Perindopril Erbumine 2 mg Tablet, 12,000-count

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)

5.1Anaphylactoid 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 ; 7.10) ]. 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.

5.2Hypotension 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 [see Dosage and Administration (2.1) ] . 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.

5.3Neutropenia/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.

5.4Fetal 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 as…

6 ADVERSE 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.

6.1Clinical 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.

6.2Postmarketing 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).

6.3Clinical 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 neutropeni…

7 DRUG 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 ).

7.1Diuretics 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 [see Warnings and Precautions (5.2) ] .

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.

7.2Potassium 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.

7.3Lithium 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.

7.4Gold 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.

7.5Digoxin 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.

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

7.7Non-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.

7.8Dual 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 tw…