CAPTOPRIL

Captopril tablets, USP are a specific competitive inhibitor of angiotensin I-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I to angiotensin II. Captopril is designated chemically as 1-((2S)-3-mercapto-2-methylpropionyl)-L-proline (MW 217.29) and has the following structural formula: C 9 H 15 NO 3 S Captopril is a white to off-white crystalline powder that may have a slight sulfurous odor; it is soluble in water (approx. 160 mg/mL), methanol, and ethanol and sparingly soluble in chloroform and ethyl acetate. Each tablet for oral administration contains 12.5 mg, 25 mg, 50 mg and 100 mg of Captopril. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide NF, croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF and microcrystalline cellulose NF. structure

Hypertension: Captopril tablets, USP are indicated for the treatment of hypertension. In using captopril, consideration should be given to the risk of neutropenia/agranulocytosis (see WARNINGS ). Captopril may be used as initial therapy for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations. Captopril is effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. Heart Failure: Captopril tablets, USP are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. Left Ventricular Dysfunction After Myocardial Infarction: Captopril tablets, USP are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction ≤40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients. Diabetic Nephropathy: Captopril tablets, USP are indicated for the treatment of diabetic nephropathy (proteinuria ˃500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy. Captopril decreases the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (death or need for renal transplantation or dialysis). In considering use of captopril, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema ). Hypertension: Captopril tablets, USP are indicated for the treatment of hypertension. In using captopril, consideration should be given to the risk of neutropenia/agranulocytosis (see WARNINGS ). Captopril may be used as initial therapy for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations. Captopril is effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. Heart Failure: Captopril tablets, USP are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. Left Ventricular Dysfunction After Myocardial Infarction: Captopril tablets, USP are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction ≤40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients. Diabetic Nephropathy: Captopril tablets, USP are indicated for the treatment of diabetic nephropathy (proteinuria ˃500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy. Captopril decreases the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (death or need for renal transplantation or dialysis). In considering use of captopril, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema ).

Captopril should be taken one hour before meals. Dosage must be individualized. Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient’s previous antihypertensive drug regimen for one week before starting captopril. The initial dose of captopril tablets, USP is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when captopril is used alone. The dose of captopril in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one-to two-week intervals until its highest usual antihypertensive dose is reached. If captopril is being started in a patient already receiving a diuretic, captopril therapy should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension ), with dosage and titration of captopril as noted above. If further blood pressure reduction is required, the dose of captopril may be increased to 100 mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril should not be exceeded. For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and captopril dosage promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision. When necessitated by the patient’s clinical condition, the daily dose of captopril may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated. Beta-blockers may also be used in conjunction with captopril therapy (see PRECAUTIONS: Drug Interactions ), but the effects of the two drugs are less than additive. Heart Failure: Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of the hypotensive effect (see WARNINGS: Hypotension ); for these patients, titration to the usual daily dosage can then occur within the next several days. For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of captopril should not be exceeded. Captopril should generally be used in conjunction with a diuretic and digitalis. Captopril therapy must be initiated under very close medical supervision. Left Ventricular Dysfunction After Myocardial Infarction: The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d. Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg t.i.d. Captopril should then be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY ). Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, beta blockers. Diabetic Nephropathy: The recommended dose of captopril for long term use to treat diabetic nephropathy is 25 mg t.i.d. Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril if additional therapy is required to further lower blood pressure. Dosage Adjustment in Renal Impairment: Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one-to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment (see WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis ). Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient’s previous antihypertensive drug regimen for one week before starting captopril. The initial dose of captopril tablets, USP is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when captopril is used alone. The dose of captopril in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one-to two-week intervals until its highest usual antihypertensive dose is reached. If captopril is being started in a patient already receiving a diuretic, captopril therapy should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension ), with dosage and titration of captopril as noted above. If further blood pressure reduction is required, the dose of captopril may be increased to 100 mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril should not be exceeded. For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and captopril dosage promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision. When necessitated by the patient’s clinical condition, the daily dose of captopril may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated. Beta-blockers may also be used in conjunction with captopril therapy (see PRECAUTIONS: Drug Interactions ), but the effects of the two drugs are less than additive. Heart Failure: Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of the hypotensive effect (see WARNINGS: Hypotension ); for these patients, titration to the usual daily dosage can then occur within the next several days. For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of captopril should not be exceeded. Captopril should generally be used in conjunction with a diuretic and digitalis. Captopril therapy must be initiated under very close medical supervision. Left Ventricular Dysfunction After Myocardial Infarction: The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d. Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg t.i.d. Captopril should then be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY ). Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, beta blockers. Diabetic Nephropathy: The recommended dose of captopril for long term use to treat diabetic nephropathy is 25 mg t.i.d. Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril if additional therapy is required to further lower blood pressure. Dosage Adjustment in Renal Impairment: Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one-to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment (see WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis ).

Captopril tablets are contraindicated in patients who are hypersensitive to this product or any other angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor). Do not co-administer aliskiren with captopril in patients with diabetes (see PRECAUTIONS: Drug Interactions ). Captopril tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer captopril within 36 hours of switching to or from sacubitril/valsartan, a nepriltsin inhibitor (see PRECAUTIONS: Drug Interactions ).

Reported incidences are based on clinical trials involving approximately 7000 patients. Renal: About one of 100 patients developed proteinuria (see WARNINGS ). Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency. Hematologic: Neutropenia/agranulocytosis has occurred (see WARNINGS ). Cases of anemia, thrombocytopenia, and pancytopenia have been reported. Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported. Flushing or pallor has been reported in 2 to 5 of 1000 patients. Cardiovascular: Hypotension may occur; (see WARNINGS and PRECAUTIONS: Drug Interactions ) for discussion of hypotension with captopril therapy. Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients. Angina pectoris, myocardial infarction, Raynaud’s syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients. Dysgeusia: Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste. Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction (see WARNINGS: Head and Neck Angioedema , Intestinal Angioedema and PRECAUTIONS: Information for Patients ). Cough: Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials (see PRECAUTIONS: General, Cough ). The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias. Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined. Body as a whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible related reactions and PRECAUTIONS: Hemodialysis ). General: Asthenia, gynecomastia. Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope. Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis. Gastrointestinal: Pancreatitis, glossitis, dyspepsia. Hematologic: Anemia, including aplastic and hemolytic. Hepatobiliary: Jaundice, hepatitis, including rare cases of necrosis, cholestasis. Metabolic: Symptomatic hyponatremia. Musculoskeletal: Myalgia, myasthenia. Nervous/Psychiatric: Ataxia, confusion, depression, nervousness, somnolence. Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis. Special Senses: Blurred vision. Urogenital: Impotence. As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Altered Laboratory Findings Serum Electrolytes: Hyperkalemia: small increases in serum potassium, especially in patients with renal impairment (see PRECAUTIONS ). Hyponatremia: particularly in patients receiving a low sodium diet or concomitant diuretics. BUN/Serum Creatinine: Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. Hematologic: A positive ANA has been reported. Liver Function Tests: Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 captopril and other agents that block the RAS. Do not coadminister aliskiren with captopril in patients with diabetes. Avoid use of aliskiren with captopril in patients with renal impairment (GFR <60 ml/min). 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, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including captopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving captopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including captopril, may be attenuated by NSAIDs. Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril. The possibility of hypotensive effects with captopril can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril tablets, USP or initiating therapy with small doses (6.25 or 12.5 mg). Alternatively, provide medical supervision for at least one hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion. Agents Having Vasodilator Activity: Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting captopril. If resumed during captopril therapy, such agents should be administered cautiously, and perhaps at lower dosage. Agents Causing Renin Release: Captopril’s effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin-angiotensin-aldosterone system. Agents Affecting Sympathetic Activity: The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive. Agents Increasing Serum Potassium: Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be co-administered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. Cardiac Glycosides: In a study of young healthy male subjects no evidence of a direct pharmacokinetic captopril-digoxin interaction could be found. Loop Diuretics: Furosemide administered concurrently with captopril does not alter the pharmacokinetics of captopril in renally impaired hypertensive patients. Allopurinol: In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when captopril and allopurinol were administered concomitantly for 6 days. Neprilysin Inhibitor: Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema. (see WARNINGS, Head and Neck Angioedema ). 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 captopril. Drug /Laboratory Test Interaction Captopril may cause a false-positive urine test for acetone.