PERINDOPRIL ERBUMINE: 1,200 Adverse Event Reports & Safety Profile

Perindopril erbumine tablets USP contain the tert-butylamine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically described as (2S,3DS,7DS)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is C 19 H 32 N 2 O 5 C 4 H 11 N. Its structural formula is: Perindopril erbumine USP is a white or almost white, crystalline powder, slightly hygroscopic with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform. Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite. Perindopril erbumine tablets USP are available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril erbumine, each tablet contains the following inactive ingredients: anhydrous lactose, silica hydrophobic colloidal anhydrous, microcrystalline cellulose, and magnesium stearate.

Chemical

Structure

AND USAGE Perindopril erbumine tablets are indicated for the treatment of patients with essential 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.

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

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 &lt;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.

Perindopril erbumine tablets are contraindicated in patients known to be hypersensitive (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 ).

REACTIONS Because clinical trials are conducted under widely varying 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> Hypotension <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> Neutropenia and agranulocytosis <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> Impaired renal function <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> Hyperkalemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span> Cough <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span>

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. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

Liver Function

Tests: Elevations in ALT (1.6% perindopril erbumine versus 0.9% placebo) and AST (0.5% perindopril erbumine versus 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.9 ; 7.10) ]</span>.

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); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The 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.

5.2 Hypotension Perindopril erbumine can cause symptomatic hypotension. Perindopril erbumine 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. Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident. In patients at risk of excessive hypotension, perindopril erbumine therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of perindopril erbumine and/or diuretic is increased. If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. Perindopril erbumine treatment can usually be continued following restoration of volume and blood pressure.

5.3 Neutropenia/Agranulocytosis ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.

5.4 Fetal Toxicity Pregnancy Category D 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>.

5.5 Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving perindopril erbumine <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>, <span class="opacity-50 text-xs">[see Drug Interactions (7)]</span>. In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including perindopril erbumine, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor. In such patients, renal function should be monitored during the first few weeks of therapy. Some perindopril erbumine-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.

5.6 Hyperkalemia Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril erbumine. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Serum potassium should be monitored periodically in patients receiving perindopril erbumine.

5.7 Cough Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

5.8 Hepatic Failure 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.

5.9 Surgery/Anesthesia In patients undergoing surgery or during anesthesia with agents that produce hypotension, perindopril erbumine may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.

INTERACTIONS Diuretics: Excessive drop in blood pressure. (7.1) Potassium-Sparing Diuretics/Potassium Supplements: Hyperkalemia. (7.2) Lithium: Increase serum lithium levels, symptoms of lithium toxicity. (7.3)

Injectable

Gold: Nitritoid reactions (facial flushing, nausea, vomiting, and hypotension). (7.4) NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect. (7.7) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7.8 )

Neprilysin

Inhibitor: risk of angioedema ( 7 ).

7.1 Diuretics Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of perindopril erbumine therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of perindopril erbumine, for at least two hours and until blood pressure has stabilized for another hour <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.

7.2 Potassium Supplements and Potassium-Sparing Diuretics Perindopril erbumine may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

7.3 Lithium Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

7.4 Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including perindopril erbumine.

7.5 Digoxin A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with perindopril erbumine, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.

7.6 Gentamicin Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies.

7.7 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including perindopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving perindopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.8 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on perindopril erbumine and other agents that affect the RAS. Do not co-administer aliskiren with perindopril erbumine in patients with diabetes. Avoid use of aliskiren with perindopril erbumine in patients with renal impairment (GFR &lt;60 mL/min). 7.9 mTOR Inhibitors Patients taking concomitant mTOR (mammalian target of rapamycin) inhibitor therapy may be at increased risk for angioedema <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

7.10 Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema. <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>