivers and machine operators due to the risk of dizziness.
Use in Pregnancy: The patient must tell the doctor if the patient thinks that she (or might become) pregnant. Coversyl is not recommended in early pregnancy, and must not be taken if the patient is more than 3 months pregnant, as it may cause serious harm to the baby if used at this stage (see "Use in Pregnancy & Lactation").
Use in Children: The use of perindopril in children and adolescents up to the age of 18 years is not recommended.

If the patient finds out that she is pregnant while taking this medicine, the patient must inform the doctor supervising her pregnancy immediately and follow his advice.
The patient should also inform the doctor if she wishes to become pregnant.
Use of this medicine is contraindicated during the second and third trimesters of pregnancy.
There are no data about the passage of this medicine into maternal milk. Consequently, administration of this medicine is not recommended in women who are breast-feeding.
THE PATIENT SHOULD ALWAYS SEEK THE ADVICE OF THE DOCTOR OR PHARMACIST BEFORE TAKING ANY MEDICINE.

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking the medicinal product and see a doctor immediately, if the patient experiences any of the following side effects that can be serious: swelling of the face, lips, mouth, tongue or throat, difficulty in breathing (angioedema) (see "Precautions") (Uncommon - may affect up to 1 in 100 people); severe dizziness or fainting due to low blood pressure (Common - may affect up to 1 in 10 people); unusual fast or irregular heartbeat, chest pain (angina) or heart attack (Very rare - may affect up to 1 in 10,000 people); weakness of arms or legs, or problems speaking which could be a sign of a possible stroke (Very rare - may affect up to 1 in 10,000 people); sudden wheeziness, chest pain, shortness of breath, or difficulty in breathing (bronchospasm) (Uncommon - may affect up to 1 in 100 people); inflamed pancreas which may cause severe abdominal and back pain accompanied with feeling very unwell (Very rare - may affect up to 1 in 10,000 people); yellowing of the skin or eyes (jaundice) which could be a sign of hepatitis (Very rare - may affect up to 1 in 10,000 people); skin rash which often starts with red itchy patches on the face, arms or legs (erythema multiforme) (Very rare - may affect up to 1 in 10,000 people).
In decreasing order of frequency, side effects can include, tell the doctor if the patient notices any of the following side effects: Common (may affect up to 1 in 10 people): Headache, dizziness, vertigo, pins and needles, vision disturbances, tinnitus (sensation of noises in the ears), light-headedness due to low blood pressure, cough, shortness of breath (dyspnoea), gastro-intestinal disorders (nausea, vomiting, abdominal pain, taste disturbances, dyspepsia or difficulty of digestion, diarrhoea, constipation), allergic reactions (such as skin rashes, itching), muscle cramps, feeling of weakness.
Uncommon (may affect to 1 in 100 people): Mood swings, sleep disturbances, bronchospasm (tightening of the chest, wheezing and shortness of breath), dry mouth, angioedema (symptoms such as wheezing, swelling of the face, tongue or throat), intense itching or severe skin rashes, formation of blister clusters over the skin, kidney problems, impotence, sweating, an excess of eosinophils (a type of white blood cells), somnolence, fainting, palpitations, tachycardia, vasculitis (inflammation of blood vessels), photosensitivity reaction (increased sensitivity of the skin to sun), arthralgia (joint pain), myalgia (muscle pain), chest pain, malaise, oedema peripheral, fever, fall, change in laboratory parameters: high blood level of potassium reversible on discontinuation, low level of sodium, hypoglycaemia (very low blood sugar level) in case of diabetic patients, increased blood urea, and increased blood creatinine.
Rare (may affect up to 1 in 1000 people): Psoriasis worsening, Changes in laboratory parameters: Increased level of liver enzymes, high level of serum bilirubin.
Very rare (may affect up to 1 in 10,000 people): Confusion, cardiovascular disorders (irregular heartbeat, heart attack and stroke), eosinophilic pneumonia (a rare type of pneumonia), rhinitis (blocked up or runny nose), erythema multiforme, acute renal failure, changes in blood values such as a lower number of white and red blood cells, lower haemoglobin, lower number of blood platelets, inflammation of the pancreas (which causes severe pain in the abdomen and the back), hepatitis.
Not known (cannot be estimated from the available data): Raynaud's phenomenon.
Cases of SIADH have been reported with other ACE inhibitors. SIADH can be considered as a very rare but possible complication associated with ACE inhibitor therapy including perindopril.
Reporting of side effects: If the patient gets any side effects, talk to the doctor or pharmacist or nurse. This includes any possible side effects not listed in this monograph.
Report side effects directly via the national reporting system. By reporting side effects it can help provide more information on the safety of this medicine.

Please tell the doctor or pharmacist if the patient is taking, has recently taken or might take any other medicines.
Treatment with Coversyl can be affected by other medicines. The doctor may need to change the dose and/or to take other precautions. These include: other medicines for high blood pressure, including angiotensin II receptor blocker (ARB), aliskiren (see also information under "Contraindications" and "Precautions"), or diuretics (medicines which increase the amount of urine produced by the kidneys); potassium-sparing drugs (e.g. triamterene, amiloride), potassium supplements or potassium-containing salt substitutes, potassium-sparing drugs used in the treatment of heart failure: eplerenone and spironolactone at doses between 12.5 mg to 50 mg by day; lithium for mania or depression; non-steroidal anti-inflammatory drugs (e.g. ibuprofen) for pain relief or high dose aspirin; medicines to treat diabetes (such as insulin or metformin); baclofen (used to treat muscle stiffness in diseases such as multiple sclerosis); medicines to treat mental disorders such as depression, anxiety, schizophrenia etc (e.g. tricyclic antidepressants, antipsychotics); immunosuppressants (medicines which reduce the defence mechanism of the body) used for the treatment of auto-immune disorders or following transplant surgery (e.g. ciclosporin, tacrolimus); trimethoprim (for the treatment of infections); estramustine (used in cancer therapy); Racecadotril: ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when used concomitantly with racecadotril (a drug used against acute diarrhea); mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see "Precautions"); allopurinol (for the treatment of gout); procainamide (for the treatment of an irregular heart beat); vasodilators including nitrates (products that make the blood vessels become wider); heparin (medicines used to thin blood); medicines used for the treatment of low blood pressure, shock or asthma (e.g. ephedrine, noradrenaline or adrenaline); gold salts, especially with intravenous administration (used to treat symptoms of rheumatoid arthritis).
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. polyacrylonitrile membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Sacubitril/Valsartan: The concomitant use of perindopril with sacubitril/valsartan is contra-indicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see "Contraindications" and "Precautions").
Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see "Precautions").

This drug must be stored at a temperature below 30°C.
Shelf-life: 3 years.

ACE Inhibitors/Direct Renin Inhibitors

C09AA04 - perindopril ; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.

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