Coversyl Plus 4mg/1.25mg

Interactions with herbal products have not been established.

Lifestyle interactions have not been established.

The presence of food in the gastrointestinal tract does not affect the rate or extent of perindopril absorption. However, the extent of biotransformation of perindopril to perindoprilat is reduced, resulting in a decrease of perindoprilat bioavailability by 35%. Due to the saturable nature of ACE inhibition, the pharmacodynamic effect, as measured by the area under the plasma ACE inhibition-time curve, is reduced by approximately 15%. Therefore it is recommended that COVERSYL PLUS LD is taken before a meal.

Interactions with laboratory products/methods have not been established.

The combined use of perindopril and indapamide in COVERSYL PLUS LD does not expose to any additional interactions with concomitant drugs other than those known for each of these components.

Treatment should be started at the normal dose of one COVERSYL PLUS LD tablet per day.

Dosage of COVERSYL PLUS LD (perindopril erbumine/indapamide) must be individualized and adjustment is required in the elderly, and in case of renal impairment.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with COVERSYL PLUS LD may need to be adjusted. The presence of food in the gastrointestinal tract reduces the bioavailability of perindoprilat.

One COVERSYL PLUS LD (perindopril erbumine/indapamide) tablet per day as a single dose, to be taken orally, preferably in the morning. In case of uncontrolled blood pressure the dose may be increased to two tablets of COVERSYL PLUS LD as a single dose or one tablet of COVERSYL PLUS.

In cases of severe renal insufficiency (creatinine clearance below 30 mL/min), treatment with COVERSYL PLUS LD is not recommended (see Warnings and Precautions).

In patients with creatinine clearance greater than or equal to 30 mL/min, no dose adjustment is required, but caution should be exercised especially in the elderly patients as greater sensitivity in the elderly cannot be ruled out.

Periodic monitoring of creatinine and potassium levels is recommended.

It is recommended that COVERSYL PLUS LD (perindopril erbumine/indapamide) is taken once daily, preferably in the morning before breakfast (see Drug Interactions, Drug-Food Interactions).

If a dose is missed, a double dose should not be taken, but just carry on with the next dose at the normal time.

abdominal pain, colitis, constipation, diarrhoea, esophageal reflux, esophagitis, functional digestive disorders, gastritis, gastroduodenitis, infective and non-infective gastroenteritis, herpes zoster, intestinal infection, nausea, periapical abscess, salivary secretion disturbance, vomiting.

Among the less common suspected adverse reactions reported, the following have been published in the medical literature and/or are classified as serious or potentially serious: Stevens-Johnson syndrome, bullous eruption, photosensitivity with bullae, erythroderma, purpura, epidermal necrolysis, erythema multiforme, angioedema, cataract, acute myopia, optic neuritis, ventricular arrhythmia, torsades de pointe, stroke, acute hypersensitivity reaction leading to interstitial nephritis and renal failure, anemia, agranulocytosis, metabolic alcalosis, hyperosmolar coma, dehydratation, hepatitis, pancreatitis, lithium toxicity, rhabdomyolysis, vasculitis, fever.

One case of synergetic effect of clofibrate with indapamide leading to hyponatremia, hypokalemia, hypoosmolarity, nausea and progressive loss of consciousness.

A relationship with the administration of indapamide has not been proved in all cases.

Rarely, elevations of liver enzymes have been reported (see Warnings and Precautions).

Minor decreases in haemoglobin (mean decrease of approximately 1 g/L) occurred in hypertensive patients treated with one or two tablets of COVERSYL PLUS LD (versus 0.1 g/L under placebo), but were rarely of clinical importance. In clinical trials, hematocrit was unaffected by treatment and no patients discontinued therapy due to anemia.

anxiety, depression, drowsiness, fall, migraine, nervousness, sleep disturbance, somnolence.

In a long-term study including 492 patients (444 were treated for three months, 420 for six months and 245 for one year or longer), the nature and frequency of adverse events were similar to those listed in the table.

The safety profile of COVERSYL PLUS LD in patients over 65 years old was comparable to that in younger adult patients; this was demonstrated in a specific 3-month placebo-controlled study involving 383 elderly patients (193 patients treated with COVERSYL PLUS LD) and a sub-population analysis on the 618 elderly patients who received COVERSYL PLUS LD in all short-term studies combined, and confirmed in a one-year follow-up on 253 elderly patients (215 were treated for three months, 177 for six months and 140 for one year or longer).

Calcium excretion is decreased by diuretics pharmacologically related to indapamide (see Warnings and Precautions, Indapamide). Serum concentrations of calcium increased only slightly with indapamide.

The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide.

During 12-week studies with COVERSYL PLUS LD, 1.8% of patients treated with one tablet o.d. and 3.9% of those treated with two tablets o.d. had at least one potassium level below 3.4 mmol/L (versus 0.3% in placebo-treated patients). These percentages were statistically significantly lower than in patients treated with indapamide alone at the usual therapeutic dose of 1.25 mg. The mean reduction of potassium level with COVERSYL PLUS LD was 0.10 mmol/L with one tablet and 0.20 mmol/L with two tablets (versus 0.03 mmol/L under placebo).

The incidence of potassium levels below 3.4 mmol/L during long-term treatment was not significantly different from that observed during short-term studies and the probability to have potassium levels below this limit did not depend on the extent of exposure.

Increases of potassium levels above 5.5 mmol/L occurred in 0.8% of patients treated with one tablet o.d. of COVERSYL PLUS LD and in 1.0% of patients treated with two tablets o.d. (versus 0.7% under placebo) (see Warnings and Precautions). Similar percentages of potassium levels variations were observed in elderly patients.

conjunctivitis, impacted cerumen, otitis media, peripheral vertigo, skin sensation disturbances, smell and taste disturbances, tinnitus, visual disturbances.

blood creatinine increased.

bloating, chest pain, edema, epistaxis, malaise, pallor and flushing, poisoning, pyrexia, tetany, weight loss.

allergic rhinitis, asthma, coryza, laryngitis, pharyngitis, pharynx diseases, respiratory insufficiency, rhinitis, sinusitis, tonsillitis, tracheitis, upper respiratory infections.

contact dermatitis, dermatomycosis, eczema, herpes zoster, local infection of skin/subcutaneous tissues, pruritus, rash.

Elevations of blood urea (>10 mmol/L) or serum creatinine (>160 µmol/L) have been observed in 3.5% and 0.5% of patients treated with one tablet o.d. of COVERSYL PLUS LD and in 2.3% and 0.3% of patients treated with two tablets o.d. (versus 1.5% and 0.14% under placebo), respectively. The mean increases in blood urea levels and serum creatinine levels were 0.4 mmol/L and 1.1 µmol/L in patients treated with one tablet of COVERSYL PLUS LD, 0.5 mmol/L and 2.1 µmol/L in patients treated with two tablets (versus 0.1 mmol/L and 0.9 µmol/L under placebo) respectively. The serum creatinine level was stable in patients with mild to moderate renal failure after 12 weeks of treatment.

backache, cervicalgia, cervicobrachial syndrome, enthesopathy of elbow region, injury, pain in limb, symptoms referable to limbs, lumbago, muscle/ligament/fascia disorders, localized osteoarthrosis, periarthritis/fibrositis of shoulder, sciatica, sprains of ankle/knee/leg.

For the adverse reactions reported with the individual components of COVERSYL PLUS LD, please refer to the Adverse Reactions sections of the separate approved Product Monographs for COVERSYL (perindopril erbumine) and LOZIDE (indapamide).

cystitis, dysuria, enuresis, frigidity, impotence, female genital neoplasm, penis disorders, polyuria, prostate hyperplasia, ureamia, urinary frequency, urinary tract infection.

COVERSYL PLUS LD has been evaluated for safety in 1974 patients, of which 1898 participated in controlled clinical trials. Long-term safety was assessed in 745 patients, of which 659 were treated for three months, 597 for six months and 385 for one year or longer.

Increases of uric acid level (>600 µmol/L) have been observed in 0.7% of patients treated with one tablet o.d. of COVERSYL PLUS LD and 0.5% of patients treated with two tablets o.d. (versus 0.1% under placebo). Uric acid level remained stable during the long-term studies including patients treated for up to one year.

Adverse events that have been reported in less than 1.0% of patients treated with COVERSYL PLUS LD in controlled clinical studies include the following:

gout, liver and biliary system disorders.

abnormal ECG, angina pectoris, heart rate and rythm disorders, hypertension, orthostatic hypotension, palpitations, Raynaud’s syndrome, syncope and collapse, tachycardia, venous insufficiency.

Although the blood pressure response and safety profile of COVERSYL PLUS LD in patients over 65 years old were comparable to those of the younger adult patients, greater sensitivity of some elderly patients cannot be ruled out.

In using COVERSYL PLUS LD, consideration should be given to the risk of angioedema (see Warnings and Precautions).

The safety and effectiveness of COVERSYL PLUS LD in children have not been established. Its use in this age group, therefore, is not recommended.

In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor.

ACE inhibitors may augment the hypotensive effects of anaesthetics and analgesics. In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, COVERSYL PLUS LD may block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Sulfonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. These possibilities should be kept in mind with the use of indapamide although no case has been reported to date.

In clinical trials in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20% of patients. Experience with ACE inhibitors suggests that these increases are usually reversible upon discontinuation of the drug. In such patients, renal function should be monitored during the first few weeks of therapy. ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis. When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney, or bilateral artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the pressure in the afferent glomerular arteriole, and transglomerular hydrostatic pressure is then maintained by angiotensin II-induced constriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration falls, and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.

Some hypertensive patients without apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient. These increases are more likely to occur in patients treated concomitantly with a diuretic and in patients with pre-existing renal impairment. Reduction of dosages of perindopril, the diuretic or both may be required. In some cases, discontinuation of either or both drugs may be necessary. Evaluation of hypertensive patients should always include an assessment of renal function (see Dosage and Administration). If deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients usage of another class of antihypertensive agent would be preferable. Patients with unilateral renal artery disease present a special problem as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.

Some ACE inhibitors have been associated with the occurrence (up to 0.7%) of proteinuria (<1 g/24 hours) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium-sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a non-steroidal anti-inflammatory drug.

Perindoprilat, the active form of perindopril, is dialysable with a clearance of 70 mL/min.

In clinical trials with the perindopril/indapamide combination, hyperkalemia (serum potassium >5.5 mmol/L) occured in approximately 1.0% of hypertensive patients. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs associated with increases in serum potassium (e.g. heparin) (see Drug Interactions, Drug-Drug Interactions).

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, COVERSYL PLUS LD should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency).

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Although the blood pressure response and safety profile of COVERSYL PLUS LD in patients over 65 years old were comparable to those of the younger adult patients, greater sensitivity of some elderly patients cannot be ruled out.

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulphate absorption have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Taste disturbances were reported to be common (prevalence up to 12.5%) with high doses of another ACE inhibitor.

Taste disturbance with ACE inhibitors have been described as suppression of taste or a metallic sensation in the mouth. Any dysgeusia usually occurs in the first weeks of treatment and may disappear in most cases within 1-3 months.

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors, in patients with or without pre-existing liver abnormalities. In most cases, the changes were reversed upon discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported with perindopril (see Adverse Reactions). Should the patient receiving COVERSYL PLUS LD experience any unexplained symptoms, particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of COVERSYL PLUS LD should be considered when appropriate.

COVERSYL PLUS LD should be used with particular caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Special caution should be used in treating patients with severe hepatic disease since diuretics may induce metabolic alkalosis in cases of potassium depletion which may precipitate episodes of hepatic encephalopathy.

Calcium excretion is decreased by diuretics pharmacologically related to indapamide. After six to eight weeks of indapamide 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of indapamide, however, serum concentrations of calcium increased only slightly with indapamide. Prolonged treatment with drugs pharmacologically related to indapamide may in rare instances be associated with hypercalcemia and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid function are performed. Like the thiazides, indapamide may decrease serum PBI levels without signs of thyroid disturbance.

The antihypertensive effect of the drug may be enhanced in the patient postsympathectomy.

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g. polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of COVERSYL PLUS LD should include appropriate assessment of renal function.

Caution should be observed when administering perindopril to patients with severely impaired renal function, since perindoprilat, the active form of perindopril, is excreted primarily by the renal route. Therefore, treatment with COVERSYL PLUS LD is not recommended in patients with a creatinine clearance below 30 mL/min.

Patients receiving indapamide should be carefully observed for signs and symptoms of electrolyte imbalance, namely hypokalemia, hyponatremia and hypochloremia, and their serum electrolytes should be closely monitored. Blood urea nitrogen, uric acid, and glucose levels should also be assessed during therapy. Hypokalemia will be more common in association with concomitant steroid or ACTH therapy and with inadequate electrolyte intake. The serum potassium should be determined at regular intervals and potassium supplementation instituted when indicated.

The signs of electrolyte imbalance are: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, gastrointestinal disturbances such as nausea and vomiting, tachycardia and ECG changes.

Perindopril can cause symptomatic hypotension. Perindopril has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients. It is more likely to occur after the first or second dose or when the dose was increased and in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea, or vomiting or with impaired renal function. Volume and/or salt depletion should be corrected before initiation of therapy with perindopril (see Dosage and Administration). In patients with ischemic heart or cerebrovascular disease and/or severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitors may cause an excessive fall in blood pressure which could result in syncope, a myocardial infarction, neurological deficits, oliguria and/or progressive azotemia and, rarely, in acute renal failure and/or death (see Adverse Reactions).

Because of the potential fall in blood pressure in patients at high risk of developing hypotension, therapy with COVERSYL PLUS LD should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of COVERSYL PLUS LD is increased.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. If hypotension recurs, treatment with COVERSYL PLUS LD should be discontinued.

Neutropenia/agranulocytosis, thrombocytopenia and anaemia 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 such as systemic lupus erythematosus or scleroderma, and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive (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.

A dry persistent irritating cough, which usually disappears only after withdrawal or lowering of the dose of perindopril has been reported. Such possibility should be considered as part of the differential diagnosis of the cough.

The cough is often worse when lying down or at night, and has been reported more frequently in women (who account for 2/3 of the reported cases). Patients who cough may have increased bronchial reactivity compared with those who do not. The observed higher frequency of this side-effect in non-smokers may be due to a higher level of tolerance of smokers to cough.

The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins, which accumulate because of ACE inhibition. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction may recur but this is not invariably the case. A change to another class of drugs may be required in severe cases.

The safety and effectiveness of COVERSYL PLUS LD in children have not been established. Its use in this age group, therefore, is not recommended.

As with other ACE inhibitors, COVERSYL PLUS LD should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy. There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators including ACE inhibitors because they do not develop as much afterload reduction. Vasodilators may tend to drop diastolic pressure, and hence coronary pressure, without producing the concomitant reduction in myocardial oxygen demand that normally accompanies vasodilation.

Intestinal angioedema has been reported 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 history of facial angioedema and C-1 esterase levels were normal. 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.

Not applicable.

Life-threatening angioedema has been reported with ACE inhibitors. The overall incidence is approximately 0.1-0.2%. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually, the angioedema is non-pitting edema of the skin mucuous membrane and subcutaneous tissue.

Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including perindopril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, COVERSYL PLUS LD should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, angioedema may be fatal due to airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000 and oxygen) should be administered promptly (see Adverse Reactions).

Treatment of progressive angioedema should be aggressive. Failing a rapid response to medical therapy, mechanical methods to secure an airway should be undertaken before massive oedema complicates oral or nasal intubation.

Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.

The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months.

Patients may have multiple episodes of angioedema with long symptom-free intervals.

Angioedema may occur with or without urticaria.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

There are reports that switching a patient to another ACE inhibitor could be followed by a recurrence of angioedema. Because of the potential severity of this rare event, another ACE inhibitor should not be used in patients with a history of angioedema (see Contraindications).

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Due to the presence of lactose, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactose deficiency should not take this medicinal product.

There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they reappeared upon inadvertent rechallenge.

The presence of concentrations of ACE inhibitor has been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.

Severe dermatological adverse reactions, some accompanied by systemic manifestations, have been rarely reported with the use of indapamide. In the majority of cases, the condition subsided within 14 days following discontinuation of indapamide therapy (see Adverse Reactions).

The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations in patients with hepatic impairment were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

Peak blood levels are obtained after 1 to 2 hours. Indapamide is concentrated in the erythrocytes and is 79% bound to plasma proteins and to erythrocytes. It is taken up by the vascular wall in smooth vascular muscle according to its high lipid solubility.

The coadministration of perindopril and indapamide in healthy volunteers and hypertensive patients does not change their pharmacokinetic properties by comparison to separate administration.

After repeated administration in elderly patients (69 to 97 years of age) and in patients with various degrees of renal failure, AUC of both indapamide and perindoprilat increased with renal failure, whereas C_max and AUC of indapamide only increased with age (1.5- to 2-fold factor). The AUC ratio between indapamide and perindoprilat was not significantly affected by age and by creatinine clearance >30 mL/min.

In a pharmacokinetic study with single dose administration, mean peak plasma concentrations of perindoprilat were significantly higher in elderly healthy volunteers (32.5 ng/mL) than in younger volunteers (13.5 ng/mL) due to both higher bioavailability and reduced renal clearance in this group.

Single and multiple dose pharmacokinetics of perindopril were evaluated in a study of elderly hypertensive patients (72 to 91 years of age). C_max and AUC were found to be approximately two-fold higher than in healthy younger subjects. The higher concentrations of perindoprilat observed in these patients were reflected in greater ACE inhibition (see Warnings and Precautions, Geriatrics (>65 years of age), and Dosage and Administration, Geriatrics).

Indapamide is rapidly and completely absorbed after oral administration.

COVERSYL PLUS LD (perindopril erbumine/indapamide) is a combination of perindopril erbumine, an angiotensin converting enzyme (ACE) inhibitor, and indapamide, a chlorosulphamoyl diuretic, in which the ACE inhibitor component is half the usual dose used for monotherapy and the diuretic component is four times lower than the highest dose recommended for monotherapy. Its pharmacological properties are derived from those of each of the components taken separately, in addition to those due to the additive synergistic action of the two products when combined.

COVERSYL PLUS LD exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure whilst supine or standing in hypertensive patients regardless of age. This antihypertensive effect lasts for 24 hours. The reduction in blood pressure is obtained in less than one month without tachyphylaxis; stopping treatment has no rebound effects. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergistic nature in relation to each of the products administered alone.

The blood pressure lowering effects of angiotensin converting enzyme inhibitors are generally lower in black patients than in non-blacks.

Seventy per cent of a single oral dose of indapamide is eliminated by the kidneys and 23% is excreted in feces. The decrease in plasma concentrations of indapamide is biphasic with a terminal half-life between 14 and 25 hours.

In patients with renal insufficiency, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30-80 mL/min, AUC is about double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

Perindopril, and its active metabolite perindoprilat, are dialysable. In a limited number of patients studied, perindopril hemodialysis clearance ranged from 41.7 to 76.7 mL/min (mean 52.0 mL/min). Perindoprilat hemodialysis clearance ranged from 37.4 to 91.0 mL/min (mean 67.2 mL/min). See also Warnings and Precautions and Dosage and Administration.

The effectiveness of COVERSYL PLUS LD was not influenced by gender.

Indapamide is metabolized to a marked degree, with approximately 5% of the total dose being recovered as unchanged drug in the urine within 48 hours after administration.

Patients with heart failure have reduced perindoprilat clearance, which may result in a dose interval AUC that is increased up to 40%.

Pharmacokinetics differences due to genetic polymorphism have not been studied.

In most patients with mild to moderate essential hypertension, administration of 4 to 8 mg daily of perindopril results in a reduction of both supine and standing blood pressure with little or no effect on heart rate. Antihypertensive activity commences within one hour with peak effects usually achieved by 4 to 6 hours after dosing. At recommended doses given once daily, antihypertensive effects persist over 24 hours. The blood pressure reductions observed at trough plasma concentration were 75-100% of peak effects. When once and twice daily dosing were compared, the twice daily regimen was slightly superior, but by no more than about 0.5 to 1.0 mmHg. Abrupt withdrawal of perindopril has not been associated with a rapid increase in blood pressure. In studies carried out in patients with mild to moderate essential hypertension, the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no change in glomerular filtration rate. When perindopril is given together with thiazide-type diuretics, the antihypertensive effects are additive.

In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long term use in this population, no effect on urinary protein excretion was seen.

The safety and effectiveness of COVERSYL PLUS LD in children have not been established. Its use in this age group, therefore, is not recommended.