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Perindopril arginine with indapamide oral


Oral formulations of perindopril (arginine and tosilate salts) with indapamide.

Drugs List

  • COVERSYL ARGININE PLUS 5mg+1.25mg tablets
  • perindopril arginine 5mg and indapamide 1.25mg tablets
  • Therapeutic Indications


    Treatment of essential hypertension



    One tablet daily, preferably taken in the morning and before a meal.

    When possible dose titration with the individual components can be recommended. When clinically appropriate, direct change from monotherapy to perindopril with indapamide may be considered.


    See Dosage; Adults.

    Patients with Renal Impairment

    Perindoprilat, the active metabolite, is excreted by the kidney and therefore should be used with caution in patients with renal impairment and the dose adjusted to the degree of renal impairment with close monitoring of creatinine and potassium levels.

    Creatinine clearance 30 to 60 ml/minute
    It is recommended to start treatment with the adequate dosage of the free combination.

    Usual medical follow-up will include frequent monitoring of creatinine and potassium.


    Children under 18 years
    Desensitisation therapy
    Within 36 hours of discontinuing a sacubitril containing product
    Addison's disease
    Haemodialysis with high flux membranes
    Haemodynamic instability
    Hepatic encephalopathy
    Hereditary angioneurotic oedema
    Idiopathic angioneurotic oedema
    Renal artery stenosis
    Renal impairment - creatinine clearance below 30 ml/minute
    Severe hepatic impairment
    Symptomatic hyperuricaemia
    Uncontrolled decompensated cardiac failure

    Precautions and Warnings

    History of allergies including anaphylaxis
    Restricted sodium intake
    Aortic stenosis
    Cerebral ischaemia
    Collagen vascular disease
    Diabetes mellitus
    Electrolyte depletion
    Glucose-galactose malabsorption syndrome
    Hepatic cirrhosis
    Hepatic impairment
    History of angioedema
    Hypertrophic cardiomyopathy
    Ischaemic heart disease
    Lactose intolerance
    Left ventricular outflow obstruction
    Metabolic acidosis
    Mitral stenosis
    Nephrotic syndrome
    Peripheral vascular disease
    Renal impairment
    Renovascular disorder
    Systemic lupus erythematosus
    Unstable cardiac disorder

    Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
    Advise patient to protect skin if restarting following photosensitivity
    Anaphylactoid reactions possible with haemofiltration or LDL apheresis
    Anaphylaxis possible with concomitant hyposensitisation to wasp/bee venom
    Advise ability to drive/operate machinery may be affected by side effects
    Afro-Caribbean or black patients may show reduced response
    Exclude renovascular disorder before treatment
    Have available adrenaline injection 1:1000 for anaphylaxis
    Contains lactose
    Place patient in supine position if severe hypotension occurs
    Evaluate renal function before and during treatment
    Monitor serum electrolytes before and during treatment
    Consider monitoring white blood cell counts in collagen vascular disease
    Monitor haematological parameters periodically
    Monitor serum potassium regularly
    Reduce dose/discontinue if serum creatinine or blood urea increases
    Advise patient to report any symptoms of infections especially sore throats
    Advise patients at risk of neutropenia to report any signs of infection
    Excess consumption of liquorice may increase the risk of hypokalaemia
    Higher incidence of angioedema in black patients
    Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
    May cause anaphylactic / anaphylactoid reactions
    May precipitate diabetes mellitus
    May precipitate gout
    Withdraw and consider hyperparathyroidism if frank hypercalcaemia develops
    Discontinue before parathyroid function tests
    Discontinue treatment 24 hours prior to surgery
    Withdraw 24 hours before desensitisation if considered necessary
    Withdraw for at least 24 hours before LDL apheresis
    Discontinue at first signs of jaundice,cholestasis,hepatitis
    Discontinue at once if hepatic encephalopathy occurs
    Discontinue if hypotension occurs, restart at lower dose and monitor
    Discontinue if jaundice or other evidence of hepatic impairment occurs
    Discontinue if laryngeal stridor/angioedema of face/tongue or glottis
    Discontinue if photosensitivity occurs
    Discontinue if symptoms of acute angle closure glaucoma occur
    Advise patient not to take NSAIDs unless advised by clinician
    Advise on problems of salt substitutes/high intake of potassium-rich food
    Female: Ensure adequate contraception during treatment

    Marked water and sodium depletion (salt free diet and/or diuretic treatment) or stenosis of the renal arteries stimulate the renin-angiotensin system. Inhibition by an ACE inhibitor, especially during the first two weeks of treatment, may lead to an abrupt fall in blood pressure and/or to functional and possibly acute renal failure, although the latter is uncommon and the time interval variable. Discontinuation of perindopril or reduction of the diuretic may be required.

    Systematic testing should be carried out for clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhoea or vomiting. Marked hypotension may require the implementation of an intravenous infusion of isotonic saline.
    Transient hypotension is not a contraindication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only one of the constituents.

    Elevated potassium levels may occur during ACE inhibitor therapy. Those especially at risk of hyperkalaemia include renal impairment, worsening of renal function, age (greater than 70 years), diabetes mellitus, inter-current events, in particular dehydration, acute cardiac decompensation and metabolic acidosis.
    Concurrent use of potassium sparing diuretics, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in plasma potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. Where combination therapy is considered essential, it should be used with caution and with frequent monitoring of plasma potassium. Advise on problems of salt substitutes/high intake of potassium-rich food.

    Perindopril should be used with extreme caution in patients with collagen vascular disease, treatment with allopurinol or procainamide and therapy with immunosuppressive agents, it may lead to increased risk of neutropenia. Monitor white blood cell counts. Serious infections, unresponsive to antibiotic may develop. Periodic monitoring of white blood count is advised. Instruct patients to report signs of infection.

    In certain hypertensive patients without pre-existing apparent renal lesion and for whom renal blood tests show functional renal impairment, treatment should be stopped and possibly restarted either at a low dose or with one constituent only. In these patients usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal impairment including renal artery stenosis.

    If renovascular hypertension is present there may be an increased risk of severe hypotension and renal impairment.

    Perindopril treatment should be stopped immediately if the patient develops angioedema of the face, extremities, lips, tongue, glottis and/or larynx. This may occur at any time during treatment. In such cases, the patient should be monitored until the oedema has disappeared. When confined to the face and lips, angioedema usually resolves without treatment. However antihistamines have been used. Angioedema involving the tongue, glottis or larynx may be fatal.
    Appropriate emergency therapy should be given (e.g. adrenaline/maintenance of patent airway). The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
    Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of angioedema while receiving an ACE inhibitor. Intestinal angioedema can occur in patients treated with ACE inhibitors, and should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

    ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in those with severe cardiac failure or in those receiving high-dose vasodilator therapy.

    Symptomatic hypotension is more likely to occur in patients who have been volume-depleted and salt-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension. Patients at risk should be closely supervised during initiation of therapy and during dose adjustment. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

    A persistent, non-productive cough may occur which usually resolves itself after therapy is discontinued. An iatrogenic aetiology should be considered in the event of this symptom. If the prescription of an ACE inhibitor is still preferred, continuation of treatment may be considered.

    The treatment of renovascular hypertension is revascularisation. Nonetheless, ACE inhibitors can be beneficial in patients with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible. Treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was stopped.

    In patients with severe cardiac insufficiency (grade IV) or in patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose. Treatment with beta blockers in hypertensive patients with coronary insufficiency should not be stopped, the ACE inhibitor should be added to the beta blocker.

    Potassium depletion with hypokalaemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (less than 3.4 mmol/L) should be prevented in some high risk populations such as elderly and/or malnourished subjects, whether or not they are taking multiple medications, cirrhotic patients with oedema and ascites, coronary patients and patients with cardiac failure. In such cases hypokalaemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders.

    Idiosyncratic reactions resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma may be caused by sulfonamide, or sulfonamide derivative drugs. Untreated acute angle-closure glaucoma can lead to permanent vision loss, prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

    Pregnancy and Lactation


    Perindopril with indapamide is contraindicated during the second and third trimesters of pregnancy and should be avoided during the first trimester. If a pregnancy is planned, the switch to alternative medication with an established safety profile for use in pregnancy should be made as soon as possible. If pregnancy is confirmed, treatment with ACE inhibitors should be stopped immediately, and if appropriate, alternative therapy should be started.

    It is not known if perindopril or its metabolite perindoprilat crosses the human placenta. The molecular weights (about 368 for the free acid and 442 for the salt form) suggest that transfer to the foetus will occur (Briggs, 2011).

    ACE inhibitors are contraindicated during the second and third trimesters of pregnancy as exposure during these trimesters is known to induce human foetal toxicity (renal dysfunction, oligohydramnios, pulmonary hypoplasia, patent ductus arteriosus, delay in skull ossification, neonatal toxicity and even death). Severe and sometimes fatal anuria in the foetus and in the newborn have been observed and is thought to be caused by the compromise of the foetal renal system. Foetal renal failure resulting from in utero exposure to ACE inhibitors has been reported where dialysis has been required shortly after birth. Evidence of a risk of teratogenicity after first trimester exposure is conflicting, however, the MHRA recommends that a risk cannot be excluded. Recent data published does associate first trimester ACE inhibitor exposure with congenital CNS and cardiovascular defects. Unless treatment with an ACE inhibitor is considered absolutely essential, women who are planning to become pregnant should be switched to an alternative drug with an established safety record. If exposure has occurred in the first trimester a detailed ultrasound diagnosis is advisable. Exposure to an ACE inhibitor during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy. In cases involving long term prenatal therapy in the second and/ or third trimesters, the foetus should be monitored for the potential development of oligohydramnios, and foetal growth should be assessed with detailed ultrasound scans (Schaefer, 2007).

    Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

    Indapamide is not recommended for use during pregnancy. Animal studies in mice, rats and rabbits, reported no impaired fertility, foetal harm, or effect on postnatal development. However, foetal growth retardation was reported in studies on rats. Diuretics are contraindicated for their possible affects on the mother and therefore the foetus. The maternal hypovolaemia characteristic of the treatment of gestational hypertension with a diuretic, would adversely affect placental perfusion, which in turn could lead to intrauterine growth retardation (IUGR). Other risks to the foetus or newborn include bone marrow depression, hypoglycaemia, thrombocytopenia, hyponatraemia, hypokalaemia, jaundice and death from maternal complications. Prolonged labour has also been described as the result of inhibition of smooth muscle action caused by diuretics (Schaefer, 2007). This product should not be used in pregnancy.

    The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( ) or if this is unavailable at the backup site ( ).


    The combination of perindopril with indapamide is contraindicated during lactation.


    The effect of perindopril treatment on nursing infants has not been determined, however, due to its molecular size it is likely that perindopril and the active metabolite perindoprilat are excreted in breast milk, lactating mothers are advised not to breast feed while taking perindopril.

    The MHRA has stated that although ACE inhibitors are not generally recommended for use by breastfeeding mothers they are not absolutely contraindicated and may be prescribed if treatment is considered essential. The MHRA state that ACE inhibitors should not be used by breastfeeding mothers in the first few weeks after delivery because of possible profound neonatal hypotension particularly in preterm infants. If ACE inhibitor therapy is considered essential for the mother the use of captopril, enalapril or quinapril may be considered when the infant is older. The infant should be carefully followed up for signs of hypotension should ACE inhibitor treatment be deemed necessary.


    Indapamide is excreted in breast milk and should not be used during the breast-feeding period due to the decrease and even suppression of the milk secretion. Hypersensitivity to sulfonamide-derived drugs, hypokalaemia, and nuclear icterus might occur.

    Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
    Specialist advice is available from the UK Drugs in Lactation Advisory Service at

    Side Effects

    Abdominal pain
    Abnormal vision
    Acute renal failure
    Altered liver function tests
    Angina pectoris
    Aplastic anaemia
    Atrial fibrillation
    Blood urea increased
    Blurred vision
    Cholestatic hepatitis
    Choroidal effusion
    Cytolytic hepatitis
    Dry mouth
    Electrolyte disturbances
    Eosinophilic pneumonia
    Epigastric pain
    Erythema multiforme
    Exacerbation of psoriasis
    Fulminant hepatic necrosis
    Gastro-intestinal disturbances
    Haemolytic anaemia
    Hepatic encephalopathy
    Hepatic failure
    Hepatic impairment
    Hypersensitivity reactions
    Impaired vision
    Increase in creatinine
    Increase in serum glucose
    Maculopapular rash
    Mood changes
    Muscle weakness
    Muscular cramps
    Myocardial infarction
    Narrow angle glaucoma
    Renal impairment
    Sleep disturbances
    Sore throat
    Stevens-Johnson syndrome
    Toxic epidermal necrolysis
    Ventricular tachycardia
    Worsening of lupus erythematosus


    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: February 2013

    Reference Sources

    British National Formulary, 64th Edition (2012) Pharmaceutical Press, London.

    Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

    Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

    Summary of Product Characteristics: Coversyl arginine plus 5 mg/1.25 mg film-coated tablets. Servier Laboratories Ltd. Revised April 2021.

    MHRA Drug Safety Update: Volume 1, Issue 5, December 2007
    Last accessed: February 20, 2013

    MHRA Drug Safety Update: Volume 2, Issue 10, May 2009.
    Last accessed: February 20, 2013

    US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
    Available at:
    Perindopril Last revised: March 1, 2012
    Last accessed: February 20, 2013

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