Clinical medicine profile
Perindopril/Indapamide
ACE inhibitor
- Route
- ORAL
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
WARNING: FETAL TOXICITY When pregnancy is detected, discontinue perindopril erbumine as soon as possible [see Warnings and Precautions (5.4) ]. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.4) ] . WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue perindopril erbumine as soon as possible [see Warnings and Precautions (5.4) ] . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [ see Warnings and Precautions (5.4) ] .
Contraindications
- (including angioedema) to this product or to any other ACE inhibitor.
- Perindopril erbumine tablets are also contraindicated in patients with hereditary or idiopathic angioedema.
- Do not co-administer aliskiren with perindopril erbumine tablets in patients with diabetes. [see Drug Interactions (7.8) ] Perindopril erbumine tablets are contraindicated in combination with neprilysin inhibitor (e.g., sacubitril).
- Do not administer perindopril erbumine tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions (5.1) ].
- Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema.
- ( 4 , 5.1 ) Do not co-administer aliskiren with perindopril erbumine tablets in patients with diabetes ( 4 , 7.8 ) Do not take a neprilysin inhibitor with perindopril erbumine tablets ( 4 ).
- Do not administer perindopril erbumine tablets within 36 hours of switching to or from sacubitril/valsartan ( 4 ).
Precautions
- 5 WARNINGS AND PRECAUTIONS Watch for anaphylactoid reactions, including angioedema.
- (5.1) Monitor renal function during therapy.
- (5.5) Assess for hypotension and hyperkalemia.
- (5.2 , 5.6) 5.1 Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including perindopril erbumine) may be subject to a variety of adverse events, some of them serious.
- Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.
- Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors, including perindopril erbumine (0.1% of patients treated with perindopril erbumine in U.S. clinical trials).
- Angioedema associated with involvement of the tongue, glottis or larynx may be fatal.
- In such cases, discontinue perindopril erbumine treatment immediately and observe until the swelling disappears.
- When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.
- Patients taking concomitant mTOR inhibitor (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions (7.9
- Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
- These patients presented with abdominal pain (with or without nausea or vomiting)
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
2 DOSAGE AND ADMINISTRATION Hypertension The recommended initial dose is 4 mg once a day. The dosage may be titrated upward until blood pressure, when measured just before the next dose, is controlled or to a maximum of 16 mg per day. (2.1) Stable Coronary Artery Disease Perindopril erbumine tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased, as tolerated, to a maintenance dose of 8 mg once daily. (2.2) 2.1 Hypertension Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses. Use in Elderly Patients: The recommended initial daily dosage of perindopril erbumine tablets for the elderly is 4 mg daily, given in one or two divided doses. Experience with perindopril erbumine tablets is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration [see Use in Specific Populations (8.5) ] . Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of perindopril erbumine tablets. Consider reducing the dose of diuretic prior to starting perindopril erbumine tablets [see Drug Interactions (7.1) ] . 2.2 Stable Coronary Artery Disease In patients with stable coronary artery disease, perindopril erbumine tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), perindopril erbumine tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated. 2.3 Dose Adjustment in Renal Impairment and Dialysis Perindoprilat elimination is decreased in renally impaired patients. Perindopril erbumine tablets are not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.
8.4 Pediatric Use Neonates With a History of in utero Exposure to Perindopril Erbumine: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants. Safety and effectiveness of perindopril erbumine in pediatric patients have not been established.
Essential monitoring; beneficial long-term in proteinuric CKD if stable creatinine/K.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Rare hepatic reactions; prodrug activation may be reduced in severe liver disease.
Use, effects & interactions
Indications
- hypertension.
- (1.1) Perindopril erbumine tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction.
- (1.2) 1.1 Hypertension Perindopril erbumine tablets are indicated for the treatment of patients with essential hypertension.
- Perindopril erbumine tablets may be used alone or given with other classes of antihypertensives, especially thiazide diuretics. 1.2 Stable Coronary Artery Disease Perindopril erbumine tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction.
- Perindopril erbumine tablets can be used with conventional treatment for management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy.
Adverse effects
- conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Hypertension: Most common adverse events (incidence greater than or equal to 5%) are cough, dizziness and back pain.
- (6.1) Stable Coronary Artery Disease: Most common adverse events leading to discontinuation were cough, drug intolerance, and hypotension.
- (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions are discussed elsewhere in labeling: Anaphylactoid reactions, including angioedema [see Warnings and Precautions (5.1) ] Hypotension [see Warnings and Precautions (5.2) ] Neutropenia and agranulocytosis [see Warnings and Precautions (5.3) ] Impaired renal function [see Warnings and Precautions (5.5) ] Hyperkalemia [see Warnings and Precautions (5.6) ] Cough [see Warnings and Precautions (5.7) ] Hypertension Perindopril erbumine has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials.
- The data presented here are based on results from the 1,417 perindopril erbumine-treated patients who participated in the U.S. clinical trials.
- Over 220 of these patients were treated with perindopril erbumine for at least one year.
- In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with perindopril erbumine and 6.7% in patients treated with placebo.
- The most common causes were cough, headache, asthenia and dizziness.
- Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with perindopril erbumine and in those treated with placebo (approximately 75% in each group).
- The only adverse events whose incidence on perindopril erbumine was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).
- Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.
- Stable Coronary Artery Disease Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease.
- The overall rate of discontinuation was about 22% on drug and placebo.
- The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension. 6.2 Postmarketing Experience Voluntary reports of adverse events in patients taking perindopril erbumine that have been received since market introduction and are of unknown causal relationship to perindopril erbumine include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia or an elevated erythrocyte sedimentation rate (ESR). 6.3 Clinical Laboratory Test Findings Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with perindopril erbumine, but are rarely of clinical importance.
Drug interactions
Open multi-drug checker ↗- One tablet daily in the morning
- Fixed-dose/multi-ingredient product.
- Clinical details partially inherited from component monographs: Perindopril/Indapamide, Indapamide.
- Confirm combination SmPC for exact dosing.
Mechanism & disposition
perindoprilat, which inhibits ACE in human subjects and animals.
Read complete mechanism
perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of perindopril erbumine remains to be elucidated. While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.
Hours; full effect weeks
12–24 hours
ORAL
Oral administration of perindopril erbumine results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed t...
Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.
Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean
of perindopril associated with most of its
Pregnancy, lactation & diet
8.1 Pregnancy Pregnancy Category D [see Boxed Warning and Warnings and Precautions (5.4) ] . Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue perindopril erbumine as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue perindopril erbumine, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to perindopril erbumine for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4) ] . Radioactivity was detectable in fetuses after administration of 14 C-perindopril to pregnant rats.
8.3 Nursing Mothers Milk of lactating rats contained radioactivity following administration of 14 C-perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when perindopril erbumine is given to nursing mothers.
Brands & loaded prices
| Brand | Manufacturer | Pack | Observed price |
|---|---|---|---|
| Bipreterax | Afya Index / Retail Reference | mg/ 1.25mg 30s | KES 813.00afya_index_book |
| Bipreterax | Servier | mg/ 0.625mg 30's | Unavailable |
Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.