An inhibitor of the Angiotensin-Converting Enzyme (ACE), perindopril (Coversyl). Patients with hypertension are the target audience for this medication. Additionally, it is employed in the treatment of IHD, heart failure, and to lessen proteinuria.

Indications of Perindopril:

• Hypertension:

  • It is indicated for the managing high blood pressure.

• Guidelines:

  • In the absence of comorbidities (such as cerebrovascular disease, chronic kidney disease, diabetes, heart failure, or ischemic heart disease), monotherapy with calcium channel blockers and thiazide diuretics is preferred due to improved cardiovascular outcomes, according to the 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.
  • ARBs and ACE inhibitors are also suitable for monotherapy. In individuals at high risk, such as those with stage 2 hypertension or an atherosclerotic cardiovascular disease [ASCVD] risk of 10% or greater, combination therapy is preferred.

• Stable coronary artery disease:

  • In patients with stable coronary artery disease, it is used to lower the risk of myocardial infarction or cardiovascular mortality.

• Guideline:

  • According to the American College of Cardiology/American Heart Association guidelines, unless contraindicated, all patients with stable ischemic heart disease who also have HTN, DM, LVEF 40%, or CKD should be administered an ACE inhibitor or ARB.

• Use: Off-Label: Adult

  • ST-elevation acute coronary syndrome
  • Non–ST-elevation acute coronary syndrome
  • Heart failure

Perindopril dose in adults:

Perindopril (Coversyl) dose in the treatment  of Heart failure (off-label):

• Initial: 2 mg per mouth, once daily, with a goal dose of 8 to 16 mg, once daily, gradually increased.

Perindopril (Coversyl) dose in the treatment of Hypertension:

• Initial: Once daily oral dose of 4 mg; titrate dose up to 16 mg as needed based on patient response.
• The maximum dose is 16 mg/day

Concomitant therapy with diuretics:

• The diuretic dose should be reduced to prevent hypotension before starting perindopril.
• If you are unable to stop taking the diuretic or change it, keep a watchful eye on your blood pressure for at least 2 hours after starting perindopril and for another hour after it has stabilised.

Perindopril (Coversyl) dose in the treatment:

• Initial: For two weeks, take 4 mg once day via oral, and as tolerated, up to 8 mg once daily.

Perindopril (Coversyl) dose in Childrens

Not recommended for use in children.

Pregnancy Risk Category: D

[US Boxed Warning]

• The first trimester is when perindopril's teratogenic effects are most evident.
• It is not recommended for use in pregnancy because it crosses the placenta, can cause fetal deaths, oligohydramnios and skeletal malformations.
• It can also lead to anuria and hypotension during pregnancy.
• In infants who are exposed to ACE inhibitors in utero, it is important to monitor for hypotension, hyperkalemia, and oliguria.
• Exchange transfusions and dialysis might improve renal function/hypotension.
• Women of childbearing years should avoid ACE inhibitors. They are also contraindicated during pregnancy for hypertension or chronic heart failure.

Perindopril use during breastfeeding:

• Breast milk contains perindopril.
• When calculated from a single breastmilk concentration, the relative infant dose (RID), is 2%. This compares to a maternal weight-adjusted dose of 20mg/day.
• When the RID of the medication is less than 10%, breastfeeding is generally acceptable.
• Calculating the RID of perindopril using a milk content of 0.9 ng/mL yielded an estimated daily infant dose via breastmilk of 135 mg/day.
• Manufacturer recommends that pregnant women should not take perindopril.

Perindopril (Coversyl) Dose adjustment in renal disease:

• Creatinine clearance >30 mL/minute:

  • Initial: 2 mg/day; maximum maintenance dose: 8 mg/day.

• Creatinine clearance <30 mL/minute:

  • Use is not recommended. 2 mg once every 48 hours has been recommended for patients with CrCl 15 to 30 mL/minute.

• Hemodialysis:

  • Perindopril and its metabolites are dialyzable. 2 mg on dialysis days (given after dialysis) has been recommended.

Dose adjustment in liver disease:

The manufacturer's labelling does not provide dosage changes; use with caution because hepatic impairment increases perindoprilat bioavailability.

Common Side Effects of Perindopril (Coversyl):

• Central nervous system:

  • Headache

• Respiratory:

  • Cough

Rare Side Effects of Perindopril (Coversyl):

• Cardiovascular:

  • ECG Abnormality
  • Chest Pain
  • Palpitations
  • Edema

• Central Nervous System:

  • Paresthesia
  • Sleep Disorder
  • Drowsiness
  • Depression
  • Nervousness
  • Hypertonia

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Menstrual Disease
  • Increased Serum Triglycerides

• Gastrointestinal:

  • Nausea
  • Abdominal Pain
  • Vomiting
  • Dyspepsia
  • Flatulence
  • Diarrhea

• Genitourinary:

  • Sexual Disorder
  • Proteinuria
  • Urinary Tract Infection

• Hepatic:

  • Increased Serum ALT

• Hypersensitivity:

  • Seasonal Allergy

• Infection:

  • Viral Infection

• Neuromuscular & Skeletal:

  • Arthralgia
  • Back Pain
  • Myalgia
  • Leg Pain
  • Arthritis
  • Arm Pain
  • Neck Pain
  • Weakness

• Otic:

  • Otic Infection
  • Tinnitus

• Respiratory:

  • Rhinitis
  • Sinusitis
  • Pharyngitis
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Fever

Contraindication:

• Intolerance to perindopril, other ACE inhibitors, or any other formulation ingredient (eg, angioedema).
• Angioedema - hereditary/idiopathic
• Patients with diabetes mellitus can combine aliskiren and combination therapy
• within 36 hours of using or stopping a neprilysin inhibitor (such as sacubitril) in combination

Canadian labeling:No Additional contraindications in US labeling

• Bilateral or unilateral renal stenosis
• Planning of conception/ Pregnancy
• Breastfeeding
• Galactose intolerance, glucose-galactose malabsorption, lactase deficiency
• Combination therapy with aliskiren in patients with moderate to severe renal impairment (GFR <60 mL/minute
• concomitant use with sacubitril/valsartan.

Warnings and precautions

• Angioedema

  • Therapy can cause angioedema at any moment.
  • Angioedema risk factors include patients who are black, those with an idiopathic angioedema or hereditary, and patients who have taken a combination of everolimus or neprilysin inhibition (eg sacubitril).
  • It is crucial to be aggressive early and appropriately managed.
  • In cases where the tongue, glottis, or larynx are implicated, prolonged observation may be required because these structures have the potential to clog the airways.
  • Patients with angioedema due to ACE inhibitor therapy are not advised to take it.

• Cholestatic jaundice

  • ACE inhibitors may cause cholestatic jaundice that can progress to fulminant hepatic neoplasm. Therefore, therapy should be stopped in the case of severe transaminitis.

• Cough:

  • A dry, non-productive cough can be caused by an ACE inhibitor. This usually happens within the first few weeks of treatment. It should resolve within one month.

• Hematologic effects

  • Rarely, ACE inhibitors can cause neutropenia.
  • Neutropenia is associated with a number of risk factors, such as renal insufficiency and collagen vascular disease, such as systemic lupus. Therefore, it's crucial to routinely check your CBC.

• Hyperkalemia:

  • Hyperkalemia can be caused by perindopril therapy DM.
  • These risk factors include renal impairment, combination therapy, potassium-sparing diuretics and/or potassium supplements.
  • It is important to monitor potassium.

• Hypersensitivity reactions

  • Hemodialysis (CVVHD, high-flux dialysis membranes, AN69, etc.) and low density lipoprotein (LDL) apheresis utilising dextran sulfatecellulose may both cause severe anaphylactic responses.
  • Patients who have received ACE inhibitors and are subject to sensitization with bee/wasp venom have had rare cases of anaphylactic reactions.

• Hypotension/syncope

  • Hypotension symptoms can develop in patients with low volume. This is treated by continuous monitoring and fluid replacement.
  • Hypotension can be treated, especially for patients with heart disease.

• Renal function deterioration:

  • Particularly in patients with poor renal blood flow (such as those with renal artery stenosis or heart failure) and whose GFR depends on efferent arterial vasoconstriction via angiotensin 2, it can cause oliguria, acute kidney failure, and progressive azotemia.
  • In the event of a worsening of renal function, drug therapy should be stopped

• Aortic stenosis

  • Patients with severe aorticstenosis should be cautious as it can reduce coronary perfusion and cause ischemia.

• Ascites:

  • Ascites caused by cirrhosis and refractory ascites should be avoided
  • If the use of these drugs is not possible, BP monitoring and RFTs monitoring will be required in order to prevent renal disease.

• Cardiovascular disease

  • During treatment for BP falls, patients with ischemic heart disease and cerebrovascular disease must be closely monitored.
  • To normalize blood pressure, fluid replacement should be performed.
  • Hypotension recurrent should be treated immediately.

• Collagen vascular disease:

  • Patients with collagen vascular disease (concomitant kidney impairment) should not use it. The risk of hematologic toxicities can increase.

• Hepatic impairment

  • Hepatic patients need to exercise caution.

• Hypertrophic cardiomyopathy with outflow tract obstruction (HCM)

  • Perindopril may cause a decrease in the afterload. This can further worsen HCM and outflow tract obstruction.

• Renal artery stenosis

  • Patients with unilateral or bilateral renal artery stenosis that is untreated need to be closely watched.
  • It's better to avoid it.

• Renal impairment

  • Rapid dosage escalation is not recommended as it can cause renal impairment.

Perindopril: Drug Interaction

Monitoring parameters:

• BP
• CBC
• Serum electrolytes
• Renal function tests/BUN

Heart Failure:

• In patients with preexisting hypotension, diabetes mellitus, hyponatremia, azotemia, or those taking potassium supplements, renal function and serum potassium should be assessed in the first two weeks of medication.

Hypertension:

• The 2017 Guideline:

  • Confirmed hypertension and known atherosclerotic cardiovascular disease (ASCVD) or 10-year ASCVD risk ≥10%:

    • Target blood pressure <130/80 mm Hg is recommended

  • Confirmed hypertension without markers of increased ASCVD risk:

    • Target blood pressure <130/80 mm Hg may be reasonable

Diabetes and hypertension: The American Diabetes Association (ADA) guidelines (ADA 2019):

• Patients 18 to 65 years of age, without ASCVD, and 10-year ASCVD risk <15%:

  • Target blood pressure <140/90 mm Hg is recommended

• Patients 18 to 65 years of age and known ASCVD or 10-year ASCVD risk >15%:

  • Target blood pressure <130/80 mm Hg may be appropriate if it can be safely attained

• Patients >65 years of age (healthy or complex/intermediate health):

  • Target blood pressure <140/90 mm Hg is recommended

• Patients >65 years of age (very complex/poor health):

  • Target blood pressure <150/90 mm Hg is recommended

How to administer?

• It should be administered after the evening meals.
• The patient should be advised to keep seated for 15 - 30 minutes after its intake to avoid first-dose hypotension (during the first week of therapy).

Mechanism of action of Perindopril (Coversyl):

• Perindopril, a prodrug to perindoprilat acts as a competitive inhibitor of ACE by reducing the level of angiotensin III(vasoconstrictor).
• It prevents angiotensin I from angiotensin 2, thereby increasing plasma renin activity, and reducing aldosterone production.

The onset of action:

• Peak effect: 1 to 2 hours

Protein binding:

• Perindopril: 60% Perindoprilat: 10% to 20%

Metabolism:

• Perindoprilat, an active metabolite (about 17–20% of a dosage), and other inactive metabolites are produced as a result of hydrolysis in the liver.

Bioavailability:

• Perindopril: 75% Perindoprilat 25% (16% with food)

Half-life elimination:

• Parent drug: 1.5 to 3 hours
• Metabolite:
  • Effective: 3 to 10 hours,
  • Terminal: 30 to 120 hours

Time to peak:

• Chronic therapy: Perindopril: 1 hour Perindoprilat: 3 to 7 hours (maximum perindoprilat serum levels are 2 to 3 times higher and T is shorter following chronic therapy)
• CHF: Perindoprilat: 6 hours

Excretion:

• Urine (75%, 4% to 12% as unchanged drug)

International Brands of Perindopril:

• Aceon
• AG-Perindopril
• APO-Perindopril
• Auro-Perindopril
• Coversyl
• JAMP-Perindopril
• M-Perindopril Erbumine
• MAR-Perindopril
• MINT-Perindopril
• PMS-Perindopril
• Priva-Perindopril Erbumine
• RIVAPerindopril
• SANDOZ Perindopril Erbumine
• TEVA-Perindopril
• Acerpril
• Acertil
• Acertil AR
• Acetec
• Adwipril
• Articel
• Bioprexum
• Covapril
• Coverene
• Coverex
• Covergim
• Coversum
• Coversyl
• Covinace
• Covrix
• Dopril
• Dorover
• Hypergo
• Indopril
• Indosyl Mono
• Inopil
• Myden
• Nexazin
• Pendrex
• Percarnil
• Pericard
• Perigard
• Perinace
• Perindal
• Perindo
• Peryndopryl Anpharm
• Prenesa
• Prenessa
• Prestarium
• Prindace
• Prinwin
• Protectopril
• Provinace
• Versil

Perindopril Brands In Pakistan: